**Author details**

Aditya Kale Department of Gastroenterology, Seth G. S. Medical College and KEM Hospital, Mumbai, India

\*Address all correspondence to<EMAIL_ADDRESS>
© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Hepatocellular Carcinoma: Diagnosis and Surveillance DOI: http://dx.doi.org/10.5772/intechopen.99839*


**3.2. Effect of production systems on SSC, TA and firmness**

SSC, TA and firmness dramatically affect strawberry fruit quality. The production systems had a significant effect on the SSC, TA and firmness of the strawberry fruits and the SSC increased, while TA and firmness decreased all through the harvest season (**Table 3**). PMRC significantly increased the SSC, TA and firmness of the strawberry fruits at all harvests compared to PM and MRS (**Table 3**). Meanwhile PM significantly enhanced SSC and TA of strawberry fruit but had no effect of firmness of strawberry fruit compared to MRS (**Table 3**). Strawberry planted under PMRC produce higher-quality fruits than those without row covers, possibly because the microclimate under the covers was modified and the soil temperature was elevated which maybe result in better root establishment and advanced growth stages [20].

LSD0.05: least significant difference at the 0.05 level.

The individual phenolic compounds of berries were analysed by HPLC, using a Varian (Varian Inc., Palo Alto, CA, USA) HPLC system. A photodiode array detector (Model 335) and a quaternary pump (Model 240) were equipped in the HPLC system. Samples were injected at 40°C, and the separation was performed with a reverse phase 4.6-mm Polaris C18-A column coupled with a 4.6-mm MetaGuard Polaris C18-A guard column (Varian Inc., Palo Alto, CA, USA). The mobile phase was acidified water containing 2.5 g/100g formic acid (A) and acidified methanol containing 2.5 g/100 g formic acid (B). The flow rate was 1.0 ml/min, with a gradient profile consisting of B with the following proportions (v/v) of A: 0–15 min, 15–30% B; 15–20 min, 30% B; 20–25 min, 30–80% B; 25–42 min, 80% B; 42–42.5 min, 80–100% B; 42.5–50.25 min, 100% B; and 50.25–51.25 min, 0% B. The detector was simultaneously monitoring the different groups of phenolics at 254, 280, 320, 350 and 510 nm. Equilibration time between samples was 15 min. Data were collected and analysed by Varian Workstation Star version 6.41. Total phenolic compounds were divided into six groups and quantified as described in our previous work [30].

Statistical analysis was performed using SAS software [31]. Data were analysed using GLM procedure, and the least significant difference (LSD) test was used for mean separation at 5% level when it was significant. The arcsine transformation was used for rank data before data analysis, and the results were presented as a rank for simplicity when the outcomes of transformed and non-transformed data were the same. The data from 2009 to 2010 were pooled together after

Yield is an important characteristic that farmers considered a lot in strawberry production. Compared to the MRS, PMRC accelerated strawberry fruit production by 8 and 10 days in 2009 and 2010, respectively, followed by PM when fruits were harvested 4 and 5 days before MRS in 2009 and 2010, respectively, similar to those observed by Jin et al. [32]. Soria et al. [33] also reported that based on two consecutive cropping seasons data, plastic tunnels improved early marketable yield, total marketable yield and first-class fruits of strawberry. The increased yield and fruit size might be due to the increase in soil temperature for PM and PMRC. The early ripening of the fruits under PM and PMRC systems will probably generate a better income due to off-season production. Total yields of PM and PMRC were significantly lower than that of MRS, but the yield per plant of PMRC was significantly higher than PM and MRS (**Table 2**). Fruits harvested from PMRC and PM were significantly larger than those harvested from MRS (**Table 2**). This might be because of less competition between the plants

analysing each year separately and testing the homogeneity of the experimental error.

since all the runners were removed under PM and PMRC but kept under MRS [24].

SSC, TA and firmness dramatically affect strawberry fruit quality. The production systems had a significant effect on the SSC, TA and firmness of the strawberry fruits and the SSC increased, while TA and firmness decreased all through the harvest season (**Table 3**). PMRC significantly

**3.2. Effect of production systems on SSC, TA and firmness**

**2.11. Statistical methods**

**3. Results and discussion**

**3.1. Effect of production systems on yield**

202 Phenolic Compounds - Natural Sources, Importance and Applications

Different lower-case letters in the same column indicate statistically significant differences between different treatments (*p* < 0.05).

**Table 2.** Total yield, yield per plant and average fruit weight of strawberry selection 'SJ8976-1' grown under three production systems.

LSD0.05: least significant difference at the 0.05 level.

Different lower-case letters in the same column indicate statistically significant differences between different treatments (*p* < 0.05).

**Table 3.** Early-, mid- and late-harvest soluble solids content (SSC), titratable acidity (TA) and firmness of strawberry selection 'SJ8976-1' grown under three production systems.

### **3.3. Effect of production systems on shelf life**

Photographs of disease development and fruit juice leakage of strawberry selection 'SJ8976-1' used for shelf life, juice leakage and presences of grey mould classification are presented in **Figure 1**. 'SJ8976-1' has a special longer shelf life (about 9 days) after storage at room temperature than the commercial strawberry varieties. Production systems significantly affected strawberry

**Figure 1.** Photographs of disease development and fruit juice leakage of strawberry selection 'SJ8976-1' used for shelf life, juice leakage and presences of grey mould classification.

shelf life, including fruit weight loss, juice leakage, glossiness and presences of grey mould during storage (**Figure 2**). Fruit weight loss, juice leakage and presences of grey mould after storage were lower, and fruit glossiness was higher for those fruits harvested from PMRC than those from the MRS. Significant lower fruit weight loss was observed for PMRC and PM compared to the MRS, and the results were more pronounced after day 7 (**Figure 2A**). It was interesting to note that PMRC had significant lower juice leakage than the MRS, but the differences between PMRC and PM and PM and MRS were not significant until day 11 (**Figure 2B**). The fruits from PMRC kept their glossiness longer during storage at room temperature than MRS and PM. The remarkable difference among different production systems was obtained at 7 days after harvest (**Figure 2C**). Similar finding was reported in Finland that plastic production systems promoted better shelf life [11]. No significant differences were observed between the production systems on the first 5 days of harvest for presences of grey mould, but significantly less grey mould were observed on fruits harvested from PMRC than those harvested from MRS and PM from day 7 to the end of the test when all fruits were ranked as non-marketable (**Figure 2D**). Lower grey mould incidence on fruit harvested from PMRC might be due to the higher TPC and TAC content of the fruits as suggested previous [25, 34] or the protection that fruits received from the row cover against pathogen and rainfall as suggested by Freeman and Gnayem [16].

shelf life, including fruit weight loss, juice leakage, glossiness and presences of grey mould during storage (**Figure 2**). Fruit weight loss, juice leakage and presences of grey mould after storage were lower, and fruit glossiness was higher for those fruits harvested from PMRC than those from the MRS. Significant lower fruit weight loss was observed for PMRC and PM compared to the MRS, and the results were more pronounced after day 7 (**Figure 2A**). It was interesting to note that PMRC had significant lower juice leakage than the MRS, but the differences between PMRC and PM and PM and MRS were not significant until day 11 (**Figure 2B**). The fruits from PMRC kept their glossiness longer during storage at room temperature than MRS and PM. The remarkable difference among different production systems was obtained at 7 days after harvest (**Figure 2C**). Similar finding was reported in Finland that plastic production systems promoted better shelf life [11]. No significant differences were observed between the production systems on the first 5 days of harvest for presences of grey mould, but significantly less grey mould

**Figure 1.** Photographs of disease development and fruit juice leakage of strawberry selection 'SJ8976-1' used for shelf

life, juice leakage and presences of grey mould classification.

204 Phenolic Compounds - Natural Sources, Importance and Applications

**Figure 2.** Early-, mid- and late-harvest fruit weight loss (A), fruit juice leakage (B), fruit glossiness (C) and incidence of grey mould (D) on strawberry selection 'SJ8976-1' during 11 days of storage at room temperature (23°C) grown under three production systems. Means with the same letter within the same day were not significantly different at 0.05 level. ◆, Matted row system; ■, plastic mulch; and ▲, plastic mulch with row covers.


*3.3. Rheological Properties*

Rheology as reported by Ambrosio et al. [48], is a useful tool to explore the relationships between the mechanical behavior and chemical properties of HA, or other biopolymer solutions. In our study, the flow behavior and viscoelastic measurement were evaluated to understand the difference in the rheological properties of HA and Ch solutions with their complex.

The variation of the viscosity as a function of the shear rate were acquired; in Figure 6a the viscosity curves, with a shear rate (γ) ranging from 0.1 s−1 to 100 s−1 , are reported.

− γ γ **Figure 6.** (**a**) Viscosity curves of the Ch, HA, and HA/Ch complex. Due to low viscosity, data for Ch were only acquired in the range (1–100) s−1 (**b**). Frequency sweep test of the Ch (γ = 20%), HA, and the HA/Ch complex (γ = 2%).

HA and Ch (black and purple curves in Figure 6a, respectively) showed different behaviours. Ch viscosity remained constant at a value of 8.8 mPa s over the entire tested shear rate range, thus showing ideal viscous flow behaviour. Such behaviour was mainly related to the sample concentration and substitution degree of chitosan—according to previous results [49]. The pseudoplasticity was inversely proportional to DS and directly correlated to the concentration of sample. For HA, viscosity was shear-dependent, viscosity decreased as γ increased, in agreement with a pseudoplastic behaviour [48]. For the complex, shear-thinning behaviour was also observed. Note that the viscosity values were higher than that for pure HA.

The rheological tests were also performed in the oscillation mode, to evaluate both the storage modulus (G') and the loss modulus (G"). The strain sweep test (data not shown) was initially performed to evaluate the LVE zone, where the intrinsic sample structural properties are independent of the applied strain:2% (HA and Complex) and 20% (Ch) strain value was selected for subsequent frequency sweeps tests. In Figure 6b, values of G' and G" as function of the angular frequency for the Ch, HA, and the complex are reported. In the investigated frequency range (from 0.628 rad/s to 628 rad/s), the mechanical spectrum of Ch showed that G" was greater than G', with both moduli strongly dependent on the frequency, as typically a liquid-like (viscous) behavior dominates over the solid-like (elastic) character. Differently, HA and HA/Ch presented a "weak gel" or viscoelastic behavior with G' and G", which became less dependent on the frequency and the crossover point, when G' = G", was observed. This suggests that at high frequencies, when G' > G", the material show a predominant solid-like behavior.

The angular frequency values, ω**c**, and the corresponding G' = G" values to the crossover point data are reported in Table 4.

**Table 4.** Rheological measurements—evaluation of G' and G" crossover.

1 value not detected in the frequency range investigated.


**4. Conclusions**

Based on above analysis, comprehensive and systematic conclusions were done on the scientific issues to be clarified in the high-purity titanium molten salt electrorefining process. The influence of anion and cation in electrolyte on ionic equilibrium of titanium was discussed systematically by chemical analysis and electrochemical testing. Specifically, the type of microstructure of the molten salt is dissected in the molten salt mainly composed of chloride. The coordination mechanism between titanium ion and fluoride ion was also revealed. The mechanism of anodic oxidation and cathodic reduction kinetics in electrolytes with different micro-structures was clarified, which provide a guiding line for optimizing electrolyte. More importantly, on the basis of full theoretical and experimental research, it proposes parameters for high-purity titanium extraction in molten salt, and provides theoretical support for the establishment of efficient, low-pollution, and lowcost metallurgical processes.


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**Chapter 14**

© 2012 Britti et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 Britti et al., licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Oleuropein an Olive Oil Compound in**

**Facts and Perspectives**

Domenico Britti, Daniela Impellizzeri,

http://dx.doi.org/10.5772/51889

Paiva-Martins *et al.*, 2009).

**1. Introduction**

Antonio Procopio and Salvatore Cuzzocrea

Additional information is available at the end of the chapter

**Acute and Chronic Inflammation Models:**

A large mass of research has been accumulating to provide evidence for the health benefits of olive oil feeding and to scientifically support the widespread adoption of traditional Mediterranean diet as a model of healthy eating (Menendez *et al.*, 2007). This evidence has been attributed to the fact that olive oil, the predominant source of fat in the Mediterranean diet (Petroni *et al.*, 1995), contains several minor non-nutrients chemicals such as α- and γtocopherols and β-carotene, phytosterols, pigments, terpenic acids, flavonoids such as luteolin and quercetin, squalene, and phenolic compounds, usually and incorrectly termed polyphenols (Menendez *et al.*, 2007; Visioli *et al.*, 2002; Trichopoulou *et al.*, 2003; Tripoli *et al.*, 2005; Servili *et al.*, 2004). The main phenolic compounds in virgin olive oil are secoiridoid derivatives of 2-(3,4-dihydroxyphenyl)ethanol (3,4-DHPEA) and 2-(4-hydroxyphenyl) ethanol (*p*-HPEA) that occur as either simple phenols or esterified with elenolic acid to form, respectively, oleuropein and its derivative demethyloleuropein, and ligstroside, their aglycones 3,4-DHPEA-EA and *p*-HPEA-EA (Figure 1) (Bendini *et al.*, 2007; Suárez *et al.*, 2009). The aglyconic form of oleuropein and ligstroside, 3,4-DHPEA-EA and *p*-HPEA-EA respectively, were reported for the first time by Montedoro et al, who also assigned their chemical structures, later confirmed by other (Montedoro *et al.*, 1992; Angerosa *et al.*, 1996; Owen *et al.*, 2000). 3,4-DHPEA-EA and *p*-HPEA-EA, associated to the intense sensory of bitterness and pungency respectively attribute in VOO (Gutierrez-Rosales *et al.*, 2003), is endowed with numerous beneficial effects on human health (Servili *et al.*, 2004; Bendini *et al.*, 2007; Esti *et al.*, 1998; Della Ragione *et al.*, 2000; Paiva-Martins *et al.*, 2001; Fabiani *et al.*, 2002; Carasco-Pancorbo *et al.*, 2005; Artajo *et al.*, 2006; Fabiani *et al.*, 2006; Fabiani *et al.*, 2008;


**1. Introduction**

Hot-stamped ultra-high strength steels have been widely used as automobile structural parts, due to the increasing requirements for safety and weight reduction of automobiles. The hot-stamped steel sheet is first heated to the austenite zone and then transferred quickly into deforming dies and hot pressed into structural components with required shapes, such as A-pillar, B-pillar, and bumpers, and finally is rapidly cooled to room temperature by flowing cooling water in dies. During the cooling process, essentially 100% martensite is produced, and the tensile strength can be up to 1500 MPa and the yield strength can reach 1100 MPa [1–3]. To avoid oxidation at high temperatures during hot stamping, the as-received steel sheets are usually pre-coated by Al-Si [4]. Resistance spot welding is one of the most important joining methods in automobile manufacture. However, the ultra-high strength steel exhibits a poor weld-ability during the spot welding process. Molten metal splash tends to occur in welding, which is related to the high hardness of the steel. On the one hand, the two overlapping steel sheets are hard to press together, and on the other, the contact resistance between the two ultra-high strength steel sheets is much higher than that of plain-carbon steels, which result in the faster melting of metal. Under the combined action of these two factors, splash is a common issue in the spot welding of ultra-high strength steel. Splash tends to cause many kinds of welding defects in the nugget and decreases the tensile capacity significantly. In order to optimize spot welding parameters of automobile steels, researchers have studied the influence of spot welding parameters, especially current, electrode force, and welding time, on the microstructure and mechanical properties

of spot welding joints [5–7]. In recent years, alternating current (AC) spot welding machines with variable frequency have been developed and more widely used in resistance spot welding in the automobile industry [8–10]. In this case, except for the above mentioned three traditional parameters, some other parameters like frequency and pulse duration would influence the spot welding process, and thereby the mechanical properties of the joints. However, studies have seldom considered the effect of austenite pre-strain, which results from electrode force during welding on the phase transformation of the heating affected zone (HAZ) after spot welding. In this work, the damage mechanism of spot welding joints of hot-stamped strengthened steels was studied in detail, and then spot welding experiments were performed with different current input modes in order to optimize the parameters of resistance spot welding and decrease the splashing ratio in welding.


4. Transforming cities in a large mosquito trap while improving their livability

Aedes-transmitted diseases are, largely, diseases emanating from neglected private and social spaces [57]. In backyards, buildings, vacant lands and empty lots, trash and untended structures provide perfect breeding places not only for Aedes mosquitoes, but also for many other urban and domestic pests. These neglected places have a negative impact on the environment and quality of life of the community, as well as on their economic development and safety [58]. Therefore, a campaign to remove mosquito breeding places is also a campaign to reinvigorate depressed or unplanned urban areas, thereby improving living conditions [59–61].

It is important to highlight that mosquito control has to be integrated into "cross-cutting" solutions for public health, turning societal vulnerabilities into resilience [61, 62] – i.e. what is good for elimination of Aedes, should also be beneficial on other societal fronts. For instance, environmental management of Aedes might discourage traditional ad hoc water storage practices such as private water-storage systems [16, 28]. But resilience to crises and catastrophes are enhanced through decentralized and resource-autonomous societies [63], for example potable water that is locally collected, treated [64] and appropriately stored (so that it is inaccessible to mosquitoes) would still be available even if the water supply from a centralized provider is unavailable, disrupted or fails.


**4. Repurposing therapeutics towards SARS-CoV-2 potential targets**

Therapeutics facilities aid physicians and scientist to help patients with the better cure for the disease and develop a vaccine. The production of novel therapeutics and vaccination is now at the earliest possible time to curb the epidemic. In addition, continuous attempts are being made at regional, national, and person levels to recognize the host, genomics, epidemiological interactions, and propagation modes of SARS-CoV-2 in order to control the epidemic. Scientists worldwide are actively working to establish an optimal antiviral agent and vaccine against SARS-CoV-2 [51]. One way of preventing this issue is to test two or three drugs with minimal prolixity that operate on various cellular signals with viral replication. A further approach that helps researchers to curb the variety of individual antimicrobials for emerging and re-emerging infectious diseases is the high-performance screening of host-virus interaction level composite libraries for synergistic combinations [52, 53]. Nevertheless, the screening of experimental small molecule drugs in combinations and other potent anti-SARS-CoV-22 agents with new and improved key characteristics can be effective which can be helpful in COVID-19 therapy. Potential medicines include previously used or tested medicines for diagnosing diseases and medicines recently discovered or developed. In most cases, the benefits of drug repurposing are safety evaluation, preclinical monitoring, and in some cases the development processes would not take much time and thus reduce the time needed for drug development. The chances of failure with repurposed drugs would be smaller as the early steps of medication efficacy and safety testing have already been completed and the treatment has already been shown to be sufficiently effective in a preclinical and human model [54]. Antiviral therapies are being investigated towards treatment of COVID-19 because the SARS-CoV-2 replication of leads to wide variation of the clinical manifestations. As significant functional proteins of SARS-CoV-2, Nsps and other structural and accessory proteins are involved in transcription of RNA, synthesis of protein, post-translational modification, viral duplication and contagion of the host. Among them, PLpro (nsp3), 3CLpro (nsp5), RdRp (nsp12), Helicase (nsp13), Spike glycoprotein (S) and Nucleocapsid (N) are the most important targets for the development of small-molecule inhibitors due to the enzyme active site and clear biological functions [55].

#### **4.1 Protease inhibitors**

Protease inhibitors are drugs that inhibit the activity of protease enzyme responsible for viral development, infection, and replication by cleaving it into smaller fragments. They bind to the active site of the enzyme, mediate and block the maturation of freshly formed virions [51]. Two major targets: PLpro and 3-CLpro in the replicase 1a and 1ab domain are essential component for virus reproduction and regulation of host cell response thus being the important target for the SARS-CoV-2 inhibitors (**Figure 9**). Ribavirin (SCH-18908) [NCT00578825], an antiviral drug acts on the replicase protein, preventing binding of the nucleotides, resulting in reduced viral replication or the formation of defective virions. Lopinavir [NCT04321174] and Ritonavir [NCT04330690], are protease inhibitors used to treat HIV infections by inhibiting the HIV protease enzyme to form an inhibitor-enzyme complex and proteolytic cleavage of the viral polyprotein precursors [3]. Darunavir [NCT01448707], another (HIV-1) nonpeptidic protease inhibitor with the inhibition activity of the dimerization and catalytic activity of HIV-1 protease. Saquinavir [DB01232] inhibiting HIV1/2 protease-mediated lysis of HIV gag and pol polyproteins was found cytotoxically active at conc. Above 50 μM [56]. Rupintrivir (DB05102) a broad-spectrum

**Figure 9.** *Repurposed protease inhibitors for COVID-19 treatment.*

antiviral agent is a potent 3C-Like protease inhibitor against norovirus, picornavirus, and coronavirus proteases in development against human rhinoviral (HRV) infections that has been recently co-crystallized with its target [57]. Larazotide acetate (AT1001) (NCT03569007) a paracellular permeability peptide inhibitor has been studied for the treatment of autoimmune diseases such as type I diabetes mellitus, gastrointestinal diseases and disorders. Studies have revealed that AT1001 potentially binds to the Mpro catalytic domain showing up intermolecular interactions [58]. Teicoplanin (DB06149), a glycopeptide antibiotic widely used to treat bacterial infections, has been reported to be active against SARS-CoV-2 in *in-vitro* studies inhibiting peptidoglycan polymerization, resulting in inhibition of bacterial cell wall synthesis and cell death [59, 60]. Nafamostat mesylate [NCT04418128], a clinical proven and synthetic serine protease inhibitor has been identified to inhibit the activity SARS-CoV-2 by targeting TMPRSS2-dependent host cell entry [61, 62]. However, *in-vitro* studies of active phytochemical compounds from the natural sources have revealed the SARS-CoV-2 proteolytic and inhibitory activity; Phaitanthrin D (*Isatis indigotica Fort*), Baicalin (*Scutellaria baicalensis*), Piceatannol (*Vitis vinifera*), Platycodin D (*Platycodon grandiflorus*), Betulonal (*Cassine xylocarpa*), 2b-Hydroxy-3,4-secofriedelolactone-27-oic acid (*Viola diffusa*), Cleistocaltone A (*Cleistocalyx operculatus*), Phyllaemblinol (*Phyllanthus emblica*) etc. [55].

### **4.2 Replicase inhibitors**

RdRp is a critical non-structural protein component of the SARS-CoV-2 genome that uses a metal-ion-dependent mechanism to catalyze viral RNA synthesis. However, due to its comprehensive knowledge about the different domains and its functions, strong preservation among evolutionary RNA viruses and the lack

#### *Repurposed Therapeutic Strategies towards COVID-19 Potential Targets Based on Genomics… DOI: http://dx.doi.org/10.5772/intechopen.96728*

of homologous sequences in mammalian cells; the ease progress and consequent access to biochemical assays to quickly detect large collections of compounds [63]. Remdesivir (GS-5734) [NCT04252664], a nucleoside analogue acts on the replicase polyprotein 1ab of SARS-CoV-2 genome preventing RNA polymerase function resulting in ending the transcription of RNA and reduces the production of viral RNA. Penciclovir [NCT00820534], another nucleoside analogue, synthetic acyclic guanine derivative with antiviral activity targets the RdRp inhibiting the DNA synthesis of virus-infected cells and terminating viral replication (**Figure 10**). β-D-N4-hydroxycytidine, an orally bioavailable, broad-spectrum antiviral ribonucleoside analogous to multiple RNA viruses like influenza, CoV, equine encephalitis and Ebola viruses have been found in *in-vitro* studies of antiviral effect on SARS-CoV-2 primarily through mutagenesis of viral RNA [64, 65]. Cefuroxime, an anti-bacterial drug is prescribed in patients with COVID-19, as a potential inhibitor with the ability of binding tightly to the active site of the enzyme, with a highest ICM score of −41.30, and mfscore of −63.04, which when compared to Remdesivir had a score of −27.4 and a mfscore of −113 [66] The natural products and derivatives with antivirus, anti-inflammation and anti-tumor effects exhibited high binding affinity to RdRp, such as 14-deoxy-11,12-didehydroandrographolide (*Andrographis paniculate*), Gnidicin (*Gnidia lamprantha*), 2b,30b-dihydroxy-3,4-seco-friedelolactone-27-lactone (*V. diffusa*), Theaflavin 3,30-di-O-gallate (*Camellia sinensis*), Betulonal (*C. xylocarpa*), 1,7-dihydroxy-3- methoxyxanthone (*Swerti apseudochinensis*) [67].

SARS-CoV-2 replication enzyme, helicase has the properties of unwinding and splitting DNA and RNA into two single-stranded nucleic acids and these

**Figure 10.**

*Repurposed replicase inhibitors for COVID-19 treatment.*

characteristic of the enzyme marks it as a potential target to be studied [68]. Bananins have been shown to inhibit SARS-CoV ATPase activity leading to inhibition of viral replication *in-vitro* with IC50 values far less than 10 mM [69] Bismuth salt, such as Bismuth potassium citrate (BPC) has been observed to dosedependently inhibit both the NTPase and RNA helicase activities of SARS-CoV-2 nsp13. Further studies indicates that SARS-CoV-2 nsp13 may be a valuable target for antivirals, which could be beneficial in attempting to regulatory mechanism of this life-threatening virus [70]. Foscarnet, a class of antiviral drug approved for the treatment of HIV/AIDS-related cytomegalovirus (CMV) infections and herpes, functions as a pyrophosphate molecule by binding to viral DNA polymerase and preventing the elongation of the DNA chain [71]. *In vitro* studies have revealed that SSYA10–001, a small inhibitor molecule of SARS-CoV helicase, has an antiviral effect on several coronaviruses by likely targeting a conserved binding pocket in nsp13 domain and can lead the production of successful wide spectrum anti-coronavirus drugs including SARS-CoV-2 [72]*.* Scutellarein isolated from *Scutellaria baicalensis* has been historically used in the treatment of inflammation and respiratory diseases, and myricetin present in fruits such as cranberry and vegetables such as *Calamus scipionum* and garlic. Were found to inhibit SARS-CoV helicase (nsp13) via inhibition of ATPase activity being a potential phytochemical inhibitor [73, 74]. Emetine could be re-purposed to treat COVID-19 based on the *in-vitro* antiviral activity against SARS-CoV-2 and its ability to shield chicken embryos from IBV [75].


**Preface to "Tetrel Bonds"**

After many decades of study of the H-bond which probed every facet of its origin and behavior, researchers realized there are a group of very similar interactions that had largely defied recognition. It was realized that the replacement of the bridging proton of the H-bond by a halogen atom led to a stabilizing interaction of strength comparable to the H-bond itself. The stability of this halogen bond was based in part on the anisotropic distribution of electron density around the halogen atom that allowed a positive region on an otherwise negatively charged atom. It was not long after that point that research turned to close parallels where the halogen atom was itself replaced by members of the chalcogen and pnicogen families, whose bonding properties were likewise parallel to those of halogen bonds. A recent addition to this pantheon is the tetrel bond, a family that encompasses Si, Ge, Sn, and the ubiquitous and immensely important C atom.

It is the tetrel bond that serves as the focus of this volume. Papers collected from a recent Special Issue of Molecules cover this topic from a range of perspectives. The first two papers concentrate on some of the theoretical aspects that contribute to the bond, providing a lens by which to understand it and how it might be used to predict certain chemical properties. Coverage next turns toward some of the structural and spectroscopic aspects of these bonds, from an understanding based on vibrational modes, to effects of geometrical distortions, and to specific lessons learned from analysis of crystal structures.

The C atom is of special importance in all of chemistry and biochemistry, and the next three papers focus attention on the tetrel bonds specifically centered on C. One common element of these papers is to alert the community to not only the widespread presence of tetrel bonds but also the importance of these bonds to methyl groups. Along with the acceptance that the presence of a negative charge on the electron donor will strengthen a H-bond, the next two contributions illustrate that the same phenomenon is true of tetrel bonds and describe how this bond enhancement can be applied to advantage. The last five papers offer a broad perspective, describing how tetrel bonds fit into the general picture of noncovalent bonds in general. This section also includes a visualization as to the roles played by π-systems, not only in the tetrel bond donor but also in the partner nucleophile.

> **Steve Scheiner** *Editor*


2.3.3. Mud Volcanoes

Mud volcanism, such as is occurring in Azerbaijan, results when sediments lack su fficient induration to allow maturing gas and oil to escape. Hydrocarbons maturing at ~14 km depth in Azerbaijan produce overpressures that make the sediments quick (as in quick sand). The result is oil- and gas-spewing mud volcanoes 1 to 3.5 km in diameter. As illustrated in a spectacular geologic atlas [66], the stratigraphy is literally turning itself inside out, and there is an observed triad of oil, gas, and diapiric structures (Figure 11).

**Figure 11.** Mud volcanoes result when hydrocarbons are generated in un-indurated sediments. Mud Volcanoes of the Azerbaijan Atlas [66].