**6.1. Intestinal retrieval**

**5. Recipient assessment**

**Figure 5.** Abdominal wall transplant.

296 Organ Donation and Transplantation - Current Status and Future Challenges

Every assessment is 'tailor-made'.

both by imaging and endoscopy.

and Epstein-Barr virus (EBV) screening.

The assessment of a potential intestinal transplant recipient is robust and rigorous and needs to be done by a multidisciplinary team. This involves transplant surgery, gastroenterology, nutritional services, anesthesia, psychiatry and social work. However, due to the frequently pre-existing multiple comorbidities, consultation with other specialties may be required.

Laboratory studies always include: full blood count (FBC), electrolytes and renal function, coagulation profile, ABO blood group, human leukocyte antigen (HLA) typing, panelreactive antibody status, HIV and hepatitis B and C virus screening, cytomegalovirus (CMV)

Liver biopsy is indicated, if liver disease is suspected. The native intestine should be assessed

• Cross-clamping of the supraceliac aorta is performed simultaneously with or immediately following venting of the IVC or atrium and cold perfusion is commenced.

Stoma output is monitored daily and will indicate the appropriate timing to resume enteral feeding via nasogastric tube or jejunostomy/gastrostomy. Some centers start elemental enteral feeding very early and gradually increase volumes depending on nasogastric tube aspirates. TPN is maintained for at least 2 weeks and can be discontinued once enteral nutrition is sufficient. Chyle leak can often be seen post-operatively due to the severed intestinal graft lymphatics. A no-fat or low-fat diet (<10 g/day) can be initiated as a first measure. Absorption of long-chain triglycerides, depends on lymphatic drainage, whereas medium-chain triglyc-

Intestinal Transplantation

299

http://dx.doi.org/10.5772/intechopen.74825

Antiviral prophylaxis with intravenous ganciclovir (5 mg/kg OD) is common practice and regular CMV polymerase chain reaction (PCR) DNA tests are sent for monitoring. Oral valganciclovir is usually prescribed for 1-year post transplantation (900 mg OD). Epstein-Barr virus (EBV) is also monitored regularly by PCR. Trimethoprim-sulfamethoxazole is commonly used to prevent pneumocystis pneumonia for 1-year post operatively. Routine cultures are sent from all lines and most centers perform regular intestinal transplant endoscopies and

Oral medication is generally avoided in the early phase due to the unpredictable absorption and thus, bioavailability. Tacrolimus can be given sublingually and regular trough levels are

Plasma citrulline levels have emerged as a measure for overall for intestinal health as it is an indicator of enterocyte mass. However, compromised renal function is an important factor when considering plasma citrulline levels as a marker of intestinal failure as this potentially can increase circulating citrulline values [31]. Reduced citrulline levels can indicate the need

The intestine is the largest lymphoid organ in the body and hence, appropriate immunosuppression has been a real challenge. The lack of effective immunosuppressive agents hampered the first attempts of ITx in the 1960s. Over the years, advances in immunosuppression have transformed ITx with the intent of attenuating the intestinal allograft immunity and shifting

Induction strategies to minimize rejection by reducing the recipient's T-cell load were implemented, initially with cyclophosphamide induction therapy, which was later replaced by daclizumab, an interleukin-2 receptor antagonist (IL2RA) [33]. Basiliximab, another IL2RA, in addition to tacrolimus and prednisone immunosuppression has also been utilized and shown

Alemtuzumab induction is becoming increasingly popular and Lauro et al. [36] reported significantly less early rejection episodes, with no sepsis implications. The use of Basiliximab monthly as part of maintenance immunosuppression has been associated with a decrease in

erides are directly absorbed into the portal circulation.

for urgent investigations and also, commencement of TPN.

to decrease the incidence of acute rejection [34, 35].

acute rejection in liver-excluding transplants [37].

biopsies via the stoma.

sent for confirmation.

**8. Immunosuppression**

it to a tolerogenic status [32].


**3. Results**

#### *3.1. Endolithic Bacterial and Phototrophic Growth*

Visual inspection of the colonized tiles showed a marked increase in both pigmentation and erosion with time (Figure 2c–f). The tiles sustained both nonphototrophic and phototrophic bacterial growth over the 9-month exposure period. Bacterial biomass increased at an average rate of 3 × 1010 16S rRNA gene copies per m−2 month−1, reaching a mean value of 1.1 × 1011 16S rRNA gene copies per m −2 at 9 months (Figure 3a). As expected, phototroph colonization followed a similar trend with photopigment content increasing at a rate of 2.3 mg m−2 month−1, reaching an average value of 7.22 mg m −2 by 9 months. (Figure 3b), at which point 16S rRNA gene counts were not significantly different from those found in steady-state climax communities described by Couradeau et al. [14] and Roush et al. [15] (Student's *t*-test, *p* < 0.05). While total chlorophyll pigment concentrations were not significantly different between 9 months and steady-state climax communities either, cyanobacteria-specific counts were actually higher at 9 months than in steady-state climax communities.

**Figure 2.** Endolithic colonization of travertine tiles. (**a**) Areal concentration of 16S rRNA gene copies. Each bar is an independent replicate. Error bars are from biological replicates. (**b**) Areal concentration of total photosynthetic chlorins (chlorophylls plus bacteriochlorophylls). Single determinations were carried out for each replicate tile. (**c**–**f**) Photographic evidence of colonization after removal of epilithic biomass by brushing. (**c**) Initial, virgin tile. Excising squares were samples used for analyses.

#### *3.2. Incidence of Anoxygenic Phototrophs*

APB abundance measured by bacteriochlorophylls increased with time but trailed in concentration by some two orders of magnitude to cyanobacterial abundance measured by chlorophylls during the colonization period. This situation obviously changed significantly later during succession, as bacteriochlorophylls were statistically as abundant as chlorophylls when compared to steady-state climax communities (Figure 3b). The magnitude of the difference between APB and cyanobacteria was less marked, but still very significant, when measured by 16S rRNA gene abundance (Figure 3a). By using this metric it was obvious that although APB trailed cyanobacteria during the colonization period, they eventually matched and even exceeded cyanobacteria in steady-state climax communities. We found very differing dynamics between populations of relevant APB groups: while Chloroflexales were only present in very small quantities during early phases (Figure 3c) and reached only 6.2 × 106 16s rRNA gene copies per m−2 after 9 months, *Erythrobacter* abundance was stable throughout the colonization, with an average of 1.2 × 109 16S rRNA gene copies per m-2 at 9 months. In comparison, the situation was reversed in steady-state mature communities, where *Erythrobacter* sp. decreased to some 1.6 × 108 16s rRNA gene copies per m−2 in steady-state climax communities, but Chloroflexales increased to populations close to those of cyanobacteria (Figure 3c). The apparent differences in trends between bacteriochlorophyll and 16S rRNA genes as proxies for population size can be explained by the relatively low bacteriochlorophyll content of *Erythrobacter* spp. compared to members of the Chloroflexales [51,52], which essentially made the total content of bacteriochlorophyll be very sensitive to the population size of the latter.

**Figure 3.** Time series of bacterial biomass proxies detected in colonized tiles and steady-state climax communities by guild or taxon. (**a**) Areal concentrations of 16S rRNA gene copies based on quantitative PCR and high-throughput sequencing phylogenetic assignments (**b**) Areal photosynthetic chlorins as biomarkers for oxygenic phototrophs (total chlorophylls) or APB (total bacteriochlorophylls) (**c**) areal population size of APB clades *Erythrobacter* spp. and Chloroflexales based on quantitative PCR and high-throughput sequencing phylogenetic assignments. (**d**) Endolithic colonization dynamics of specific microboring cyanobacterial clades, based on qPCR and bioinformatic placement of high-throughput environmental sequences using the Cydrasil cyanobacterial reference tree and database. Error bars are for biological sample triplicates.

#### *3.3. Cyanobacterial Succession: Diversity and Composition*

Unexpectedly, cyanobacterial richness gauged by the number of observed amplicon sequence variants (ASVs) was not significantly different across time points and when compared to steady-state climax communities (Kruskal–Wallis, *p* = 0.33; Table 1), whereas ASV evenness (measured as Pielou's Evenness) decreased significantly (Kruskal–Wallis, *p* = 0.04) with time. Pairwise Kruskal–Wallis comparisons indicated that the difference was driven by a drop in evenness between early (3 and 6 months) and late succession communities (9 month and steady-state climax) (adjusted *p* = 0.07 for all four comparisons). Shannon's diversity also followed the evenness trend, with significant differences with time (Kruskal–Wallis, *p* = 0.02) where late succession samples were less diverse than early succession samples (adjusted *p* = 0.06 for all four comparisons). Regarding cyanobacterial community composition (beta-diversity), all time points and steady-state climax communities were significantly different from each other (PERMANOVA, *p* < 0.05, pairwise Kruskal–Wallis *p* < 0.05), a result also supported statistically by a PCOA (principal coordinates ordination analysis; Weighted UniFrac metric; Figure S2).

**Table 1.** Alpha diversity metrics of cyanobacterial endolithic communities in tiles placed in the intertidal zone of Isla de Mona and metrics from geographically similar natural substrate communities on Isla de Mona described by Roush et al. [15].

Community composition of steady-state climax communities was taken from calcite samples published in Roush 2018. Lower-case letters denote samples not significantly different (α = 0.1). ASVs, amplicon sequence variants.

#### *3.4. Identification of Endolithic Cyanobacteria Clades*

In nonporous virgin substrates, only euendolithic organisms can colonize and grow to large abundance. Since we removed all epilithic biomass before sequencing, those organisms found to be abundant early on can be deemed to be bona fide euendoliths since they must have been able to excavate the substrate. Therefore, to identify pioneer euendolithic cyanobacterial clades, the most abundant cyanobacterial ASVs from the 3-month-old tiles were placed using the RAxML Evolutionary Placement Algorithm into the Cydrasil reference cyanobacterial 16S rRNA gene tree containing 980 curated cyanobacterial sequences, which includes all full-length 16S rRNA gene sequences traceable to known euendolithic cyanobacteria (Figure 3d and Figure S3). Euendolithic sequences that were not full length were included in the query sequence list and checked for correlation with known clades. In order to pare down the dataset for placement, we ranked each sample's cyanobacterial ASVs in order of abundance until cumulative counts reached 95% of the total abundance in each sample, yielding 213 unique ASVs across all tile samples and steady-state climax communities. We then placed the resulting pared ASV dataset into the Cydrasil reference tree. Of the 213 initial ASVs, 139 were placed with high confidence and clustered onto four distinct tree nodes. Two of the nodes contained known euendolithic species: Cluster 2 (containing 37 unique ASVs) encompassed endolithic members in the Pleurocapsales, and Cluster 3 (27 ASVs) contained *Mastigocoleus testarum*. The other two did not align with known euendoliths: one contained *Leptolyngbya* species (Cluster 1; 60 ASVs) and the other was a novel clade that contained only environmental sequences lacking taxonomic assignment and only distantly related (<95.2% similarity) to *Stanieria cyanosphaera*. We named this clade UBC (15 ASVs), for "unknown boring cluster".

#### *3.5. Colonization Dynamics of Euendolithic Cyanobacterial Clades*

To quantify colonization dynamics, qPCR-normalized abundances of the euendolithic clusters were plotted over time (Figure 3d and Figure S3). Members of the UBC were double to an order of magnitude more abundant than the other groups after 3 months of exposure, with an average biomass of 9.1 × 109 16S rRNA gene copies per m-2. UBC abundance remained stable throughout the experiment and was not significantly di fferent when compared to steady-state climax communities. Cluster 1 (*Leptolyngbya-*like) population size lagged that of UBC, reaching a maximum after 6 months (1.1 × 109 16s rRNA gene copies per m−2). Clusters 2 (Pleurocapsalean) and 3 (*Mastigocoleus-*like) colonized substrate at the slowest rate, reaching maximum populations after 9 months (8.7 × 1010 and 9.9 × 109 16S rRNA gene copies per m−2, respectively). Clusters 2 (Pleurocapsalean) and 3 (*Mastigocoleus-*like) also decreased in abundance in steady-state climax communities.

#### *3.6. Di*ff*erential Abundance Analysis*

In order to identify which cyanobacterial colonizers were driving compositional di fferences between early (3-month) and late (9-month) tiles, we conducted a di fferential abundance analysis. The most abundant and significant ASVs at both time points were members of the four clades delineated

above (Figure S4). At 3 months, representatives of the UBC were three of the four most abundant cyanobacteria (*p* < 0.05), both in total sequence count and in di fferential relative abundance (fold change) with respect to 9-month communities. The fourth ASV was a member of Cluster 1, allied to *Leptolyngbya*. At 9 months, Cluster 2 (Pleurocapsalean) and Cluster 3 (*Mastigocoleus*-like) sequences were found to be the most di fferentially abundant with respect to 3-month communities.

#### *3.7. New Pioneer Euendolith Clade*

Both qPCR-adjusted relative abundance and di fferential abundance analysis revealed that the previously unknown UBC clade played a significant role in early colonization of hard intertidal carbonates. In order to better constrain its identification, we conducted a maximum-likelihood phylogenetic reconstruction of 395 sequences, largely from cyanobacterial isolates (Figure 4), but including those of the most di fferentially abundant UBC and the seven sequences most similar to UBC that we could find by BLAST analyses. As before (i.e., Figure 3d), UBC members were only distantly related (<5.2% similar) to cultured cyanobacteria, the nearest being *Stanieria cyanosphaera* (formerly *Chroococcidiopsis cyanosphaera*), an epilithic freshwater unicellular cyanobacterium [53]. UBC was distant from the canonical euendolithic groups, with the Cluster 2 (Pleurocapsalean) being the closest. However, UBC members were phylogenetically close to environmental sequences obtained from marine carbonate microbialites, a habitat not dissimilar from the interior of hard carbonates and containing known euendoliths [54].


**2. The experimental researches into variation of tribological properties of the interacting surfaces**

#### **2.1 Research into tribological properties on the high-speed twin disk machine**

A great number of scientific works are devoted to ascertainment of laws of variation of tribological properties of the interacting surfaces and with perfection of machines, actuality of such works increases. Despite the considerable quantity of works in this direction, the expected results are not obtained yet. The unexpected and catastrophic failure, unlike fatigue, corrosion and other slowly progressing wear types, are subjected some heavy loaded interacting surfaces of gear teeth, cams and followers, sleeve bearings etc. The wheel and rail contact zone is characterized by heavy operational conditions [33] (direct impact of the environmental conditions, high relative sliding and contact stresses) that enhances adhesive and fatigue processes. The wheel and rail contact zone is characterized by the heavy operational conditions (direct impact of the environmental conditions, high relative sliding and contact stresses) that enhances adhesive and fatigue processes raise the problems to be solved for many-sided study of these processes.

Experimental research was performed at rolling of discs with up to 20% of sliding. The rollers had diameters of 40 mm and widths of 10 and 12 mm. The tests were performed at single application of the friction modifier on the interacting surface of the rollers. After certain number of revolutions, a thin layer of the friction modifier (FM) was destroyed that was revealed by sharp increase of the friction moment and initial signs of scuffing on the surfaces. Without repeated feeding of the friction modifier the damage process were progressed. The rollers with various degrees of damage are shown in **Figure 7**: (a) with initial signs of damage; (b) damage in the form of a narrow strip; (c) damage of the whole

*The twin disk machine model MT1 and measuring means: 1 - twin disk machine, 2 - tribo-elements, 3 - the*

*A New Concept of the Mechanism of Variation of Tribological Properties of the Machine…*

The graphs of dependences of the friction coefficient and number of revolutions

The graphs of dependences of the friction coefficient and number of revolutions

of rollers until appearance of the first signs of scuffing on the contact stress for initial linear contact of disks are shown in **Figure 8**. It is seen from these graphs that for the initial linear contact, when the contact stress is in the range of 0.65-0.77 GPa increase of the contact stress leads to decrease of the friction coefficient. It can also be seen that increase of the contact stress leads to decrease of number of revolutions

of rollers until appearance of the first signs of scuffing on the contact stress for initial point contact of disks and anti-frictional friction modifiers are shown in

*The stages of damage of the interacting surfaces: (a) damage in the separate points; (b) damage in the form of*

until the destruction of the third body and onset of scuffing.

*the narrow strip; (c) damage on the whole area of the contacting surfaces.*

*wear products, 4 - tester, 5 - personal computer, 6 – vibrometer.*

*DOI: http://dx.doi.org/10.5772/intechopen.93825*

contacting area.

**Figure 6.**

**Figure 9**.

**Figure 7.**

**137**

For some heavy loaded interacting surfaces of machines are typical unpredictable change of tribological properties and sharp increase of the friction coefficient and wear intensity, so called catastrophic wear. As main cause of the latter is considered the heaviest form of the adhesive wear – scuffing [4] that is not properly studied yet [34] and whose signs are appearance of pits and scratches on the surfaces and transfer of the material from one surface on the other. The various aspects of the complex physical, tribo-chemical and mechanical processes proceeding in the contact zone are not properly studied yet that is accordingly reflected on the operation quality and resource. As an example can be cited interaction of the wheel and rail that occurs on: the tread surfaces during rolling, traction and braking; steering surfaces mainly in curves; flange root and rail corner at rolling, traction, braking and steering. The friction coefficient for wheel-rail interaction can vary in the range 0.05 - 0.8. The values of the friction coefficient for the tread and steering surfaces must be correspondingly in the ranges of 0.25-0.4 and <0.1 [32]. The optimal value of the friction factor for tread surfaces is 0.35 [32] and for steering surfaces - as low as possible. The scuffing on the wheel and rail steering surfaces causes rise of the friction coefficient, energy consumed on rolling, vibrations, nose, wear intensity and probability of derailment.

For more detailed study of the properties and state of the third body in the contact zone we performed the experimental researches on the twin disk machine MT 1 (**Figure 6**) with the use of existing lubricants and ecologically friendly friction modifiers, developed by us.

The tests were performed at single application of the friction modifier on the rolling surface of the roller. After certain number of revolutions, a thin layer of the friction modifier was destroyed that was revealed by sharp increase of the friction moment and initial signs of scuffing on the surfaces. Without repeated feeding the friction modifier, the damage process was progressed. The rollers with various degree of damage are shown in **Figure 7**: (a) with initial signs of damage; (b) damage in the form of a narrow strip; (c) damage on the whole contacting area.

*A New Concept of the Mechanism of Variation of Tribological Properties of the Machine… DOI: http://dx.doi.org/10.5772/intechopen.93825*

#### **Figure 6.**

For revealing the factors influencing tribological properties of the interacting surfaces, the experimental researches were carried out on the high-speed and serial

*Tribology in Materials and Manufacturing - Wear, Friction and Lubrication*

**2. The experimental researches into variation of tribological properties**

**2.1 Research into tribological properties on the high-speed twin disk machine**

A great number of scientific works are devoted to ascertainment of laws of variation of tribological properties of the interacting surfaces and with perfection of machines, actuality of such works increases. Despite the considerable quantity of works in this direction, the expected results are not obtained yet. The unexpected and catastrophic failure, unlike fatigue, corrosion and other slowly progressing wear types, are subjected some heavy loaded interacting surfaces of gear teeth, cams and followers, sleeve bearings etc. The wheel and rail contact zone is characterized by heavy operational conditions [33] (direct impact of the environmental conditions, high relative sliding and contact stresses) that enhances adhesive and fatigue processes. The wheel and rail contact zone is characterized by the heavy operational conditions (direct impact of the environmental conditions, high relative sliding and contact stresses) that enhances adhesive and fatigue processes raise the

problems to be solved for many-sided study of these processes.

wear intensity and probability of derailment.

friction modifiers, developed by us.

contacting area.

**136**

For some heavy loaded interacting surfaces of machines are typical unpredictable change of tribological properties and sharp increase of the friction coefficient and wear intensity, so called catastrophic wear. As main cause of the latter is considered the heaviest form of the adhesive wear – scuffing [4] that is not properly studied yet [34] and whose signs are appearance of pits and scratches on the surfaces and transfer of the material from one surface on the other. The various aspects of the complex physical, tribo-chemical and mechanical processes proceeding in the contact zone are not properly studied yet that is accordingly reflected on the operation quality and resource. As an example can be cited interaction of the wheel and rail that occurs on: the tread surfaces during rolling, traction and braking; steering surfaces mainly in curves; flange root and rail corner at rolling, traction, braking and steering. The friction coefficient for wheel-rail interaction can vary in the range 0.05 - 0.8. The values of the friction coefficient for the tread and steering surfaces must be correspondingly in the ranges of 0.25-0.4 and <0.1 [32]. The optimal value of the friction factor for tread surfaces is 0.35 [32] and for steering surfaces - as low as possible. The scuffing on the wheel and rail steering surfaces causes rise of the friction coefficient, energy consumed on rolling, vibrations, nose,

For more detailed study of the properties and state of the third body in the contact zone we performed the experimental researches on the twin disk machine MT 1 (**Figure 6**) with the use of existing lubricants and ecologically friendly

The tests were performed at single application of the friction modifier on the rolling surface of the roller. After certain number of revolutions, a thin layer of the friction modifier was destroyed that was revealed by sharp increase of the friction moment and initial signs of scuffing on the surfaces. Without repeated feeding the friction modifier, the damage process was progressed. The rollers with various degree of damage are shown in **Figure 7**: (a) with initial signs of damage; (b) damage in the form of a narrow strip; (c) damage on the whole

twin-disk machines.

**of the interacting surfaces**

*The twin disk machine model MT1 and measuring means: 1 - twin disk machine, 2 - tribo-elements, 3 - the wear products, 4 - tester, 5 - personal computer, 6 – vibrometer.*

Experimental research was performed at rolling of discs with up to 20% of sliding. The rollers had diameters of 40 mm and widths of 10 and 12 mm. The tests were performed at single application of the friction modifier on the interacting surface of the rollers. After certain number of revolutions, a thin layer of the friction modifier (FM) was destroyed that was revealed by sharp increase of the friction moment and initial signs of scuffing on the surfaces. Without repeated feeding of the friction modifier the damage process were progressed. The rollers with various degrees of damage are shown in **Figure 7**: (a) with initial signs of damage; (b) damage in the form of a narrow strip; (c) damage of the whole contacting area.

The graphs of dependences of the friction coefficient and number of revolutions of rollers until appearance of the first signs of scuffing on the contact stress for initial linear contact of disks are shown in **Figure 8**. It is seen from these graphs that for the initial linear contact, when the contact stress is in the range of 0.65-0.77 GPa increase of the contact stress leads to decrease of the friction coefficient. It can also be seen that increase of the contact stress leads to decrease of number of revolutions until the destruction of the third body and onset of scuffing.

The graphs of dependences of the friction coefficient and number of revolutions of rollers until appearance of the first signs of scuffing on the contact stress for initial point contact of disks and anti-frictional friction modifiers are shown in **Figure 9**.

**Figure 7.**

*The stages of damage of the interacting surfaces: (a) damage in the separate points; (b) damage in the form of the narrow strip; (c) damage on the whole area of the contacting surfaces.*

executed with the use of the high-speed roller machine with independent drive of

*High speed twin disk machine (a), experimental pieces (b) and a working surface of the roller with traces of*

*A New Concept of the Mechanism of Variation of Tribological Properties of the Machine…*

• Diameters of rollers 183 mm and 143,3 mm; width of rollers 12 mm and 17 mm;

;

During experiments at the given loading and rolling velocity, the friction torque, sliding velocity and lubricant film thickness were measured. For measurement of speeds of rotation was utilized magnetic pickups, for measurement of the friction torque was utilized the strain gage transducer and contactless skate. The lubricant film thickness was measured by capacitance method [35]. The beginning of scuffing was revealed by the surges of the friction moment. Development of the friction process was accompanied by sharp rise of temperature and characteristic noise.

The studies have shown that with increase of the rolling speed, the thickness of the lubricating film initially increases (in our case up to 14 m/s) and then decreases

With increase of the sliding velocity, sharp decrease of the lubricated film thickness is observed. Though measurement of the particularly thin film (boundary

*Dependence of relative lubricant film thickness (h/R), linear scuffing load (Pllsc) and coefficient of friction (f) until the appearance of the first signs of scuffing from rolling speed (Vr) and sliding velocity (Vs) at various viscosities (ν) of lubricants: (1) h/R = φ(Vr), Pll = 106 H/m; ν = 157 cSt, (2) h/R = φ(Vsl), Pll = 2 106 H/m, ν = 157 cSt, Vr = 50 m/s, (3) Pllsc = φ(Vsl), ν = 49 cSt, Vr = 50 m/s, (4) Pllsc = φ(Vr), ν = 157 cSt, Vsl = 22 m/s, (5) f = φ(Vsl), Pll = 1.5 106 H/m, ν = 49 cSt; Vr = 50 m/s, (6) f = φ(Vr), Pll = 106 H/m, ν = 157 cSt.*

rollers. Conditions of the experiments and measured sizes were:

*scuffing (c) at total speed of rolling 7 m/s, sliding speeds of 3 m/s, linear load 100 N/m.*

• Rolling speed – up to 70 m/s;

*DOI: http://dx.doi.org/10.5772/intechopen.93825*

• Sliding velocity- up to 35 m/s;

slightly.

**Figure 11.**

**139**

**Figure 10.**

• Contact pressure – 5 105 – 2 106 N/м;

Results of experimental research are shown in **Figure 11**.

• Dynamic viscosity 49-140 mNs/m2

#### **Figure 8.**

*Dependences of friction coefficients (a) and numbers of revolutions (b) until appearance of the first signs of scuffing on the contact stress for initial linear contact of disks and different anti-frictional friction modifiers.*

**Figure 9.**

*Dependences of friction coefficients (a) and numbers of revolutions (b) until appearance of the first signs of destruction of the third body (first signs of scuffing) on the contact stress for initial point contact of disks and three different frictional FM-s.*

When the contact stress is in the range of 2.42-3.96 GPa the friction coefficient increases with increase of the contact stress. It can also be seen that increase of the contact stress leads to decrease of the number of revolutions until the destruction of the third body and onset of scuffing more intensive than in the previous case.

#### **2.2 Research into tribological properties on the high-speed twin disk machine**

At high working velocities, the maximal power and thermal stresses approach to the surfaces and intensity of the third body destruction/restoration and sensitivity of the contact zone tribological properties to working conditions, increase. To promote the mentioned problem, the experimental researches were carried out on the high-speed twin disk machine with independent drive of rollers (**Figure 10**).

During experiments were studied the character of the wear process of working surfaces, influence of various parameters on the lubricant film thickness and friction coefficient at the use of popular mineral lubricants. The researches were

*A New Concept of the Mechanism of Variation of Tribological Properties of the Machine… DOI: http://dx.doi.org/10.5772/intechopen.93825*

**Figure 10.**

*High speed twin disk machine (a), experimental pieces (b) and a working surface of the roller with traces of scuffing (c) at total speed of rolling 7 m/s, sliding speeds of 3 m/s, linear load 100 N/m.*

executed with the use of the high-speed roller machine with independent drive of rollers. Conditions of the experiments and measured sizes were:

During experiments at the given loading and rolling velocity, the friction torque, sliding velocity and lubricant film thickness were measured. For measurement of speeds of rotation was utilized magnetic pickups, for measurement of the friction torque was utilized the strain gage transducer and contactless skate. The lubricant film thickness was measured by capacitance method [35]. The beginning of scuffing was revealed by the surges of the friction moment. Development of the friction process was accompanied by sharp rise of temperature and characteristic noise. Results of experimental research are shown in **Figure 11**.

The studies have shown that with increase of the rolling speed, the thickness of the lubricating film initially increases (in our case up to 14 m/s) and then decreases slightly.

With increase of the sliding velocity, sharp decrease of the lubricated film thickness is observed. Though measurement of the particularly thin film (boundary

#### **Figure 11.**

When the contact stress is in the range of 2.42-3.96 GPa the friction coefficient increases with increase of the contact stress. It can also be seen that increase of the contact stress leads to decrease of the number of revolutions until the destruction of the third body and onset of scuffing more intensive than in the previous case.

*Dependences of friction coefficients (a) and numbers of revolutions (b) until appearance of the first signs of destruction of the third body (first signs of scuffing) on the contact stress for initial point contact of disks and*

*Dependences of friction coefficients (a) and numbers of revolutions (b) until appearance of the first signs of scuffing on the contact stress for initial linear contact of disks and different anti-frictional friction modifiers.*

*Tribology in Materials and Manufacturing - Wear, Friction and Lubrication*

**Figure 8.**

**Figure 9.**

**138**

*three different frictional FM-s.*

**2.2 Research into tribological properties on the high-speed twin disk machine**

surfaces, influence of various parameters on the lubricant film thickness and friction coefficient at the use of popular mineral lubricants. The researches were

At high working velocities, the maximal power and thermal stresses approach to the surfaces and intensity of the third body destruction/restoration and sensitivity of the contact zone tribological properties to working conditions, increase. To promote the mentioned problem, the experimental researches were carried out on the high-speed twin disk machine with independent drive of rollers (**Figure 10**). During experiments were studied the character of the wear process of working

*Dependence of relative lubricant film thickness (h/R), linear scuffing load (Pllsc) and coefficient of friction (f) until the appearance of the first signs of scuffing from rolling speed (Vr) and sliding velocity (Vs) at various viscosities (ν) of lubricants: (1) h/R = φ(Vr), Pll = 106 H/m; ν = 157 cSt, (2) h/R = φ(Vsl), Pll = 2 106 H/m, ν = 157 cSt, Vr = 50 m/s, (3) Pllsc = φ(Vsl), ν = 49 cSt, Vr = 50 m/s, (4) Pllsc = φ(Vr), ν = 157 cSt, Vsl = 22 m/s, (5) f = φ(Vsl), Pll = 1.5 106 H/m, ν = 49 cSt; Vr = 50 m/s, (6) f = φ(Vr), Pll = 106 H/m, ν = 157 cSt.*

film) is technically difficult, its presence in the contact zone is indicated by the magnitude and stability of the friction coefficient. Further worsening of the working conditions leads to destruction of the third body in individual places of interacting surfaces.

At high velocities of interacting surfaces, despite several works in this area [39–43], some problems have not yet been resolved. The thermal load of the factual contact zone, velocity of the surface, tribo-chemical reaction of the environment and resistance of deformation increase, whereas time of the thermal action and thickness of the superficial heated up layer decrease. In such conditions, at destruction of the third body, due to rupture of the seized places, the jerks of high frequency and comparatively low amplitudes and instability of the friction coefficient take place and relatively small-size asperities (pits, scratches, asperities, cracks and layers) appear on the surfaces. This is correspondingly reflected on the damage type and roughness of the surfaces. Under the conditions of our experiments at a high rolling speed (more than 40 m/s), traces of fatigue damage and scuffing are not

*A New Concept of the Mechanism of Variation of Tribological Properties of the Machine…*

Thus, destruction of the third body causes sharp worsening of tribological properties of the interacting surfaces and necessary condition of its avoidance is separation of these surfaces from each other by continuous third body with due

It was ascertained by the experimental researches that destruction of the third body begins in individual points of the factual contact zone that is revealed by appearance of signs of the scuffing in these points. Restoration of the individual damaged points was often observed at unchanged operational conditions but at worsening, the operational conditions the superficial damage quantity increased and multiple damages appeared. At further worsening the operational conditions, a narrow strip of damage is generated spreading afterwards over the whole surface that causes worsening of the tribological parameters and catastrophic wear. The above-mentioned damage stages of the third body are shown in **Figure 12**.

Usually the friction process proceeds at presence of the continuous or discontinuous (restorable or progressively destructible) third body stipulating the character of variation of the friction coefficient. Experimentally it was revealed that to negative friction corresponds the continuous or discontinuous but restorable third body; to neutral friction – multiple seizures of the interacting surfaces and to positive friction – increasing scuffing process that is spread on the whole surface. In

As it were shown by our experimental researches, at presence of the continuous third body increase of the relative sliding velocity leads to increase of the friction power and contact temperature; decrease of the lubricant viscosity, film thickness and friction force (**Figure 13**, "negative friction"), stable (or smoothly variable) friction torque and low destruction rate of the surfaces. Worsening of the working conditions caused by the partial, non-progressive damage of the third body in the separate unit places corresponds to the separate small impulses of the friction moment. Destruction of the third body in the multiple places leads to the multiple damage of the third body, multiple adhesive junctions of micro-asperities, disruption of these junctions, and a bit little increased impulses of the friction torque and

**Figure 13** is shown variation of the tractive (friction) force with creep [37].

*The damage stages of the interacting surfaces. (a) Unit seizures; (b) multiple seizures; (c) seizures on the*

visually observed, however, a high wear rate remains.

*DOI: http://dx.doi.org/10.5772/intechopen.93825*

properties.

to "neutral friction."

*narrow strip; (d) seizures on the whole area.*

**Figure 12.**

**141**

A particular instability of the friction coefficient was observed at low velocities and high loads: intensive impulses of low frequency were marked and the scuffing marks of significant sizes – scratches and pits were noticed on the rollers surfaces. With increase of the velocity, the time of dwelling of the surfaces in the real contact zone and duration of the thermal impact, values of the amplitude of the friction force variable component decrease; the frequency increases and the individual impulses turn into noise. With further increase of the velocity the friction process is progressed, the temperature on the actual contact area of the interacting surfaces reaches the metal melting point, tonality of the noise rises and turns into whistle and when the frequency exceeds 20 KHz it becomes imperceptible for man.


*2.1. Search Strategy*

We used the PubMed database to identify studies investigating DBS for MDD and screened all studies for inclusion.  All studies were considered, including studies written in other languages. The search was conducted on 10/16/2019, and the analysis followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.

### *2.2. Study Inclusion and Exclusion Criteria*

Only studies that investigated the e fficacy of DBS for MDD were included. We excluded studies that utilized other therapies to treat MDD (e.g., ECT, epidural stimulation, vagal nerve stimulation, transcranial magnetic stimulation, or tDCS). We also excluded studies that investigated comorbid depression in the context of other disorders, such as epilepsy, dystonia, Tourette syndrome, anorexia nervosa, obsessive–compulsive disorder, schizophrenia, headache, ET, and PD. We excluded all non-human studies. Of the studies relevant to DBS as a treatment for MDD, we excluded case reports, non-systematic reviews, perspectives, commentaries, editorials, and opinions. We included the remainder of the studies for our qualitative review. For the quantitative meta-analysis, we only included studies in which sham stimulation was compared to active stimulation in a blinded fashion (either single- or double-blind). The clinical trial designs were varied and included both crossover and parallel studies.

### *2.3. Data Extraction and Outcome Measures*

Our primary outcome was the e fficacy of DBS as a treatment for depression as assessed by changes in the Hamilton Depression Rating Scale (HDRS) or Montgomery–Åsberg Depression Rating Scale (MADRS) scores. We compared sham stimulation scores to active stimulation scores. The data were extracted from tables when provided. If tables with the raw data were not provided, the WebPlotDigitizer tool was used to extract data from published graphs. We also extracted the number of patients, stimulation target, side e ffects of treatment, adverse events, study design, and depression rating scale used.


**Abstract**

Ginger (*Zingiber officinale* Rosc.), a member of the Zingiberaceae family, is a medicinal herb utilized for its anti-inflammatory and antioxidant qualities. Ginger's influence on health was discovered due to its high phytochemical content, which includes compounds that eliminate free radicals created by biological systems. Gingerol, shogaol, and other related ginger chemicals limit the body's production of prostaglandins and leukotrienes. They can also suppress the production of pro-inflammatory cytokines, such as IL-1, TNF-, NF-B, and IL-8. According to our knowledge, NF-B activation is associated with a number of inflammatory disorders, including cancer, kidney injury, and Alzheimer's disease.

**Keywords:** ginger, anti-inflammatory, antioxidant, shogaol, anticancer


**4. Conclusion**

The three "de"-perspectives culminate in a common political center-point that we can adequately circumscribe with the notions of "communalism" or "libertarian municipalism", two concepts that have been coined by Murray Bookchin [40]. Among other things, they express the necessity to withdraw particular goods and services from the market because they satisfy the basic needs of all people, irrespective of income, social status or any other discriminatory difference. They are common goods. Besides goods and services of health and education, mobility, food and water, safe and livable environment, it is housing in its material and social-relational conditions. Libertarian municipalism conflates the singularity of women and men with their socially derived individual aspirations on the one hand and the collectivity of the local neighborhood in which they are socially embedded on the other.

In order to re-strengthen the commitment to the local spatial and social environment, political decentralization becomes one core ingredient in future housing policies. To put the housing's function of social infrastructure to the fore and defend its primary purpose as a means of cohabitation aligns with the UN's Sustainable Development Goals and does not inevitably jeopardize its value-preserving meaning. In fact, this latter meaning remains relevant, considering the ecological sustainability of our societal transformation in the Anthropocene. The commodification of the home is neither necessary nor desirable any longer, which, in turn, fosters decommodification as another core ingredient in future housing policy. The local is not an isolated and unconnected spot on the earth's surface like a sand grain on a sand hill, but a node in a network of interrelated nodes. The relations may functionally vary, but the essential point is that distance is not metric but relational. This functional shift produces a different pattern of collaboration and cohabitation, surmounting the traditional understanding of territorial inclusion and exclusion. Not least, deterritorialization turns out to be the third core ingredient in future housing policy. There is no ideal or perfect point where all three "de"-perspectives merge. The decisive moment is that they have left the corner points of their counterparts.


**11. Uncommon diseases cause hyperglycemia and DM**

#### **11.1. Endocrine diseases**

more often [223,224]. In addition, the mutations in other genes include glucokinase (GCK), HLA antigens, insulin receptor (INSR), insulin-like growth factor-2 (IGF2), HNF4A, insulin gene (INS-VNTR), plasminogen activator inhibitor 1 (PAI-1), potassium inwardly rectifying channel subfamily J, member 11 (KCNJ11), hepatocyte nuclear factor-4a (HNF4A) and 1α (HNF1A) [224] suggest the susceptibility to increase the risk of GDM in certain patients.

The stimulators or the inducers of IR and phosphorylate insulin receptor substrate (IRS) proteins are activated in uncontrollable method several kinases, including inhibitor of nuclear factor ĸB kinase β (IKK β), c-Jun N-terminal kinase (JNK), mammalian target of rapamycin (mTOR), protein kinase C (PKC) and ribosomal S6 protein kinase (S6K). Substance P is a potent cytokine and is considered one of the crucial activators that contribute in the development of IR by impairment of insulin signaling [225]. The genetic variants in TCF7L2 is the strongest gene associated with GDM risk among other minor alleles of rs7903146 (TCF7L2), rs1225 5372 (TCF7L2), rs1799884 (-30G/A, GCK), rs5219 (E23K, KCNJ11), rs7754840 (CDKAL1), rs4402960 (IGF2BP2), rs10830963 (MTNR1B), rs1387153 (MTNR1B) and rs1801278 (Gly972Arg, IRS1) significantly associated with a higher risk of GDM. There are 12 SNPs from 10 genes are

The E23K polymorphism of KCNJ11 seems to predispose to GDM in Scandinavian women [226] and the polymorphism of TCF7L2 (rs7903146 C/T) gene, and the G972R polymorphism of the IRS1 gene, seems to predispose to GDM in Greek women [227]. In women of Han nationality in north China, The defect in sulfonylurea receptor-1 (SUR1) gene (cc and AA) may contribute to insulin hypersecretion, which might be the cause of increased body weight and

In animals but not in human, Galanin inhibits glucose-stimulated insulin release [230]. In the human, the initial postprandial rise of glucose and insulin are suppressed by galanin admin‐ istration [231]. Galanin and IL-6 were found to be significantly associated with IR markers in GDM, thus may play important roles in the regulation of glucose hemostasis [232].The higher

In late pregnancy the relative proinsulin secretion is mainly related to IR and does not necessarily reflect β-cell function. T2DM is not independently associated with hyperproinsu‐ linemia as measured by the proinsulin-to-C-peptide ratio. While, in pregnant women, the increased in IR is associated with decreased proinsulin to C-peptide ratio, independently of

The islet amyloid pancreatic polypeptid hypersecretion is characteristic for pregnancy and might partially decrease hyperinsulinemia in pregnancy by inhibiting insulin secretion [235].

The β- cells dysfunction and IR are the core in the pathogenesis of T2DM and both are mediated by Adiponectin. Therefore, in late pregnancy the Adiponectin is an independent factor

In pregnancy IR and GDM caused by the placental hormones and cytokines such as tumor necrosis factor alpha (TNFα), resisten and leptin. All of these are secreted by placenta inde‐ pendently. The human chorionic somatomammotropin (HCS), cortisol, estrogen, progester‐

decreased IS and genotype cc of SUR1 is connected with severe type of GDM [229].

level of plasma galanin is a novel biomarker for the prediction of GDM [233].

associated GDM [228].

84 Treatment of Type 2 Diabetes

glucose tolerance status [234].

correlated with β- cells dysfunction [236].

Acromegaly and hypercortisolism are frequently associated with IGT and T2DM. It is a recognized finding of occurrence of secondary T2DM with many hormonal diseases (pituitary, adrenal/or thyroid disease). Patients with Acromegaly have IR, both in the liver and in the periphery displaying hyperinsulinemia and increased glucose turnover in the basal postabsorptive states. There is increase in blood glucose level and free fatty acids due to stimulation of gluconeogenesis and lipolysis. Although, insulin growth factor-1(IGF-1) level is increased but it is unable to counteract IR induced by abnormal excess GH level. On the other hand, IS primarily enhanced in the skeletal muscles by increased IGF-1. The excess of the GH and IGF-1 in patients with Acromegaly could be controlled by somatostatin analogues (SSAs) therapy in most of the patients. On the contrast, the overall glucose tolerance might be complicated by the inhibitory effect of SSAs on pancreatic insulin secretion.

The visceral obesity and IR are induced by hypercortisolemia. It also leads to hyperglycemia and reduced glucose tolerance, determines IR and stimulates hepatic gluconeogenesis and glycogenolysis. The hyperglycemia is due to decreased insulin secretion in patients with neuroendocrine tumors (NETs), patients with pancreatic surgery and in those with pheochro‐ mocytoma. While in somatostatinoma or gluconoma the hyperglycemia is related to alteration in the counterbalance between these hormones. In the symptomatic treatment of NETs, the SSAs represent a valid therapeutic choice and it may have a significant impact on the preva‐ lence of glucose metabolism imbalance.

Hyperthyroidism is the principally cause of hyperglycemia among thyroid disorders [241]. IR is associated positively with abnormal increase in the thyroid hormone levels [242]. The uncontrolled diabetes in patient with diabetes developing thyrotoxicosis is related to the stimulation of hepatic glucose production by thyroid hormones acting via a sympathetic pathway from the hypothalamus and FT3 influenced the transcriptional regulators of meta‐ bolic and mitochondrial genes may contribute to the development of IR. In contrast, hypo‐ thyroidism is linked to decreased IS. The thyroid hormones have insulin antagonistic effects at the liver that lead to an increase in glucose hepatic output, via an enhanced rate of gluco‐ neogenesis and glycogenolysis. Lipid metabolism (lipogenesis and lipolysis) are stimulated by FT3 further aggravating the dysregulation of liver glucose and lipid metabolism predispose to IR There are several genes are involved in gluconeogenesis, glycogen metabolism, insulin signaling and many hepatic glucogenic enzymes are regulated by thyroid hormones. The thyroid hormones also could cause an increase in hepatic glucose output, through increased hepatic expression of the glucose transporter GLUT2 [243].

#### **11.2. Polycystic ovary syndrome**

The features of PCOS are hyperinsulinemia, IR and hyperandrogenesim. The later present‐ ed in those patients with hirsutism, acne, irregular periods and reproductive disorders. These features are more marked and severe in obese females and the combination of both (these features with obesity) have a synergistic effect on increased insulin secretion by βcells and development of compensatory hyperinsulinemia. Subsequently, with the decline of the β-cell compensatory response a relative or absolute insulin secretion and produc‐ tion insufficiency develops which may lead to dysglycemia (IFG, IGT and T2DM). There‐ fore, it is well-known that PCOS and IR are considered risk factors for GDM [244]. This risk is increased in obese females, presence of family history of T2DM and to the severity of high androgenic activity. Therefore, the dysglycemia could occur in earlier age group than normal population. It could be in the 3rd or 4th decade of life and it is approximately 5 to 10 folds higher than normal population. No doubt, it is higher compared with age and weight matched control age group [245].

#### **11.3. Pancreatic damage or β-cell damage of the pancreas**

Chronic alcoholism and tropical calcified pancreatitis are most commonly associated with diabetes [247]. Pancreatic exocrine disease associated with hyperglycemia or DM has a unique clinical and metabolic form. It is painless occasionally and malabsorption occurs after clinical hyperglycemia or DM following failure or impairment of endocrine and exocrine pancreatic function of both α and β cells [246]

#### **11.4. Hereditary hemochromatosis**

Iron overload and excessive tissues deposition of iron including the pancreas. It is an autosomal recessive genetic disorder caused by a mutation in the HFE gene located on the short arm of chromosome 6. Approximately 50% of patients diagnosed with hemochromatosis will have either type 1 or T2DM [248].

#### **11.5. Cystic fibrosis**

Diabetes Mellitus is the most common morbidity in patients with cystic fibrosis (CF). It occurs in about 20% of adolescent and 40-50% of adults with this disease. CF primarily caused by insulin insufficiency. However, there is a role for IR in acute and chronic stages of this disease due to fluctuation level of insulin. DM has a unique distinct entity in patient with CF because it has mixed features of TIDM and T2DM [249].

**Other causes** of damage of the pancreas are toxins like alcohol, surgical resection of the pancreas and pancreatic cancer.

#### **11.6. Smoking**

neogenesis and glycogenolysis. Lipid metabolism (lipogenesis and lipolysis) are stimulated by FT3 further aggravating the dysregulation of liver glucose and lipid metabolism predispose to IR There are several genes are involved in gluconeogenesis, glycogen metabolism, insulin signaling and many hepatic glucogenic enzymes are regulated by thyroid hormones. The thyroid hormones also could cause an increase in hepatic glucose output, through increased

The features of PCOS are hyperinsulinemia, IR and hyperandrogenesim. The later present‐ ed in those patients with hirsutism, acne, irregular periods and reproductive disorders. These features are more marked and severe in obese females and the combination of both (these features with obesity) have a synergistic effect on increased insulin secretion by βcells and development of compensatory hyperinsulinemia. Subsequently, with the decline of the β-cell compensatory response a relative or absolute insulin secretion and produc‐ tion insufficiency develops which may lead to dysglycemia (IFG, IGT and T2DM). There‐ fore, it is well-known that PCOS and IR are considered risk factors for GDM [244]. This risk is increased in obese females, presence of family history of T2DM and to the severity of high androgenic activity. Therefore, the dysglycemia could occur in earlier age group than normal population. It could be in the 3rd or 4th decade of life and it is approximately 5 to 10 folds higher than normal population. No doubt, it is higher compared with age and

Chronic alcoholism and tropical calcified pancreatitis are most commonly associated with diabetes [247]. Pancreatic exocrine disease associated with hyperglycemia or DM has a unique clinical and metabolic form. It is painless occasionally and malabsorption occurs after clinical hyperglycemia or DM following failure or impairment of endocrine and exocrine pancreatic

Iron overload and excessive tissues deposition of iron including the pancreas. It is an autosomal recessive genetic disorder caused by a mutation in the HFE gene located on the short arm of chromosome 6. Approximately 50% of patients diagnosed with hemochromatosis will have

Diabetes Mellitus is the most common morbidity in patients with cystic fibrosis (CF). It occurs in about 20% of adolescent and 40-50% of adults with this disease. CF primarily caused by insulin insufficiency. However, there is a role for IR in acute and chronic stages of this disease due to fluctuation level of insulin. DM has a unique distinct entity in patient with CF because

hepatic expression of the glucose transporter GLUT2 [243].

**11.2. Polycystic ovary syndrome**

86 Treatment of Type 2 Diabetes

weight matched control age group [245].

function of both α and β cells [246]

**11.4. Hereditary hemochromatosis**

it has mixed features of TIDM and T2DM [249].

either type 1 or T2DM [248].

**11.5. Cystic fibrosis**

**11.3. Pancreatic damage or β-cell damage of the pancreas**

There are several studies suggestive of smoking is a risk factor for T2DM, it is an independent and modifiable risk. The early weight gain following smoking cessation is far more beneficial compared with the long term effect of smoking. This weight gain could increase the risk of diabetes [250-252]. Smoking deteriorates glucose metabolism and it is considered a possible a risk factor for development of IR and subsequently T2DM [253]. Smoking is also through a body mass index independent mechanism increasing the risk of T2DM [254, 255]. Pancreatic damage by toxic agents cause insufficient insulin secretion and development of the disease. Tobacco is one of the toxic agent to the human body and organ damage; on the pancreas it is also considered a risk factor of pancreatic cancer and chronic pancreatitis [256].

#### **11.7. Prematurity and birth weight**

Hofman PL in 2004 reported an association between low birth weight, commonly a reflection of an adverse in utero environment, and the subsequent development of diseases such as T2DM and hypertension in later life is now generally accepted as is an association between an adverse perinatal environment and a permanent reduction in IS [257, 258].This concept was changed in other report by the evidence has accumulated that small for gestational age children have long-term adult health consequences including obesity, T2DM, hypertension, coronary artery disease and stroke. This increased risk of later adult disease is likely a consequence of an early, persistent reduction in IS [259]. Reduced fetal growth is associated with increased risk of diabetes and suggested a specific association with thinness at birth [260]. Prevalence of T2DM and IGT depended on the synergic effect of thin body size at birth and obesity during adulthood [261]. IGT and T2DM are early signs and indications of growth retardation in early life. The raise in plasma levels of 32-33 split proinsulin is closely related to growth retardation and reflects the β-cells dysfunction [262]. A review and analysis of 14 studies low birth weight (<2,500 g), as compared with a birth weight of >/=2,500 g, was associated with increased risk of T2DM. The risk is the same in high birth weight (>4,000 g), as compared with a birth weight of (</=4,000 g) [263]. The two strongest predictor factors for development of T2DM in adult life are low birth weight and abdominal obesity. The risk of T2DM in Chinese adults is inversely correlated to birth weight. Subjects with high risk of developing hypertension and abdominal obesity are those with the lowest or highest birth weight [264].


**3. Chemical composition of lycopene**

Lycopene is a lipophelic, 40-carbon atom highly unsaturated, straight chain hydrocarbon containing 11 conjugated and 2 non-conjugated double bonds. The all-trans isomer of lycopene is the most predominant isomer in fresh tomatoes and is the most thermodynamically stable from (figure 1). The many conjugated double bonds of lycopene make it a potentially powerful antioxidant, a characteristic believed to be responsible for its beneficial effects. The antioxidant activity of lycopene is high light by its singlet oxygen-quenching property and its ability to trap peroxy1 radicals. This singlet quenching ability of lycopene is twice as high as that of βcarotene and 10 times higher than that of α-tocopherol and butylated hydroxyl toluene.

**Figure 1.** All-*trans* Lycopene.

490 Lipoproteins – Role in Health and Diseases

other lycopene containing fruits and vegetables.

**3. Chemical composition of lycopene**

Source Lycopene content (mg/100g wet basis)

**Table 1.** shows the lycopene content of tomatoes, some commonly consumed tomato products and

and may help lower the risk of chronic diseases including cancer and heart disease.

Lycopene is a lipophelic, 40-carbon atom highly unsaturated, straight chain hydrocarbon containing 11 conjugated and 2 non-conjugated double bonds. The all-trans isomer of lycopene is the most predominant isomer in fresh tomatoes and is the most thermodynamically stable from (figure 1). The many conjugated double bonds of lycopene make it a potentially powerful antioxidant, a characteristic believed to be responsible for its beneficial effects. The antioxidant

Lycopene is also widely distributed in the human body. It is one of the major carotenoids found in the human serum (between 21 and 43% of total carotenoids) with plasma levels ranging from 0.22 to 1.06 nmol/ml (Cohen, 2002). It is also found in various tissues throughout the body such as the liver, kidney, adrenal glands, tests, ovaries and the prostate gland (Basu & Imrhan, 2006). Unlike other carotenoids like α-and β-carotene, lycopene lacks the β.:onone rang structure common to other carotenooids (Agarwal & Rao, 2000). Although it lacks provitamine an activity, lycopene is known to be a potent antioxidant (Livny *et al.,* 2002). Reactive oxygen (ROS) species have been implicated in playing a major role in the causation and progression of several chronic diseases. These ROS are highly reactive oxidant molecules that are generated endogenously through regular metabolic activity. They react with cellular components, causing oxidative damage to such critical cellular biomolecules as lipids, proteins and DNA. Antioxidants are protective agents that inactive ROS and therefore, significantly delay or prevent oxidative damage associated with chronic disease risk. Lycopene is one of the most potent antioxidants among the dietary carotenoids

Tomatoes fresh 0.72 – 20 Tomato juice 5.00 – 11.60 Tomato sauce 6.20 Tomato paste 5.40 – 15.00 Tomato soup 7.99 Ketchup 9.90 – 13.44 Pizza sauce 12.71 Watermelon 2.30 – 7.20 Pink guava 5.23 – 5.50 Pink grapefruit 0.35 – 3.36 Papaya 0.11 – 5.30 Carrot 0.65 – 0.78 Pumpkin 0.38 – 0.46 Sweet potato 0.02 – 0.11 Apricot 0.01- 0..05

As a result of the 11 conjugated carbon-carbon double bonds in its backbone, lycopene can theoretically assume 211 or 2048 geometrical configurations (Omani & Aluko, 2005).

However, it is now known that the biosynthesis in plants leads to the all-*trans*-form, and this is independent of its thermodynamic stability. In human plasma, lycopene is an isomeric mixture, containing at least 60% of the total lycopene as cis- isomers ( Kim *et al.,* 2012).

All-*trans*, 5-*cis*, 9-*cis*, 13-*cis*, and 15-*cis* are the most commonly identified isomeric forms of lycopene with the stability sequence being 5-*cis*>all-*trans*>9-*cis*>13-*cis*>15- *cis*>7-*cis*>11-*cis*, (Agarwal & Rao, 2000) so that the 5-*cis*-form is thermodynamically more stable than the all*trans*-isomer. Whereas a large number of geometrical isomers are theoretically possible for all-*trans* lycopene, according to only certain ethylenic groups of a lycopene molecule can participate in *cis-trans* isomerization because of steric hindrance. In fact, only about 72 lycopene *cis* isomers are structurally favorable. Figure 2 illustrates the structural distinctions of the predominant lycopene geometrical isomers.

**Figure 2.** Geometrical isomers of lycopene

#### **4. Mechanisms action of lycopene**

A cellular and molecular study have shown lycopene to be one of the most potent antioxidants and has been suggested to prevent atherogenesis by protecting critical bimolecules such as DNA, proteins, lipids and low density lipoproteins (Pool-zobel *et al.,* 1997). Lycopene, because of its high number of conjugated double bonds, exhibits higher singlet oxygen quenching ability compared to β-carotene or α-tocopherol (Di-Mascio *et al.,* 1989). Cis lycopene has been shown to predominate in both benign and malignant prostate tissues, suggesting a possible beneficial effect of high cis-isomer concentrations, and also the involvement of tissue isomerases in vivo isomerization from all trans to cis form (Clinton *et al.,* 1996). Where as Levin *et al.,* (1997) have shown that 9- cis- β-carotene is a better antioxidant than its all-trans counterpart, no such mechanistic data have been reported in case of individual lycopene isomers. Handley *et al.,* (2003) reported a significant increase in 5-cis lycopene concentrations following a 1- week lycopene-restricted diet, and a subsequent reduction in 5-cis, and a concomitant increase in cis-β, cis-D and cis-E lycopene isomers during the 15-day dietary intervention with tomato products in healthy individuals. Although this study reported a decrease in LDL oxidizability due to the intervention with tomato lycopene, the individual antioxidant role of lycopene isomers and their inter conversions remain unclear. At a physiological concentration of 0.3 μmol/1, lycopene has been shown to inhibit growth of non-neoplastic human prostate epithelial cells in vitro, through cell cycle arrest which may be of significant implications in preventing benign prostate hyperplasia, a risk factor for prostate cancer (Obermuller-Jevic *et al.,* 2003). Lycopene has also been shown to significantly reduce LNCaP human prostate cancer cell survival in a dose-dependent manner, and this anti-neoplastic action may be explained by increased DNA damage at high lycopene concentrations (> 5μm), whereas lower levels of lycopene reduced malondialdehyde formation, with no effects on DNA (Hwang & Bowen, 2005). Physiologically attainable concentrations of lycopene have been shown to induce mitochondrial apoptosis in LNCaP human prostate cancer cells, although no effects were observed on cellular proliferation or necrosis (Hantz *et al.,* 2005). Lycopene has also been shown to interfere in lipid metabolism, lipid oxidation and corresponding development of atherosclerosis. Lycopene treatment has been shown to cause a 37% suppression of cellular cholesterol synthesis in J-774A.1 macrophage cell line, and augment the activity of macrophage LDL receptors (Fuhrman *et al.,* 1997). Oxidized LDLs are highly atherogenic as they stimulate cholesterol accumulation and foam cell formation, initiating the fatty streaks of atherosclerosis (Libby, 2006). LDL susceptibility to oxidative modifications is decrease by an acyl analog of platelet-activating (PAF), acyl-PAF, which experts its beneficial role during the initiation and progression of atherosclerosis. Purified lycopene in association with αtocopherol or tomato lipophillic extracts has been shown to enhance acyl-PAF biosynthesis in endothelial cells during oxidative stress (Balestrieri *et al.,* 2004). Fuhrman *et al.,* (2000) further reported comparative data in which tomato oleoresin exhibited superior capacity to inhibit in vitro LDL oxidation in comparison with pure lycopene by up to fivefold. A combination of purified lycopene (5μmol/I) with α-toopherol in the concentration range of 1-10μmol/I resulted in a significant greater inhibition of in vitro LDL oxidation, than the expected additive individual inhibitions. In this study, purified lycopene was also shown to act synergistically with other natural antioxidants like the flavonoid glabridin, the phenolics rosmarinic acid and carnosic acid, and garlic acid in inhibiting LDL oxidation in vitro. These observations suggested a superior antiatherogeneic characteristic of tomato oleoresin over pure lycopene. The combination of lycopene with other natural antioxidants, as in tomatoes, may be more potent in inhibiting lipid peroxidation, than lycopene per se. The antiatherogenic effects of lycopene are generally believed to be due to its antioxidant properties. Dietary lycopene increases blood and tissue lycopene levels and acting as an antioxidant, lycopene traps reactive oxygen species and reduce the oxidative damage to lipids (lipoproteins and membrane lipids), proteins including important enzymes, and DNA, therapy lowering oxidative stress. This reduced oxidative stress then leads to a reduced risk for chronic diseases associated with oxidative stress such as cardiovascular disease (Omani & Aluko 2005). Alternatively, some non-oxidative mechanisms may be responsible for the beneficial effects of lycopene. The increased lycopene status in the body may regulate gene functions, improve intercellular communication, modulate hormone and immune response, or regulate metabolism, thus lowering the risk for chronic disease (Agarwl & Rao, 2000). A possible mechanism speculated for the protective role of lycopene in heart disease is via the inhibition of cellular HMGCoA reducate, the rate-limiting enzyme in cholesterol synthesis (Fuhrman *et al.,* 1997).