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Aluminum phosphide (AlP) is a popular fumigant used widely for the safe storage of food grain. Although A1P is free from toxic residues, it releases phosphine which acts on mitochondrial components of almost all types of pests. Unfortunately A1P is also a common suicidal agent in developing countries with no known antidote. In addition, accidental exposure to phosphine may also occur. AlP poisoning affects cardiac and vascular tissue directly and can result in multiorgan system failure leading to death in severe cases. There is no specific biomarker for diagnosing AlP poisoning and management depends on a high level of clinical suspicion. Although acetylcholinesterase has been suggested as a surrogate biomarker of AlP exposure, there are opposing views. In this review, we analyzed the relevant published material with emphasis on the need to recognize and explore the use of plasma mitochondrial enzyme activity as a potential biomarker for AlP exposure.

Meat fraud is an ongoing issue. So, Identification of meat adulterant as well as bacterial contamination is utmost need. Advance technology like Multiplex and digital droplet PCR are the two currently used methods for diagnosing contamination of meat. However, simultaneous testing of adulterant and bacterial contamination in livestock are not done profoundly. Here, we have design PCR primers which can be used to identify adulterant and bacterial contamination concurrently.

Irradiation of proteins with intense X-ray radiation generates specific structural and chemical alterations, such as metal-ion reduction, reduction of disulfide bonds and decarboxylation reactions. An analysis of a set of disulfide bonds in known structures suggests that the most susceptible disulfide bonds feature a carbonyl O atom positioned along the extension of the S—S bond vector, forming a stabilizing S⋯O interaction, which upon irradiation leads to polarization of the disulfide bond and its eventual reduction., Radiation-induced damage to protein crystals during X-ray diffraction data collection is a major impediment to obtaining accurate structural information on macromolecules. Some of the specific impairments that are inflicted upon highly brilliant X-ray irradiation are metal-ion reduction, disulfide-bond cleavage and a loss of the integrity of the carboxyl groups of acidic residues. With respect to disulfide-bond reduction, previous results have indicated that not all disulfide bridges are equally susceptible to damage. A careful analysis of the chemical environment of disulfide bonds in the structures of elastase, lysozyme, acetylcholinesterase and other proteins suggests that S—S bonds which engage in a close contact with a carbonyl O atom along the extension of the S—S bond vector are more susceptible to reduction than the others. Such an arrangement predisposes electron transfer to occur from the O atom to the disulfide bond, leading to its reduction. The interaction between a nucleophile and an electrophile, akin to hydrogen bonding, stabilizes protein structures, but it also provides a pathway of electron transfer to the S—S bond, leading to its reduction during exposure of the protein crystal to an intense X-ray beam. An otherwise stabilizing interaction can thus be the cause of destabilization under the condition of radiation exposure.

Tuberculosis is a health concern worldwide. The anti-tubercular drugs (particularly rifampicin) used for its management offers side effects like acute kidney injury. Creatinine, which is recognised as an important biomarker for the renal function, is commonly estimated with Jaffe's reaction (alkaline picrate reaction). However, interference of Jaffe's reaction with non-creatinine chromogens has been reported. In this context, we have checked the possibility of interference by Rifampicin and Isoniazid at therapeutic concentration with the Jaffe's reaction. Through in-silico study, we have studied the reaction prediction of picric acid with other chemicals/reactant (i.e. Rifampicin, Isoniazid and non-creatinine chromogens) in terms of confidence value. It is observed that the confidence value of reaction prediction between picric acid and INH and Rifampicin is much more than the same of pyruvic acid (non-creatinine chromogen). Further, we have checked the absorbance value of Jaffe's reaction mixture in aqueous media in the presence of both the drugs at 520nm. It is observed that the absorbance of alkaline picric acid increases with an increase in drug concentration. However, the increasing trend of absorbance is much more in the case of rifampicin compared to INH. It appears from our result rifampicin, and isoniazid has the potential to behave as non-creatinine chromogen and can give false positive creatinine results in Jaffe's reaction. Thus, it can cause misdiagnosis in patients consuming these drugs. We recommend study in the biological matrix for further validation of the result.

The surge of variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is a global concern to public health as the mutations in the genome may alter the virulence of the virus, which poses a challenge to manage the disease. The virus depends on RNA dependent RNA polymerases [RdRp(s)] and its associated non-structural proteins for replication. Therefore, RdRp is a target of antiviral drugs. Several mutations in RdRp in SARS-CoV2 from all over the world have been identified. Some of the mutations are known to alter the RdRp structure. This may have an implication on the effectiveness of the drugs being approved for combating the disease. Therefore, we believe elaborate studies are necessary to identify and characterize mutations in RdRp with respect to drug binding ability. Herein, using molecular docking, we have studied the interaction of the approved drug, Ledipasvir, with wild type and different mutant RdRps to gain mechanistic insights into structural changes which can affect the drug binding and may be responsible for drug resistance. We observed a change in the binding energy of ledipasvir with wild type and mutant polymerases. Further, deviation in the orientation of the drug was observed in the case of mutants in comparison to wild type RdRp. These findings suggest that it is of utmost importance to study RdRp mutants to assess drug resistance.

Tuberculosis, a global threat, is a highly infectious disease intensified by the emergence of drug-resistant strains. In tuberculosis disease spectrum, a typical situation is a dormant or latent phase where a person exposed to Mycobacterium tuberculosis has the reservoir of the disease that may or may not result in an active state. Existence of the dormant state is retarding the eradication of tuberculosis. Transcription of several genes helps M. tuberculosis to survive in nonreplicative mode. DosR transcription factor is the hallmark for this genesis. Diabetes mellitus is a predisposition factor leading to the development of tuberculosis and latent tuberculosis. High plasma insulin concentrations in the prediabetic state can increase the tuberculosis bacterium. On the other hand, antidiabetic drug metformin is known to reduce active tuberculosis disease when provided in combination with antitubercular therapy. However, the effect of the same on latent tuberculosis is still unknown. In the present work using tools of computational biology, we have tried to find the consequence of adding metformin in combination with rifampicin, a well-known antitubercular drug, on molecular mechanisms of latent tuberculosis. We have investigated whether metformin and rifampicin interact with DosR machinery or not. Our results indicate that if metformin-bound DosR-DNA complex binds with rifampicin, it will result in the conversion of active tuberculosis to latent tuberculosis.

Vitamin D has generated interest in the context of COVID-19 pandemic. Some authorities believe that it is beneficial; others think that without proven deficiency it should not be administered. The results of clinical trial are still awaited. Therefore nothing regarding the matter is conclusively known. In this context we believe that selocalcitol, a Vitamin D analogue if administered via inhalational route, has the potential to prevent SARS-CoV2 infection. The basis of this idea is presented here.

Hypertension is a public health concern. Low dose thiazide diuretics are known to effectively control blood pressure compared to that of other classes of antihypertensive drugs. In this context, we have performed an in-silico study and found that the two Sulphonamide Diuretics Hydrochlorothiazide and Indapamide bound the NADPH binding region of bacterial Dihydrofolate Reductase. Therefore, akin to Sulphonamide Antibiotics, Sulphonamide Diuretics may have antibiotic activity and thereby have the potential to modulate the gut microbiome in a way beneficial to vascular health. The in-silico experiment results were analyzed in the context of the relevant literature. We postulate that Sulphonamide Diuretics exert their antihypertensive role by modulating the gut microbiome, specifically by increasing butyrate-producing taxa in the gut. We recommend extending such work as it is plausible that Indapamide and other Sulphonamide Diuretics may be beneficial for both diabetes and hypertension. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40203-020-00056-9) contains supplementary material, which is available to authorized users.

The management of chronic lung diseases such as cancer, asthma, COPD and pulmonary hypertension remains unsatisfactory till date, and several strategies are being tried to control the same. Metformin, a popular anti-diabetic drug has shown promising effects in pre-clinical studies and has been subject to several trials in patients with debilitating pulmonary diseases. However, the clinical evidence for the use of metformin in these conditions is disappointing. Recent observations suggest that metformin use in diabetic patients is associated with an increase in butyrate-producing bacteria in the gut microbiome. Butyrate, similar to metformin, shows beneficial effects in pathological conditions found in pulmonary diseases. Further, the pharmacokinetic data of metformin suggests that metformin is predominantly concentrated in the gut, even after absorption. Butyrate, on the other hand, has a short half-life and thus oral supplementation of butyrate and metformin is unlikely to result in high concentrations of these drugs in the lung. In this paper, we review the pre-clinical studies of metformin and butyrate pertaining to pathologies commonly encountered in chronic lung diseases and underscore the need to administer these drugs directly to the lung via the inhalational route.

Human serum albumin (HSA) is a major plasma protein and binding of drugs with this plasma protein has a great importance. It possess esterase activity which can cleave the drugs containing ester bond and thus, can regulate the effect of drugs. Till date no systematic study has been done to analyse binding of such drugs and to compare the results with the drugs which do not have ester bond. Therefore, in the present study two different categories-ester and non-ester drugs have been considered to analyse their interaction with HSA at two principle drug binding sites using molecular modelling tools. It is observed that the drugs irrespective of ester or non-ester nature prefer either Sudlow site I or II by hydrogen bond and hydrophobic interactions. The information obtained from the study can assist to study pharmacokinetics of the drugs and that in turn will help in noval drug discoveries.

The association between hypoalbuminemia and coronary artery disease is known from some time. However, the reason as to how such phenomenon is correlated remains unknown. We have observed from published scientific literature that HSA has the potential to control cholesterol biosynthesis due to its pseudoesterase activity. In-silico observations have supported our view since acetyl coA, the precursor molecule of cholesterol biosynthesis is shown to bind with Tyr 411 of HSA. Incidentally, Tyr411 is a critical moiety for pseudoesterase activity of albumin. With this frame of reference in mind we hypothesize that pseudoesterase activity of HSA is an important determinant of lipid metabolism including cholesterol biosynthesis. Therefore, albumin has the potential to influence the atherosclerotic state important for pathogenesis of coronary artery diseases.

Detection of microalbuminuria is an analytical challenge. There are dye-based methods and immunochemical methods. However, these methods are less specific and sensitive respectively. So, people are trying new approaches for microalbuminuria detection. In this context, we have developed a fluorescent spectroscopic method to detect human serum albumin using its pseudoesterase property. Recently, we had discovered that neostigmine does not inhibit Human serum albumin pseudoesterase activity. Using such a phenomenon, we have devised a specific fluorimetric detection method of HSA using 2NA as a substrate for the pseudoesterase activity. The developed method can sense as low as 0.1 μM of HSA in the urine matrix without dye or antibody. We have proposed a scheme of automation of the proposed method.

Drug resistant pathogens are vibrant global problem. Penicillin binding protein 5 (PBP5) plays important role in bacterial cell wall biosynthesis. Mutation in PBP5 is a well-known mechanism for development of drug resistant strain of bacteria. In this context we have designed a peptide that fits better at the ligand-binding site of mutant PBP5 compared to wild type PBP5. It is expected that the designed peptide will halt the growth of drug resistant pathogen harboring mutant variety of PBP5. We have recommended experimental validation of the above concept.

Melamine adulteration of food is a public health concern. It has been seen that melamine causes disease in many organs. Melamine-induced kidney disease is a well-recognized clinicopathological entity. Inflammation is thought to be important in melamine-induced pathology. Melamine is expected to bind with albumin because it has a positive charge. Albumin binds arachidonic acid. So if binding of melamine with albumin takes place, it has the potential to displace arachidonic acid from the albumin bound state. This phenomenon may be the source of mediators of inflammation in the melamine exposure state. This aspect is investigated in the present study by docking and molecular dynamics simulation. It is observed that melamine binds with some known arachidonic acid binding sites of albumin. This can lead to formation of more free arachidonic acid. It is also observed that melamine does not bind with extracellular signal regulated kinase 2 (ERK2). Therefore, the signal transduction mediated process involving ERK2 is not a likely mechanism of melamine-induced inflammation. Therefore, we think that an increased free arachidonic acid level may contribute more to inflammation in the melamine exposure state.

Synergism in action of tucatinib and trastumab is reported in breast cancer management. However, its molecular basis is yet to be determined. In this context we attempted to provide an explanation at the molecular level by performing in silico experimentation and coupling its result with already available published observations. Our study will provide basis for planning further experimental study for unravelling the truth.

Acetylcholinesterase (AChE) is the primary target of organophosphorus pesticides (OPs). Ellman's method using Acetylthiocholine (ATCh) is the standard approach for the detection of AChE activity. Though ATCh is a popular substrate, it has certain drawbacks as well. Because of these limitations, there is a need for the development of reliable and rapid assays for determination of AChE activity in cases of OP poisoning. In the present work, we have used 1-Naphthyl acetate (1-NA) as a fluorogenic substrate for the estimation of AChE activity of human erythrocytes. It is well known that due to inter-individual variation in AChE activity, the baseline value cannot be correctly predicted. Therefore, using 1-NA, we have developed a rapid, sensitive and baseline free assay for the estimation of AChE activity. The assay is based on reactivation and fluorescence quenching using a cocktail of oximes for the determination of cholinesterase activity in a post-exposure sample. Moreover, it is free from interference due to oximolysis which is an established limitation of ATCh. We feel that such an assay using 1-NA has the potential to be explored at the point of care for rapid detection of OP poisoning.

The sudden and uncontrolled proliferation of cells is a common cause of mortality. Cancer is a multifactorial disorder which involves both exogenous and endogenous factors for initiation, promotion and progression. The interplay between genes and environment induces genetic and epigenetic alterations to cause chronic diseases including cancers. The management of cancer is far from addressing genetic and epigenetic alterations. The major limitation of current therapy is that it affects the non-targeted tissues also. In this respect, anticancer drugs which are derived from natural resources are considered as good leads for drug development. The natural products have shown anticancer activity in various types of cancer. Thus, the use of the natural product in cancer chemotherapy is gaining attention. In this chapter, the recent plant-derived secondary metabolites with potential for therapeutic management of cancer are discussed.

Cancer is the second leading cause of mortality according to the current WHO report, which states that 30–50% of cancer cases can be prevented by maintaining a healthy lifestyle. One of the ways to maintain a healthy lifestyle is by consumption of healthy food containing antioxidant molecules and enzymes. Curcumin and polyphenolic compounds are now proven as anticarcinogenic molecules. The structures of these molecules are the reason for their anticarcinogenic property. There are many compounds available in nature that may be used as anticancer or antioxidant molecules. Some of these molecules have similar chemical structures and some have different structures. Moreover, in the absence of the known 3D structure of the natural compound, design and optimization of lead molecules are based on physicochemical properties and quantitative structure activity relationships. In this chapter, ligand-based designing of naturally available anticarcinogenic molecules is discussed.

Erythrocyte acetylcholinesterase (AChE) is a preferred biomarker for the detection of organophosphorus poisoning. Acetylthiocholine (ATCh) is the most popular substrate for the detection of AChE activity. However, oximolysis is a prominent feature with ATCh. In this context, we have searched alternative substrates for AChE using in silico tools for screening of a better substrate. The in silico approach was performed to understand the fitness and the Total Interaction Energy (TIE) of substrates for AChE. The alternative substrates for AChE were screened in terms of high Goldscore and favorable TIE in comparison to acetylcholine (ACh)-AChE complex and other relevant esterases. Among the screened substrates, 1-Naphthyl acetate (1-NA) exhibited the most favorable interaction with AChE in terms of highest TIE and corresponding high Goldscore. The Molecular Dynamic (MD) simulation of the 1-NA-AChE complex showed a stable complex formation over a period of 5 ns. The results obtained in the in silico studies were validated in vitro using pure erythrocyte AChE and hemolysate. We observed 1-NA to be a better alternative substrate for AChE than ATCh in terms of lower Km value. Its specificity appeared at least similar to ATCh. Therefore, we propose that 1-NA can be an attractive chromogenic substrate for the measurement of AChE activity, and it possess the potential to detect organophosphorus pesticide (OP) poisoning.

Metformin is a popular anti-diabetic drug currently being explored for its role in cancer and gut microbiome amongst other areas. Recently, Adak T et al. explicatively reviewed metformin's effects as an anti-cancer drug and a gut microbiome modulator. We feel that the authors have not adequately addressed some of the key concerns around metformin in their report and in this correspondence, we seek to add some of the issues that need to be addressed by researchers.

Sequences in the stem-loop part of 16S ribosomal RNA (rRNA) are considered to be crucial for predicting antibiotic resistance. Mutant sequences have been reported to be helpful in the prediction of spectinomycin resistance. It is expected that such mutations alter the 16S rRNA stem-loop conformation, which affects antibiotic binding. Metagenomic database provides 16S ribosomal DNA sequences isolated from environmental samples. Using in silico tools, we observed that the existence of specific mutation does not alter the stem-loop structure of 16S rRNA along with its three-dimensional conformation. Our observation suggests that the three-dimensional structure is a better guide to understand whether a specific mutation can cause spectinomycin resistance.

Background: Hypererythropoietinemia is associated with common diseases like non-uremic anaemia where infection burden is high. Erythropoietin (EPO) is also given as therapy for anaemia associated with chronic kidney disease and cancer and in those who are at a higher risk of infections. EPO is known to have an effect on macrophages by which it helps in the growth of some intracellular pathogens. However, its direct role on bacterial growth is currently unknown. Summary: Here, we investigated the direct effect of recombinant human erythropoietin (rhuEPO) on the growth of pathogenic Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. In silico experiments were designed to gain insight into the mechanisms. We found that 30 IU/L rhuEPO promoted the growth of E. coli and S. aureus and inhibited the growth of P. aeruginosa. In silico observations suggest that bacterial cell surface proteins may interact with the EPO and may cause the observed effects. Key Message: It appears that some pathogens can explore EPO to proliferate and growth of others are inhibited by the same. The consequence of such observation is a matter of widespread concern for future research.

Tuberculosis is continuing as a problem of mankind. With evolution, MDR and XDR forms of tuberculosis have emerged from drug sensitive strain. MDR and XDR strains are resistant to most of the antibiotics, making the management more difficult. BCG vaccine is not providing complete protection against tuberculosis. Therefore new infections are spreading at a tremendous rate. At the present moment there is experimental evidence to believe that Vitamin A and Vitamin D has anti-mycobacterial property. It is in this context, we have hypothesized a host based approach using the above vitamins that can cause possible prevention and cure of tuberculosis with minimal chance of resistance or toxicity.

The scenario of tuberculosis has gone deadly due to its high prevalence and emergence of widespread drug resistance. It is now high time to develop novel antimycobacterial strategies and to understand novel mechanisms of existing antimycobacterial compounds so that we are equipped with newer tuberculosis controlling molecules in the days to come. Iron has proven to be essential for pathogenesis of tuberculosis and retinoic acid is known to influence the iron metabolism pathway. Retenoic acid is also known to exhibit antitubercular effect in in vivo system. Therefore there is every possibility that retinoic acid by affecting the iron metabolism pathway exhibits its antimycobacterial effect. These aspects are reviewed in the present manuscript for understanding the antimycobacterial role of retinoic acid in the context of iron metabolism and other immunological aspects.

Diabetes mellitus is one of the biggest challenges to human health globally, with an estimated 95% of the global diabetic population having type 2 diabetes. Classical causes for type 2 diabetes, such as genetics and obesity, do not account for the high incidence of the disease. Recent data suggest that infections may precipitate insulin resistance via multiple mechanisms, such as the proinflammatory cytokine response, the acute-phase response, and the alteration of the nutrient status. Even pathogen products, such as lipopolysaccharide and peptidoglycans, can be diabetogenic. Therefore, we argue that infections that are known to contribute to insulin resistance should be considered as risk factors for type 2 diabetes.

Prediabetic individuals are characterized by high levels of insulin, an anabolic hormone having an important role in the maintenance of glucose homeostasis. However, insulin has also been found to increase the growth of certain bacteria which form the non-butyrate producing part of the gut microbiome. The gut microbiome is recently in focus for its strong association with many chronic diseases such as type 2 diabetes mellitus and obesity. Metformin, a widely popular anti-diabetic medication has been shown to prevent weight gain in many trials. There are many studies postulating the mechanisms of the anti-obesity effect of metformin including improvement in insulin sensitivity (and consequently a reduction in insulin levels). Recently, however, it is becoming evident that metformin's action is likely to be primarily mediated by the gut. Further, metformin has also shown to affect the growth characteristics of certain bacteria which form the part of the human gut microbiome. With this frame of reference in mind, we hypothesize that metformin is likely to exert its anti-obesity effect by altering the composition of the gut microbiome. If proved, this has the potential to contribute to the management of obesity and pave the way for the development of novel anti-obesity drugs.

Food adulteration is a curse for mankind. It has been happening since times immemorial and continuing in the recent times. To control such problems, various technologies have been developed. In the present work, the detection methods of food adulteration are reviewed with a focus on detection of common food adulterants.