Antimicrobial resistance: new insights and therapeutic implications.

Antimicrobial resistance has not been a new phenomenon. Still, the number of resistant organisms, the geographic areas affected by emerging drug resistance, and the magnitude of resistance in a single organism are enormous and mounting. Disease and disease-causing agents formerly thought to be contained by antibiotics are now returning in new forms resistant to existing therapies. Antimicrobial resistance is one of the most severe and complicated health issues globally, driven by interrelated dynamics in humans, animals, and environmental health sectors. Coupled with various epidemiological factors and a limited pipeline for new antimicrobials, all these misappropriations allow the transmission of drug-resistant organisms. The problem is likely to worsen soon. Antimicrobial resistance in general and antibiotic resistance in particular is a shared global problem. Actions taken by any single country can adversely or positively affect the other country. Targeted coordination and prevention strategies are critical in stopping the spread of antibiotic-resistant organisms and hence its overall management. This article has provided in-depth knowledge about various methods that can help mitigate the emergence and spread of antimicrobial resistance globally. KEY POINTS: • Overview of antimicrobial resistance as a global challenge and explain various reasons for its rapid progression. • Brief about the intrinsic and acquired resistance to antimicrobials and development of antibiotic resistance in bacteria. • Systematically organized information is provided on different strategies for tackling antimicrobial resistance for the welfare of human health.

Metabolite fingerprinting of phytoconstituents from Fritillaria cirrhosa D. Don and molecular docking analysis of bioactive peonidin with microbial drug target proteins.

Fritillaria cirrhosa D. Don (Liliaceae), a valuable and critically endangered medicinal herb of northwest India, including Jammu and Kashmir, grows in temperate to alpine regions of the Himalaya. It is known as the traditional herb for cardiovascular diseases, respiratory diseases, and metabolic disorders. The plant bulbs are precious and are used to cure many other health complications. The current study analysed the phytoconstituents by liquid chromatography-mass spectrometry (LC-MS) of different crude extracts (methanolic, petroleum ether, and ethyl acetate) of F. cirrhosa. The LC-MS analysis from the bulbs of F. cirrhosa yielded 88 bioactive compounds, with the vast majority having therapeutic applications. Further, determination of minimum inhibitory concentrations (MICs) by broth microdilution method of F. cirrhosa against tested bacterial and fungal pathogens showed remarkable results with MICs ranging between 6.25-200 µg/mL and 50-400 µg/mL, respectively. Subsequently, these 88 identified phytocompounds were tested for their bioactivity through ADMET prediction by SwissADME and in silico molecular docking studies. Results revealed that Peonidin might have maximum antibacterial and antifungal activity against various microbial protein drug targets among the phytochemical compounds identified. Furthermore, the highest binding affinity complex was subjected to molecular dynamic simulation (MDS) analysis using Desmond Schrodinger v3.8. The root-mean-square deviation (RMSD) graphs obtained through the molecular dynamic simulations indicated the true bonding interactions, further validated using the root-mean-square fluctuation (RMSF) graphs which provided a better understanding of the amino acids present in the proteins responsible for the molecular motions and fluctuations. To our best knowledge, this is the first description of the phytochemical constituents of the bulbs of F.cirrhosa analyzed through LC-MS, which show pharmacological significance. The in silico molecular docking and molecular dynamics study of peonidin was also performed to confirm its broad-spectrum activities based on the binding interactions with the antibacterial and antifungal target proteins. The present study results will create a way for the invention of herbal medicines for several ailments by using F. cirrhosa plants, which may lead to the development of novel drugs.

In vitro and in silico evaluation of antimicrobial properties of Delphinium cashmerianum L., a medicinal herb growing in Kashmir, India.

ETHNOPHARMACOLOGICAL RELEVANCE: Microorganisms are developing resistance to synthetic drugs. As a result, the search for novel antimicrobial compounds has become an urgent need. Medicinal plants are commonly used as traditional medicine and Delphinium is one of the prominent genus used in the treatment of several diseases. AIM OF THE STUDY: The present study aimed to determine the in vitro and in silico antimicrobial activities of petroleum ether, ethyl acetate and methanol extracts from the leaf samples of plant (Delphinium cashmerianum L.) against various bacterial and fungal strains. MATERIAL AND METHODS: Three extracts of Delphinium cashmerianum prepared and 88 bioactive compounds were analyzed through LC-MS data with the vast majority of them having therapeutic applications. These extracts have been screened for the antimicrobial activity against various bacterial (Escherichia coli, Micrococcus luteus, Klebsiella pneumoniae, Streptococcus pneumonia, Haemophilus influenzae, Neisseria mucosa) and fungal (Candida albicans, Candida glabrata, Candida paropsilosis) species through in silico molecular docking approach using autodock vina software, molecular dynamic simulation (MDS), in vitro disc diffusion and broth microdilution method for minimum inhibitory concentration (MIC) evaluation. RESULTS: Our results demonstrated that all three extracts were active against the whole set of microorganisms. The ethyl acetate extract was the most active against S.pneumonia, K. pneumoniae and C. albicans with a minimum inhibitory concentration (MIC) value of 6.25, 25 and 50 µg/ml, respectively. The petroleum ether and methanol extracts were active against S.pneumonia and N.mucosa with MIC values of 25 and 50 µg/ml. Furthermore, we also performed the in silico virtual screening of all these compounds obtained from LC-MS data analysis against various known drug targets of bacterium and fungi. Upon analysis, we obtained 5 compounds that were efficiently binding to the drug targets. However, after performing exhaustive molecular docking and molecular dynamic simulation (MDS) analysis, it was observed that Daidzein compound is bound to drug targets more efficiently. CONCLUSION: The results showed that these plant extracts exhibit antimicrobial activity and ethyl acetate extract proved to exhibit the most effective antibacterial and antifungal properties.

Microbiome dysbiosis and epigenetic modulations in lung cancer: From pathogenesis to therapy.

The lung microbiome plays an essential role in maintaining healthy lung function, including host immune homeostasis. Lung microbial dysbiosis or disruption of the gut-lung axis can contribute to lung carcinogenesis by causing DNA damage, inducing genomic instability, or altering the host's susceptibility to carcinogenic insults. Thus far, most studies have reported the association of microbial composition in lung cancer. Mechanistic studies describing host-microbe interactions in promoting lung carcinogenesis are limited. Considering cancer as a multifaceted disease where epigenetic dysregulation plays a critical role, epigenetic modifying potentials of microbial metabolites and toxins and their roles in lung tumorigenesis are not well studied. The current review explains microbial dysbiosis and epigenetic aberrations in lung cancer and potential therapeutic opportunities.

Nanobodies: The "Magic Bullets" in therapeutics, drug delivery and diagnostics.

Antibodies represent a well-established class of clinical diagnostics for medical applications as well as essential research and biotechnological tools. Although both polyclonal and monoclonal antibodies are indispensable reagents in basic research and diagnostics but both of them have their limitations. Hence, there is urgent need to develop strategies aimed at production of alternative scaffolds and recombinant antibodies of smaller dimensions that could be easily produced, selected and manipulated. Unlike conventional antibodies, members of Camelidae and sharks produce antibodies composed only of heavy chains with small size, high solubility, thermal stability, refolding capacity and good tissue penetration in vivo. The discovery of these naturally occurring antibodies having only heavy-chain in Camelidae family and their further development into small recombinant nanobodies represents an attractive alternative in drug delivery, diagnostics and imaging. Nanobody derivatives are soluble, stable, versatile, have unique refolding capacities, reduced aggregation tendencies and high-target binding capabilities. They can be genetically customized to target enzymes, transmembrane proteins or molecular interactions. Their ability to recognize recessed antigenic sites has been attributed to their smaller size and the ability of the extended CDR3 loop to quickly penetrate into such epitopes. With the advent of molecular engineering and phage display technology, they can be of potential use in molecular imaging, drug delivery and therapeutics for several major diseases. In this review we present the recent advances in nanobodies for modulating immune functions, for targeting cancers, viruses, toxins and microbes as well as their utility as diagnostic and biosensor tools.

Trans-anethole, a terpenoid ameliorates hyperglycemia by regulating key enzymes of carbohydrate metabolism in streptozotocin induced diabetic rats.

Trans-anethole (TA), a terpenoid and a principle constituent of many essential oils from medicinal plants possess hypoglycemic and antioxidant activities. This study was undertaken to explore beneficial effects of TA on key enzymes of carbohydrate metabolism in streptozotocin (STZ)-induced type 2 diabetic rats. Diabetes was induced in male albino Wistar rats by intraperitoneal administration of STZ (40 mg/kg BW). TA was administered to diabetic rats at a dose of 20, 40 and 80 mg/kg BW for 45 days. However, the dose at 80 mg/kg BW, resulted in a significant reduction in the levels of plasma glucose, glycosylated haemoglobin (HbA1c) and increase in the levels of insulin and haemoglobin (Hb). Upon administration of TA, the altered levels of liver glycolytic enzyme (hexokinase), hepatic shunt enzyme (glucose-6-phosphate dehydrogenase) and gluconeogenic enzymes (glucose-6-phosphatase and fructose-1,6-bisphosphatase) in the liver and kidney of diabetic rats significantly reverted to near normal levels. In addition to this, TA also improved the hepatic and muscle glycogen content in diabetic rats. The histological studies showed the ameliorative effect of TA on the ß-cells of pancreas in diabetic rats. The results were compared with glibenclamide, a standard oral hypoglycemic drug. These encouraging findings suggest that TA may be used as a propitious bioactive compound in the development of therapeutic agents against type 2 diabetes mellitus.

Tyrosol, a phenolic compound, ameliorates hyperglycemia by regulating key enzymes of carbohydrate metabolism in streptozotocin induced diabetic rats.

The present study was designed to evaluate the effects of tyrosol, a phenolic compound, on the activities of key enzymes of carbohydrate metabolism in the control and streptozotocin-induced diabetic rats. Diabetes mellitus was induced in rats by a single intraperitoneal injection of streptozotocin (40 mg/kg body weight). Experimental rats were administered tyrosol 1 ml intra gastrically at the doses of 5, 10 and 20mg/kg body weight and glibenclamide 1 ml at a dose of 600 µg/kg body weight once a day for 45 days. At the end of the experimental period, diabetic control rats exhibited significant (p<0.05) increase in plasma glucose, glycosylated hemoglobin with significant (p<0.05) decrease in plasma insulin, total hemoglobin and body weight. The activities of key enzymes of carbohydrate metabolism such as phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase were significantly (p<0.05) increased and the activities of hexokinase and glucose-6-phosphate dehydrogenase were significantly (p<0.05) decreased in the liver and kidney of diabetic control rats. Further, antioxidants were lowered in diabetic control rats. A significant (p<0.05) decline in glycogen level in the liver and muscle and glycogen synthase activity in the liver and a significant (p<0.05) increase in the activity of liver glycogen phosphorylase were observed in diabetic control rats compared to normal control rats. Oral administration of tyrosol to diabetic rats reversed all the above mentioned biochemical parameters to near normal in a dose dependent manner. Tyrosol at a dose of 20mg/kg body weight showed the highest significant effect than the other two doses. Immunohistochemical staining of pancreas revealed that tyrosol treated diabetic rats showed increased insulin immunoreactive ß-cells, which confirmed the biochemical findings. The observed results were compared with glibenclamide, a standard oral hypoglycemic drug. The results of the present study suggest that tyrosol decreases hyperglycemia, by its antioxidant effect.

Histopathological findings of the pancreas, liver, and carbohydrate metabolizing enzymes in STZ-induced diabetic rats improved by administration of myrtenal

This study aims to evaluate the efficacy of myrtenal, a natural monoterpene, for its antihyperglycemic effects and beta cell protective properties in streptozotocin (STZ)-induced diabetic rats. Oral administration of myrtenal at doses of 20, 40, and 80 mg/kg body weight to diabetic rats for 28 days resulted in a significant reduction (P < 0.05) in the levels of plasma glucose, glycosylated hemoglobin (HbA1c), and an increase in the levels of insulin and hemoglobin (Hb). Protection of body weight loss of diabetic rats by myrtenal was noted. The altered activities of the key metabolic enzymes involved in carbohydrate metabolism such as hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, and hepatic enzymes AST, ALT, and ALP levels of diabetic rats were significantly improved by the administration of myrtenal in STZ-induced diabetic rats. Moreover, myrtenal treatment improved hepatic and muscle glycogen content in diabetic rats. Histopathological studies further revealed that the reduced islet cells were restored to near-normal conditions on treatment with myrtenal in STZ-induced diabetic rats. An alteration in liver architecture was also prevented by myrtenal treatment. Our results suggest that myrtenal possess antihyperglycemic and beta cell protective effects. Hence, myrtenal could be considered as a potent phytochemical for development as a new antidiabetic agent (AU)

Histopathological findings of the pancreas, liver, and carbohydrate metabolizing enzymes in STZ-induced diabetic rats improved by administration of myrtenal.

This study aims to evaluate the efficacy of myrtenal, a natural monoterpene, for its antihyperglycemic effects and ß cell protective properties in streptozotocin (STZ)-induced diabetic rats. Oral administration of myrtenal at doses of 20, 40, and 80 mg/kg body weight to diabetic rats for 28 days resulted in a significant reduction (P < 0.05) in the levels of plasma glucose, glycosylated hemoglobin (HbA1c), and an increase in the levels of insulin and hemoglobin (Hb). Protection of body weight loss of diabetic rats by myrtenal was noted. The altered activities of the key metabolic enzymes involved in carbohydrate metabolism such as hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, and hepatic enzymes AST, ALT, and ALP levels of diabetic rats were significantly improved by the administration of myrtenal in STZ-induced diabetic rats. Moreover, myrtenal treatment improved hepatic and muscle glycogen content in diabetic rats. Histopathological studies further revealed that the reduced islet cells were restored to near-normal conditions on treatment with myrtenal in STZ-induced diabetic rats. An alteration in liver architecture was also prevented by myrtenal treatment. Our results suggest that myrtenal possess antihyperglycemic and ß cell protective effects. Hence, myrtenal could be considered as a potent phytochemical for development as a new antidiabetic agent.