CRISPR for detection of drug resistance genes.

Melatonin alleviates endoplasmic reticulum stress and its mediated inflammation in adipocytes via the PER1/ATF6 signal.

Icariin inhibits autophagy and promotes apoptosis by regulating mitochondrial division in Triple-negative breast cancer.

The nociceptin/orphanin FQ opioid peptide receptor (NOPr) is a member of the opioid receptor family under investigation for the treatment of depression, Parkinson's disease, addiction, and pain. Opioid analgesics such as morphine act through μ-opioid receptor (MOPr) activation but cause MOPr-driven side effects that include respiratory depression, tolerance, addiction, and constipation. Bivalent NOPr/MOPr agonists have been shown to confer effective analgesia with an improved side effect profile. However, the development of new NOPr-targeting drugs is challenged by a paucity of pharmacological tools to characterize NOPr-ligands and visualize receptor expression. We report the design, synthesis, and pharmacological evaluation of the first high affinity small molecule NOPr-targeting fluorescent ligands, based on the antagonist: (2R)-1-(phenylmethyl)-N-(3-spiro[1H-2-benzofuran-3,4'-piperidine]-1'-ylpropyl)pyrrolidine-2-carboxamide (C24). These ligands display excellent selectivity for the NOPr against MOPr, δ (DOPr), and κ (KOPr) opioid receptors and are effective tracers for competition binding assays to evaluate NOPr-ligand affinity and in live cell imaging to visualize NOPr expression.

Background: Non-steroidal anti-inflammatory drugs re commonly used medications as anti-inflammatory, analgesic and antipyretic agents. However, they have many limitations due to the adverse effect, such as gastric irritation and gastric ulceration. Recently, β-lactams have been approved as chosen scaffolds due to their wide range of biological characteristics. Objective: goal of this research was the development of a series of new azetidin-2-one derivatives (B1-6) and assessment of their function as cox-2 inhibitory agents. Methods: crystal structure diclofenac complexed with active site of cyclooxygenase-2 from protein data bank, then docked with our new azetidine-2-one derivatives. Results: molecular docking protocol results proposed that these azetidine-2-one derivatives have sufficiently strong binding interactions within active site of COX-II. they have PLP fitness scores ranges between 66-74 respectively, whereas the fitness score of the standard drug (diclofenac) was (69). Additionally, newly designed ligands show good Swiss-ADME variables, revealing that they might be compounds with good bioavailability when taken orally. Conclusion: Three ligands exhibit superior PLP fitness compared to the reference ligand, while one demonstrates a comparable score at the active site of COX-II. This suggests that the new derivatives yield encouraging outcomes and may serve as modeling substances for the development of new anti-inflammatory drugs. Nevertheless, more pharmacological assessment is required.

Renal ischemia-reperfusion injury (IRI) is a common clinical condition that triggers a complex cascade of biological responses, including inflammation, oxidative stress, and apoptosis. These responses can lead to impaired renal function and acute kidney injury (AKI). Despite advancements in therapeutic agents, there is still a need for safe and effective drugs. In this study, we investigated the therapeutic effects and mechanisms of Gancao Xiexin Decoction (GCXXD), an herbal compound known for its anti-inflammatory, antioxidant, and immunomodulatory properties, in treating renal IRI. We utilized network pharmacology to identify the intersection targets of the active ingredients in GCXXD and AKI. Cytoscape software was used to obtain core targets, and the String database was used to map the interaction network of these targets. GO and KEGG enrichment analyses were conducted to assess the biological functions and potential pathways involved. Molecular docking simulations were performed to examine the binding of the main active components of GCXXD to the key pathways. Validation experiments were conducted using an IRI mouse model and a hypoxia-reoxygenation-mediated HK2 injury model. A total of 11 core targets of GCXXD for the treatment of AKI were identified. GO and KEGG analyses revealed enrichment in biological functions related to oxidative stress, apoptosis, and the PI3K/AKT signaling pathway. Molecular docking results indicated strong binding affinity between the key active components (baicalein, ginsenoside Rh2, quercetin, and wogonin) of GCXXD and the PI3K/AKT pathway. In both in vivo and ex vivo experiments, GCXXD activated the PI3K/AKT pathway and ameliorated renal IRI. This study demonstrated that GCXXD effectively improved ischemia-reperfusion-induced renal injury primarily via activating the PI3K/AKT pathway. These findings provided a scientific basis for the clinical application of GCXXD and paved the way for the development of new drugs and therapeutic strategies.

Mass spectrometry (MS)-based proteomics is a disruptive platform in drug discovery that offers an exhaustive view of the proteome's complexity. Focusing on bottom-up MS proteomics, this technology enables high-throughput analysis of protein expression, interactions, and modifications, far surpassing the capabilities of traditional single-protein methods. The MS proteomics toolbox is essential in both early- and late-stage development of new drugs. The techniques discussed here, such as unlabeled and labeled proteomics and chemoproteomic approaches (e.g., thermal proteome profiling and photoaffinity labeling), facilitate target binding site exploration and the identification of putative off-targets. By accelerating the identification of new druggable proteins and supporting early biomarker discovery, MS proteomics significantly accelerates the preclinical-to-clinical transition. Ongoing progress in data acquisition, new computational tools, and artificial intelligence further enhances the high-throughput properties of these approaches, marking a significant step toward personalized medicine.

The development of new drugs and drug delivery systems relies heavily on careful acquisition and interpretation of large amounts of experimental data, to identify and select promising candidates for therapeutic and prophylactic use. Predictive mathematical modeling can expedite this process by capturing the complex interplay of physical, chemical and biological factors that influence drug delivery. However, traditional compartmental models of pharmacokinetics and pharmacodynamics typically rely on oversimplified approximations of drug transport mechanisms and may fail to accurately represent the key deterministic processes that drive drug mass transport - particularly in complex delivery scenarios where the drug targets are close to the sites of drug administration. Here, we present a deterministic mathematical framework that addresses a challenging drug delivery modality: the injection of a fluid drug vehicle that undergoes phase separation upon entering poroelastic tissue. This phase change improves localized retention of the loaded drug in a finite volume near the injection site. Our model is directly relevant to in situ-gelling injections of chemotherapeutic agents into superficial tumors - a strategy gaining attention in the development of improved cancer therapeutics. Our approach uniquely incorporates both diffusion and convection, accounts for tissue poroelasticity, and uses Cahn-Hilliard theory to describe the phase separation behavior of the injected material. Simulations across a broad parameter space indicate that drug retention is enhanced in softer tissues and with high-rate, low-volume injections. This computational framework is currently being used to guide the design of improved therapeutic strategies for ethanol-based ablation, when co-injected with ethyl cellulose as a phase-transitioning agent for superficial tumors.

The development of an oropharyngeal gonorrhoea controlled human infection model (CHIM) could result in important translational outcomes, including accelerated development of new drugs and vaccines. Ethical study design for such a model requires community consultation, including assessment of the acceptability of the proposed CHIM among key stakeholders. This qualitative study involved: (i) semi-structured interviews and focus groups with individuals who would be eligible for participation in the proposed oropharyngeal gonorrhoea CHIM, defined as healthy men who have sex with men (MSM) aged 18-50 years living in Victoria (Australia); and, (ii) semi-structured interviews with gonorrhoea experts. Data were analysed using inductive thematic analysis supported by NVivo. Twenty-seven semi-structured interviews and one focus group were undertaken with 32 individuals between July and November, 2024, comprising 22 potential CHIM participants, and 10 experts. Overall, an oropharyngeal gonorrhoea CHIM was acceptable to most participants. Financial compensation and including only MSM who do not have sex with women were highlighted as key areas of debate. Participants highlighted that recruitment strategies should be sensitive to the stigma associated with gonorrhoea and history of stigma experienced by MSM. An oropharyngeal gonorrhoea CHIM is acceptable to key stakeholders but must be carefully designed to avoid exacerbation of stigma.

As the primary form and means of clinical treatment, traditional Chinese medicine formulas (TCM formulas) embody the core of traditional Chinese medicine’s syndrome differentiation and treatment approach and serve as a bridge between TCM theory and clinical practice. Exploring the relationship between the chemical constituents of TCM formulas and the body’s vital activities, along with their complex interactive mechanisms, represents one of the key scientific challenges in modern TCM research. However, due to the complexity of TCM chemical constituents and the inherent vast systemic nature of the human body, coupled with the fragmented, experiential, and semi-quantitative nature of TCM formulas pharmacology research, bottlenecks such as complex composition, unclear mechanisms, and insufficient standardization and refinement constrain its in-depth development. Technical guidelines for non-clinical pharmacology research of traditional Chinese medicine formulas systematically review and summarize the research content and relevant advances in non-clinical pharmacology of TCM formulas, integrate multidisciplinary technical approaches, and establish research standards, providing practical standards for systematically elucidating the integrated mechanisms of action between multi-component drugs and the body. This article interprets the core content of the technical guidelines, thereby initiating the following discussion on TCM formulas pharmacology: analyzing critical points, elucidating the complete evidence chain, and describing research content and application scenarios, which aims to enhance the scientization and reliability of TCM formulas pharmacology and to facilitate the research and development of new TCM drugs. Graphical abstract:http://links.lww.com/AHM/A196

Research and development of natural product Salidroside: Pharmacology, total synthesis and structural modifications.

Medical Therapies of Cushing's Disease-Part 2.

RA is a recurrent autoimmune disease that has significant adverse effects on the physical and mental health of patients. Traditional Chinese medicine has shown significant advantages in the prevention and treatment of RA. Numerous clinical and experimental studies have confirmed that traditional Chinese medicine components have clear therapeutic effects and minimal adverse reactions in treating RA. The research on traditional Chinese medicine for the prevention and treatment of RA has become a hot topic in the field of autoimmune diseases. The related references about the mechanisms and Q-markers of anti-RA of traditional Chinese medicine in this review were collected from Willy, SpringLink, Web of Science, Elsevier, PubMed, SciFinder, Scopus, ACS publications, Baidu Scholar, Google Scholar, and CNKI. The traditional Chinese medicine components such as terpenoids, flavonoids, and alkaloids have significant anti-RA effects, and their mechanisms are mainly to inhibit NF-κB signaling pathway, inhibit the proliferation of RA fibroblasts like synovial cells, and regulate Th1/Th2 cell balance, and so on. Predicting and studying the Q-markers of traditional Chinese medicine anti-RA by plant phylogeny and chemical componentss, traditional medicinal properties, pharmacokinetics, component measurability, correlation between composition and efficacy, and gut microbiota will provide scientific foundations for the research and further development of anti-RA traditional Chinese medicine. The active components of traditional Chinese medicine exhibited the characteristic of multiple mechanisms in the treatment of RA, such as terpenoids had anti-angiogenesis effects, flavonoids had anti-inflammatory and cartilage protective effects, and alkaloids had antiinflammatory and analgesic effects. The proposal of Q-markers for anti-RA provided new research ideas for promoting the development of new drugs for anti-RA and ensuring the safety and effectiveness of clinical medications.

Marine natural products with anti-MRSA activities: promising candidates for antibacterial drug discovery.

Promising efficacy of nitrogen-containing bisphosphonates against the infection of Cryptosporidium spp.

Juglone targets MMP-1 to inhibit gastric cancer progression.

Virtual screening, synthesis, optimization and anti-inflammatory activity of novel chromones as specific COX-2 inhibitors.

CaMK4, a key target for treating pathogenesis of depression?

ABSTRACT Bacterial infection caused by intracellular pathogens such as Shigella flexneri is a rapidly increasing global health concern that requires urgent and necessary action. The dearth of licensed vaccines against shigellosis and the decline in susceptibility to conventional antibiotics has encouraged the development of new antibiotic principles and drugs. The treatment options are decreasing faster than the discovery rate of new antibacterial agents. Combinatorial approach of antibiotics with non-antibiotic adjuvants is a promising aspect to treat resistant bacterial infections. Asiatic acid, a membrane-disrupting triterpenoid with wide antimicrobial and immunomodulatory properties, can potentiate antibiotics, but the exact mechanisms remain broadly unexplored. Therefore, in this study, we screened the interaction of asiatic acid with several antibiotics. The results showed synergistic interactions of asiatic acid with antibiotics against susceptible and multidrug-resistant S. flexneri clinical isolates. Particularly important was the interaction of asiatic acid with the quinolone antibiotics ciprofloxacin and nalidixic acid. A detailed study showed that combined treatment of asiatic acid with ciprofloxacin inhibited S. flexneri biofilm formation and resistance development. An increase in membrane disruption and depolarization upon co-treatment was evident by surface electron and confocal microscopy. In addition, asiatic acid and ciprofloxacin synergism was identified to inhibit efflux activity and intracellular bacterial viability. However, asiatic acid showed no synergistic toxicity with ciprofloxacin towards mammalian cells. The antibacterial activity was further verified in a S. flexneri infected mice model. Therapeutic benefits were evident with reduced bacterial burden, recovery from intestinal tissue damage and increase in mice survivability. The results showed that this combination can target the bacterial membrane, efflux pump proteins and biofilm formation, thereby preventing resistance development. The combination treatment offers a proof of concept in targeting essential bacterial activities and might be developed into a novel and efficient treatment alternative against S. flexneri.

Abstract Background Sepsis-associated acute gastrointestinal injury (SAGI) represents a core pathological mechanism contributing to high mortality rates in critically ill patients, fundamentally rooted in a vicious cycle between uncontrolled systemic inflammatory responses and intestinal barrier dysfunction. Aucklandiae Radix (Muxiang), a traditional Chinese medicinal herb, exhibits multiple pharmacological activities including anti-inflammatory, antioxidant, and gastrointestinal mucosal barrier protective effects, suggesting significant potential for intervening in SAGI. However, the specific therapeutic efficacy of Aucklandiae Radix against SAGI and its underlying molecular mechanisms remain to be systematically elucidated. Methods A sepsis-associated acute gastrointestinal injury (SAGI) model was established using cecal ligation and puncture (CLP). By evaluating survival rates, intestinal microstructural alterations, serum inflammatory cytokine levels, and intestinal tissue oxidative stress markers across different mouse groups, preliminary evidence was obtained demonstrating the potential therapeutic effect of Aucklandiae Radix on SAGI. Subsequently, active components of Aucklandiae Radix were screened using the TCMSP database. Potential targets for Aucklandiae Radix intervention in SAGI were identified by integrating data from GEO, PubChem, SwissTargetPrediction, and GeneCards databases. The STRING database was used to construct a protein interaction network and screen core targets. Gene functional enrichment analysis was performed using the DAVID database. Finally, the CB-Dock2 molecular docking platform was employed to validate the binding affinity between active components and core targets and visualize the results. Results Animal experiments revealed that after treatment with Aucklandiae Radix, model mice exhibited increased daily food and water intake, while the 7-day survival rate rose from 13.5 to 33.3% and 53.3% ( P < 0.05). Histopathological examination further demonstrated that Aucklandiae Radix reduced inflammatory cell infiltration in the submucosal layer of the intestine and alleviated villous edema, while promoting structural repair of the intestinal barrier. At the molecular level, treatment with Aucklandiae Radix significantly reduced levels of oxidative stress markers (MDA, SOD, and GSH-Px) in intestinal tissues and pro-inflammatory cytokines (IL-1β and TNF-α) in serum. Collectively, these findings suggest that Aucklandiae Radix may exert protective effects against sepsis-induced acute gastrointestinal injury by enhancing intestinal antioxidant defenses and suppressing systemic inflammatory responses. Based on network pharmacology and bioinformatics analysis, three key active components of Aucklandiae Radix and six core targets for their intervention in SAGI were identified. Gene enrichment analysis revealed significant activation of the IL-17 signaling pathway. Molecular docking results demonstrated high affinity between the active components and core targets. Conclusion This study employed a logical chain from phenotype to target, preliminarily validating the therapeutic effect of Aucklandiae Radix on SAGI through animal experiments. Network pharmacology methods were then applied to identify the potential molecular mechanisms underlying Aucklandiae Radix’s treatment of SAGI. Network pharmacology and molecular docking results suggest that IL-17, as a potential signaling pathway, may play a crucial role in the treatment of SAGI by Aucklandiae Radix. This provides potential targets and significant reference value for future development of new clinical drugs and basic research. Graphical Abstract