Identification of Phialomustin‑B (PHL-B) as a Novel Natural TRPA1 Channel Inhibitor.

The TRPA1 channel has recently emerged as a critical target for pain relief since its antagonists target the beginning of the pain transduction pathway and, thus, are devoid of side effects such as sedation, dizziness, somnolence, or cognitive impairment. Despite this clinical significance, currently, no TRPA1 inhibitors suitable for therapeutic usage exist to target these channels. Since ancient times, natural products have been known to be a rich source of new drugs, useful therapeutic agents, as well as pharmacological tools.

Diverse chemotypes of polyketides as promising antimicrobial agents: latest progress.

Microorganisms, including bacteria, viruses, fungi, and protozoa, significantly impact human health by causing infections that can lead to serious health issues, including mortality and morbidity. Antimicrobials, including antibacterials, anti-virals, anti-fungals, and anti-parasitics, effectively prevent and treat infections in humans and animals. However, pathogens have developed resistance to these antimicrobials, enabling them to survive and persist even in the presence of antibiotics.

Inhibition of Mycobacterium tuberculosis UvrB by small molecules: Potent NER disruption and structural insights into dimer conformation.

The nucleotide excision repair (NER) pathway in Mycobacterium tuberculosis (Mtb) is important for DNA damage repair and bacterial survival under stress, yet specific inhibitors targeting its components remain scarce. Here, we targeted the UvrB protein, a central component of the Mtb UvrABC NER pathway, and identified novel small molecule inhibitors against its nucleotide binding domain (NBD). Using in silico structure-based screening involving the Maybridge library (~54,000 compounds), Molecular dynamics (MD) simulations, and Biolayer interferometry (BLI), we identified four potent inhibitors: SPB08143, RJC04069, NRB00936, and DP00786 with IC50 values of 9.

RNAi of mitochondrial sirtuin, sir-2.2 reduces alpha-synuclein clearance and impairs energy homeostasis in C. elegans.

Mitochondria are the regulators of energy production and play a vital role in modulating ageing and age-associated diseases. We investigated the role of sirtuins, a well-studied class of longevity-associated proteins (NAD+-dependent histone deacetylases), in mitochondrial biology and Parkinson's disease pathology. In particular, we endeavored to study the functional implications of mitochondrial sirtuin, sir-2.

The Emergence of Bioactive Peptides as Anti-diabetic Agents: A Review.

A complex condition called diabetes mellitus is characterized by insufficient or resistant insulin production. The incidence of diseases is rising quickly, placing a significant economic, social, and health burden on the modern world. Interventions in nutrition and improved physical activity could make a big difference in controlling this disease.

Comprehensive biological evaluation of Rheinal as a potent antimicrobial, alone and in combination with gentamicin and minocycline targeting MDR S. aureus in vitro and in vivo.

Antimicrobial resistance is recognized as a threat to healthcare systems worldwide and consequently, discovery and development of new antimicrobials is a top priority. Natural products and their derivatives have historically been an excellent source of antimicrobials. In this context, anti-bacterial activity of synthesized natural product derivative, Rheinal, was assessed against a panel of Gram-positive and Gram-negative bacterial pathogens where it exhibited potent bactericidal activity against S.

Human sclerostin-inspired short peptides reverse osteoporosis and suppress joint degeneration in osteoarthritis via opposing Wnt pathways.

Sclerostin, a key regulator of Wnt/β-catenin signaling, exhibits dual therapeutic potential in bone disorders: its inhibition promotes bone formation in osteoporosis, while its mimicry suppresses aberrant bone growth in osteoarthritis (OA). Using structural insights from NMR studies, we identified two sclerostin-derived peptides: SC-1 (an 18-mer) from loop 2, and SC-3 (a 14-mer) from loop 3. Molecular modeling showed that SC-1 binds to the first ectodomain of LRP6, potentially displacing sclerostin through competitive inhibition to activate Wnt signaling.

Harnessing the power of α-diazo compounds: emerging strategies and expanding applications.

α-Diazo compounds have long been recognized as versatile reagents in organic synthesis, traditionally employed in metallocarbene chemistry. Recent advances have expanded their scope beyond conventional carbene-based transformations, leading to diverse applications in heterocycle synthesis and functionalization strategies. This review highlights the evolution of α-diazo compounds as key reagents in modern synthetic methodologies, focusing on their unique reactivity patterns, including cycloadditions, homologations, ring expansions, and carbene-free functionalizations.

Kyasanur Forest Disease Virus: Epidemiological Insights, Pathogenesis, Therapeutic Strategies, and Advances in Vaccines and Diagnostics.

Kyasanur Forest disease virus (KFDV), a tick-borne Orthoflavivirus endemic to the Indian subcontinent, is a public health threat due to its recurrent outbreaks and expanding geographic range. This review provides a comprehensive overview of KFDV, encompassing its epidemiological trends, transmission dynamics, and ecological determinants that influence its spread. We delve into the current understanding of KFDV pathogenesis, highlighting key viral and host factors that drive infection and disease progression.

IGSF11-Mediated Immune Modulation: Unlocking a Novel Pathway in Emerging Cancer Immunotherapies.

Immunoglobulin superfamily member 11 (IGSF11) has recently emerged as a critical immune checkpoint ligand that interacts with the V-domain immunoglobulin suppressor of T-cell activation (VISTA) receptor to inhibit T-cell activation and promote immune escape. Preclinical studies have demonstrated that targeting the IGSF11-VISTA axis effectively reverses immunosuppression by enhancing T-cell effector functions and increasing the secretion of prostimulatory cytokines such as IFN-γ. This immune modulation shifts the tumor microenvironment from an immune "cold" state, characterized by low immune infiltration and activity, to a more immunoreactive "hot" state that is more susceptible to immune-mediated destruction.

Chondroitin Sulfate-Mediated Targeted Delivery of Docetaxel and Silibinin-Loaded Nanoparticles for Amelioration of Anticancer Efficacy in Breast Cancer.

Breast cancer is the second leading cause of mortality in women worldwide. Chemotherapeutic drugs like docetaxel (DTX) remain key molecules in cancer management. Silibinin (SLB) is an effective agent causing apoptosis and autophagy resulting in cancer cell death.

LC-MS/MS method for co-estimation of doxorubicin and piperine: formulation development and pharmacokinetic studies.

Introduction: Oral metronomic chemotherapy employs a low-dose combination of chemotherapeutics administered regularly to minimize toxicity while enhancing anticancer efficacy. The clinical utility of Doxorubicin (DOX) is limited due to severe cardiotoxicity. Interestingly, Piperine (PIP) has been explored to mitigate DOX-induced toxicity while enhancing its therapeutic efficacy.

Alectinib Synthesis through Formal α-Arylation of Enone.

A new synthetic route for the synthesis of Alectinib, which is used as an adjuvant and first line of treatment in ALK-positive non-small cell lung cancer, is reported. The developed route starts from readily available starting materials (4-(4-methoxyphenyl)butyric acid or 2-ethyl anisole) and employs Suzuki-Miyaura cross-coupling and reductive cyclization as key steps. Good yield and no regioisomeric mixture formation are the key highlights of this route.

Leveraging RAS-mSIN1 interaction to selectively inhibit mTORC2 employing competitive RAS binding peptide: implications in breast cancer metastasis.

The pivotal role of mTORC2 in cancer progression and metastasis underscores its potential as drug target. Despite this, selective inhibition of mTORC2 without affecting mTORC1 represents an unmet need in cancer therapy. We aimed to exploit RAS-mSIN1 interaction for selective mTORC2 targeting.

Comparative Profiling of Withanolides in Tissues of Withania somnifera and Datura metel Using UHPLC-MS/MS.

Withania somnifera and Datura metel, two medicinally significant members of the Solanaceae family, are known for their content of pharmacologically active withanolides. This study investigates the structural diversity and tissue-specific distribution of withanolides in these species using UHPLC-tandem mass spectrometry (MS/MS). Identified 36 distinct withanolides based on characteristic MS/MS fragmentation patterns and accurate mass measurements.

Pseudo-Infection Model: A Bottom-Up Synthetic Approach to Cellular Entry of Enveloped Viruses and Virus Mimics.

Viruses are the most abundant biological entities on Earth. They function as obligate intracellular parasites across all three domains of life. Enveloped viruses, which are surrounded by a lipid membrane, are known to cause significant pandemics and epidemics.

Hydrogen Sulfide-Releasing Insulin Polypeptide Mitigates Hyperglycemia-Induced Neurotoxicity and Cognitive Deficits .

Hyperglycemia, a characteristic of diabetes, is increasingly associated with an elevated risk of neurodegenerative disorders, such as Parkinson's disease. Hyperglycemia serves as a comorbidity and hastens neurodegenerative processes in Parkinson's disease. We report the development of HS-releasing human insulin polypeptide (SHI), which will colocalize metabolic release of HS near insulin action, and a thorough investigation of their combined efficacy in mitigating Parkinson's disease and hyperglycemia-associated symptoms.

Missense Variants Disrupt Polycomb Repression and Enable Ectopic Mesenchymal Lineage Conversion During Human Neural Differentiation.

Polycomb Repressive Complex 1 (PRC1) catalyzes H2AK119ub1 to facilitate transcriptional repression during development. dominant missense variants in , the principal E3 ligase of PRC1, are the genetic basis of Luo-Schoch-Yamamoto syndrome. To investigate the developmental impact of catalytically impaired RNF2 alleles, we engineered hESC lines harboring homozygous hypomorphic missense alleles ( ) that stably expresses RNF2 but results in reduced H2AK119ub1.

Cupressuflavone Isolated from Cupressus torulosa Ameliorates Diabetic Nephropathy by Inhibiting Oxidative Stress and Inflammation Through Nrf-2/NF-κB Signalling Axis.

Cupressuflavone (CTM-01), a potential biflavonoid isolated from exhibited antimicrobial, analgesic, cytotoxic and wound-healing properties. The present study aims to evaluate the renoprotective effects through and models as well as elucidate the underlying mechanisms of its nephroprotective action under diabetic conditions. The effects of CTM-01 on cell viability (25, 50, and 100 µM) and intracellular ROS production were evaluated in cultured normal rat proximal epithelial cells (NRK-52E) grown under high glucose conditions (30 mM) while streptozotocin (STZ) induced rats were treated with CTM-01 at 25 mg/kg for four weeks and the effects on different biochemical, histological, and molecular parameters were studied.

Exploration of New Dihydroindazole Derivatives as Promising Anti-TB Agents: Design, Synthesis, In Silico, and Biological Evaluation.

The escalating threat of drug-resistant Mycobacterium tuberculosis (Mtb) necessitates the discovery of novel chemotherapeutic agents. In this study, a series of dihydroindazole-based derivatives were designed, synthesized, and evaluated for their antimycobacterial potential. Among the synthesized compounds, 8u exhibited the most potent in vitro activity against Mtb HRv with a minimum inhibitory concentration (MIC) of 2 µg/mL, while 8i and 8q showed moderate activity (MIC = 8 µg/mL).

25-Hydroxy cholesterol effectively inhibits Japanese encephalitis virus infection in a cellular model.

The Japanese encephalitis virus (JEV) is a mosquito-borne, enveloped flavivirus that causes acute encephalitis. Although JEV is increasingly recognized as a global threat, there is currently no FDA-approved treatment available for JEV. 25-hydroxycholesterol (25-HC) is an oxysterol produced through the oxidation of cholesterol, a process catalyzed by cholesterol 25-hydroxylase (CH25H), which is an interferon-stimulated gene that is upregulated during viral infections.

Ligand-Enabled Room-Temperature Three-Component Strategy for Mono-α-arylation of Acetone with Cyclic Diaryliodonium Salts and Alkenes.

Selective mono-α-arylation of the simplest ketone, acetone, is a highly sought-after yet challenging transformation. Herein, we present a Pd-catalyzed three-component cascade approach that achieves mono-α-arylation of acetone at room temperature. The ligand was crucial in accomplishing the reaction at room temperature.

Validation of Hv channel functions in BV2 microglial cells using small molecule modulators.

Microglia are the first responders to insults or damages in the brain where they display both beneficial and detrimental effects. Excessively activated microglia aggravate the secondary damage by producing several proinflammatory mediators. Voltage-gated proton channels, Hv are selectively expressed in the microglia where they modulate microglial activation.

Dearomatization-scission-aromatization of anilines: En route to synthesis of 3,3-disubstituted oxindoles with a wide range of heteroatom nucleophiles.

Herein, we report a catalytic, redox-neutral method for the difunctionalization of oxindoles using ketimines derived from anilines and heteronucleophiles. The reaction proceeds through a dearomatization-aromatization strategy a tetra-substituted alkene intermediate stabilized by extended resonance, facilitating the selective formation of 3,3-disubstituted oxindoles with a wide chemical space in good-to-high yields.