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Alteration of gut microbiota and microbial metabolites such as short-chain fatty acids (SCFAs) coexisted with stress-generated brain disorders, including depression. Herein, we investigated the effect of SCFAs in a treatment-resistant depression (TRD) model of rat. Rats were exposed to chronic-unpredictable mild stress (CUMS) and repeated adrenocorticotropic hormone (ACTH) injections to generate a TRD-like phenotype. The cecal contents of these animals were engrafted into healthy-recipient rats and allowed to colonize for 4 weeks (TRD-FMT group). Blood, brain, colon, fecal, and cecal samples were collected for molecular studies. Rats exposed to CUMS + ACTH showed TRD-like phenotypes in sucrose-preference (SPT), forced swim (FST), and elevated plus maze (EPM) tests. The TRD-FMT group also exhibited anxiety- and depression-like behaviors. Administration of SCFAs (acetate, propionate, and butyrate at 67.5, 25, and 40 mM, respectively) for 7 days exerted robust antidepressant and antianxiety effects by restoring the levels of SCFAs in plasma and fecal samples, and proinflammatory cytokines (TNF-α and IL-6), serotonin, GABA, norepinephrine, and dopamine in the hippocampus and/or frontal cortex of TRD and TRD-FMT animals. SCFAs treatment elevated the expression of free-fatty acid receptors 2/3, BDNF, doublecortin, and zonula-occludens, and reduced the elevated plasma levels of kynurenine and quinolinic acid and increased mucus-producing goblet cells in TRD and TRD-FMT animals. In 16S sequencing results, decreased microbial diversity in TRD rats corresponds with differences in the genus of Faecalibacterium, Anaerostipes, Allobaculum, Blautia, Peptococcus, Rombustia, Ruminococcaceae_UCG-014, Ruminococcaceae_UCG-002, Solobacterium, Subdolibacterium, and Eubacterium ventriosum. SCFAs may impart beneficial effects via modulation of tryptophan metabolism, inflammation, neurotransmitters, and microbiota-gut-brain axis in TRD rats.

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Cancer diagnoses have been increasing worldwide, and solid tumors are among the leading contributors to patient mortality, creating an enormous burden on the global healthcare system. Cancer is responsible for around 10.3 million deaths worldwide. Solid tumors are one of the most prevalent cancers observed in recent times. On the other hand, early diagnosis is a significant challenge that could save a person's life. Treatment with existing methods has pitfalls that limit the successful elimination of the disorder. Though nanoparticle-based imaging and therapeutics have shown a significant impact in healthcare, current methodologies for solid tumor treatment are insufficient. There are multiple complications associated with the diagnosis and management of solid tumors as well. Recently, surface-conjugated nanoparticles such as lipid nanoparticles, metallic nanoparticles, and quantum dots have shown positive results in solid tumor diagnostics and therapeutics in preclinical models. Other nanotheranostic material platforms such as plasmonic theranostics, magnetotheranostics, hybrid nanotheranostics, and graphene theranostics have also been explored. These nanoparticle theranostics ensure the appropriate targeting of tumors along with selective delivery of cargos (both imaging and therapeutic probes) without affecting the surrounding healthy tissues. Though they have multiple applications, nanoparticles still possess numerous limitations that need to be addressed in order to be fully utilized in the clinic. In this review, we outline the importance of materials and design strategies used to engineer nanoparticles in the treatment and diagnosis of solid tumors and how effectively each method overcomes the drawbacks of the current techniques. We also highlight the gaps in each material platform and how design considerations can address their limitations in future research directions.

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The urgent development of newer alternatives has been deemed a panacea for tackling emerging antimicrobial resistance effectively. Herein, we report the design, synthesis, and biological evaluation of 1,3-diaryl substituted pyrazole-based urea and thiourea derivatives as antimicrobial agents. Preliminary screening results revealed that compound 7a (3,4-dichlorophenyl derivative) exhibited potent activity against S. aureus (MIC = 0.25 µg mL-1) and compound 7j (2,4-difluorophenyl derivative) against Mycobacterium tuberculosis (MIC = 1 µg mL-1). Compounds 7a and 7j were non-toxic to Vero cells with a favorable selectivity index of 40 and 200, respectively, and demonstrated good microsomal stability. Compound 7a exhibited equipotent activity (MIC = 0.25 µg mL-1) against various multidrug-resistant strains of S. aureus, which include various strains of MRSA and VRSA, and elicited bacteriostatic properties. In an enzymatic assay, 7a effectively inhibited DNA gyrase supercoiling activity at a concentration of 8 times MIC. Further, molecular modeling studies suggested that compound 7a binds at the active site of DNA gyrase with good affinity.

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INTRODUCTION: The COVID-19 outbreak has put enormous pressure on the scientific community to detect infection rapidly, identify the status of disease severity, and provide an immediate vaccine/drug for the treatment. Relying on immunoassay and a real-time reverse transcription polymerase chain reaction (rRT-PCR) led to many false-negative and false-positive reports. Therefore, detecting biomarkers is an alternative and reliable approach for determining the infection, its severity, and disease progression. Recent advances in liquid chromatography and mass spectrometry (LC-MS/MS) enable the protein biomarkers even at low concentrations, thus facilitating clinicians to monitor the treatment in hospitals. AREAS COVERED: This review highlights the role of LC-MS/MS in identifying protein biomarkers and discusses the clinically significant protein biomarkers such as Serum amyloid A, Interleukin-6, C-Reactive Protein, Lactate dehydrogenase, D-dimer, cardiac troponin, ferritin, Alanine transaminase, Aspartate transaminase, gelsolin and galectin-3-binding protein in COVID-19, and their analysis by LC-MS/MS in the early stage. EXPERT OPINION: Clinical doctors monitor significant biomarkers to understand, stratify, and treat patients according to disease severity. Knowledge of clinically significant COVID-19 protein biomarkers is critical not only for COVID-19 caused by the coronavirus but also to prepare us for future pandemics of other diseases in detecting by LC-MS/MS at the early stages.

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BACKGROUND: Due to the rising cases of treatment-refractory affective disorders, the discovery of newer therapeutic approaches is needed. In recent times, probiotics have garnered notable attention in managing stress-related disorders. Herein, we examined the effect of Bacillus coagulans Unique IS-2® probiotic on anxiety- and depression-like phenotypes employing maternal separation (MS) and chronic-unpredictable mild stress (CUMS) model in rats. METHODS: Both male and female Sprague-Dawley rats were subjected to MS + CUMS. Probiotic treatment was provided for 6 weeks via drinking water. Anxiety- and depression-like phenotypes were assessed using sucrose-preference test (SPT), forced-swimming test (FST), elevated-plus maze test (EPM), and open-field test (OFT). Blood, brain, intestine, and fecal samples were obtained for biochemical and molecular studies. RESULTS: Stress-exposed rats drank less sucrose solution, showed increased passivity, and explored less in open-arms in SPT, FST, and EPM, respectively. These stress-generated neurobehavioral aberrations were alleviated by 6-week of Bacillus coagulans Unique IS-2 treatment. The overall locomotor activity in OFT remained unchanged. The decreased levels of BDNF and serotonin and increased levels of C-reactive protein, TNF-α, IL-1ß, and dopamine, in the hippocampus and/or frontal cortex of stress-exposed rats were reversed following probiotic treatment. Administration of probiotic also restored the systemic levels of L-tryptophan, L-kynurenine, kynurenic-acid, and 3-hydroxyanthranilic acid, villi/crypt ratio, goblet-cell count, Firmicutes to Bacteroides ratio, and levels of acetate, propionate, and butyrate in fecal samples. These results indicate remodeling of the microbiome gut-brain axis in Bacillus coagulans Unique IS-2 recipient rats. However, protein levels of doublecortin, GFAP, and zona occludens in the hippocampus and occludin-immunoreactivity in the intestine remained unchanged. No prominent sex-specific changes were noted. CONCLUSION: Anxiolytic- and antidepressant-like effects of Bacillus coagulans Unique IS-2 in MS + CUMS rat model may be mediated via reshaping the microbiome gut-brain axis.

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Aldehyde oxidase (AO) has garnered curiosity as a non-CYP metabolizing enzyme in drug development due to unexpected consequences such as toxic metabolite generation and high metabolic clearance resulting in the clinical failure of new drugs. Therefore, poor AO mediated clearance prediction in preclinical nonhuman species remains a significant obstacle in developing novel drugs. Various isoforms of AO, such as AOX1, AOX3, AOX3L1, and AOX4 exist across species, and different AO activity among humans influences the AO mediated drug metabolism. Therefore, carefully considering the unique challenges is essential in developing successful AO substrate drugs. The in vitro to in vivo extrapolation underpredicts AO mediated drug clearance due to the lack of reliable representative animal models, substrate-specific activity, and the discrepancy between absolute concentration and activity. An in vitro tool to extrapolate in vivo clearance using a yard-stick approach is provided to address the underprediction of AO mediated drug clearance. This approach uses a range of well-known AO drug substrates as calibrators for qualitative scaling new drugs into low, medium, or high clearance category drugs. So far, in vivo investigations on chimeric mice with humanized livers (humanized mice) have predicted AO mediated metabolism to the best extent. This review addresses the critical aspects of the drug discovery stage for AO metabolism studies, challenges faced in drug development, approaches to tackle AO mediated drug clearance's underprediction, and strategies to decrease the AO metabolism of drugs.

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Depression is a debilitating mental disorder that affects >322 million people worldwide. Despite the availability of several antidepressant agents, many patients remain treatment refractory. A growing literature study has indicated the role of gut microbiota in neuropsychiatric disorders. Herein, we examined the psychobiotic-like activity of multi-strain probiotic formulation in maternal separation (MS) and chronic unpredictable mild stress (CUMS) models of anxiety- and depression-like phenotypes in Sprague-Dawley rats. Early- and late-life stress was employed in both male and female rats by exposing them to MS and CUMS. The multi-strain probiotic formulation (Cognisol) containing Bacillus coagulans Unique IS-2, Lactobacillus plantarum UBLP-40, Lactobacillus rhamnosus UBLR-58, Bifidobacterium lactis UBBLa-70, Bifidobacterium breve UBBr-01, and Bifidobacterium infantis UBBI-01 at a total strength of 10 billion cfu along with l-glutamine was administered for 6 weeks via drinking water. Neurobehavioral assessment was done using the forced swim test (FST), sucrose preference test (SPT), elevated plus maze (EPM), and open field test (OFT). Animals were sacrificed after behavioral assessment, and blood, brain, and intestine samples were collected to analyze the levels of cytokines, metabolites, and neurotransmitters and histology. Animals exposed to stress showed increased passivity, consumed less sucrose solution, and minimally explored the open arms in the FST, SPT, and EPM, respectively. Administration of multi-strain probiotics along with l-glutamine for 6 weeks ameliorated the behavioral abnormalities. The locomotor activity of animals in the OFT and their body weight remained unchanged across the groups. Cognisol treatment reversed the decreased BDNF and serotonin levels and increased CRP, TNF-α, and dopamine levels in the hippocampus and/or frontal cortex. Administration of Cognisol also restored the plasma levels of l-tryptophan, l-kynurenine, kynurenic-acid, and 3-hydroxyanthranilic acid; the Firmicutes-to-Bacteroides ratio; the levels of acetate, propionate, and butyrate in fecal samples; the villi/crypt ratio; and the goblet cell count, which manifested in the restoration of intestinal functions. We suggest that the multi-strain probiotic and glutamine formulation (Cognisol) ameliorated the MS + UCMS-generated anxiety- and depression-like phenotypes by reshaping the gut microbiome-brain activity in both sexes.

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Knowledge of the metabolic stability of a new drug substance eliminated by biotransformation is essential for envisaging the pharmacokinetic parameters required for deciding drug dosing and frequency. Strategies aimed at modifying lead compounds may improve metabolic stability, thereby reducing the drug dosing frequency. Replacement of selective hydrogens with deuterium can effectively enhance the drug's metabolic stability by increasing the biological half-life. Further, cyclization, change in ring size, and chirality can substantially improve the metabolic stability of drugs. The microsomal t1/2 approach for measuring drug in vitro intrinsic clearance by automated LC-MS/MS offers sensitive high-throughput screens with reliable data. The obtained in vitro intrinsic clearance from metabolic stability data helps predict the drug's in vivo total clearance using different scaling factors and hepatic clearance models. This review summarizes all the recent approaches and technological advancements in metabolic stability studies for narrowing down the potential lead compounds in drug discovery. Further, we summarized the potential pitfalls and assumptions made during the in vivo intrinsic clearance estimation from in vitro intrinsic clearance.

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