Vet Res Commun. 2024 Dec 28;49(1):59. doi: 10.1007/s11259-024-10628-1.

ABSTRACT

Camel mastitis especially caused by Staphylococcus aureus (S. aureus), is a major risk to animal health and milk production. The current investigation evaluated the antibiotic susceptibility and virulence factors of S. aureus isolates from subclinical mastitis in camels. A total of 384 milk samples were collected and submitted to isolate S. aureus. The S. aureus isolates exhibiting resistance to Penicillin and Cefoxitin disc on Kirby-Bauer disc diffusion method were considered as β-lactam resistant S. aureus (BRSA) and methicillin-resistant S. aureus (MRSA) which were further confirmed by PCR targeting blaZ and mecA genes, respectively. The results showed that S. aureus was found in 57.06% of subclinical (SCM) positive camel milk samples. A high molecular prevalence of BRSA and MRSA were found to be 48.51% and 46.53% respectively depicting that treating these infections is challenging due to their high resistance levels. The phylogenetic analysis revealed a significant resemblance of the study isolates with each other and with already reported sequences from different countries which shows the potential for the spread of pathogen. Virulence profiling of antibiotic resistance strains showed the presence of virulence markers (nuc and coag genes), intercellular adhesion genes (icaA, icaD), Panton-Valentine leukocidin (pvl) gene, and enterotoxin-producing genes including sea, seb, sec, and sed. In-vitro antibiotic susceptibility testing revealed that the most resistant antibiotic group was penicillin followed by aminoglycosides and cephalosporins. Drug repurposing analysis of different non-antibiotics for combination therapies with resistant antibiotics was done to combat the S. aureus isolates harboring the mecA and blaZ genes. The results revealed the synergistic effect of amoxicillin, sulfamethoxazole, gentamicin, and doxycycline with ketoprofen, amikacin with flunixin meglumine, and gentamicin with N-acetylcysteine (NAC) against study isolates. The current investigation provides the status of antibiotic-resistant strains and virulence factors of S. aureus in the udder of dromedary camels. The combinational therapy of resistant antibiotics with non-antibiotics provides a potential therapeutic option for the treatment of resistant strains.

PMID:39731665 | DOI:10.1007/s11259-024-10628-1

Sci Rep. 2024 Dec 28;14(1):31006. doi: 10.1038/s41598-024-82177-1.

ABSTRACT

Articular cartilage has a limited regenerative capacity, resulting in poor spontaneous healing of damaged tissue. Despite various scientific efforts to enhance cartilage repair, no single method has yielded satisfactory results. With rising drug development costs, drug repositioning has emerged as a viable alternative. This study aimed to identify a drug capable of improving cartilage defects by analyzing chondrogenesis-related microarray data from the Gene Expression Omnibus (GEO) public database. We utilized datasets GSE69110, GSE107649, GSE111822, and GSE116173 to identify genes associated with cartilage differentiation, employing StringTie for differential gene expression analysis and extracting drug data from the Drug-Gene Interaction database. Additionally, we aimed to verify the cartilage regeneration potential of the identified drug through experiments using cellular and animal models. We evaluated the effects of aripiprazole on adipose-derived mesenchymal stem cells (ADMSCs) and chondrocytes using qRT-PCR and a 3D pellet culture system. In vivo, we assessed cartilage restoration by combining aripiprazole with a scaffold and implanting it into artificially induced cartilage defects in Sprague-Dawley rats. Subsequent mRNA sequencing provided insights into the mechanistic pathways involved. Our results showed that aripiprazole significantly increased mRNA expression of COL2A1 and SOX9, markers of chondrogenesis, and promoted chondrogenic condensation in vitro. Furthermore, aripiprazole effectively enhanced cartilage regeneration in the rat model. KEGG pathway and Gene Ontology Biological Processes (GOBP) analyses of the mRNA sequencing data revealed that aripiprazole upregulated genes related to ribosomes and cytoplasmic translation, thereby facilitating chondrogenesis. In conclusion, our findings suggest that aripiprazole is a promising candidate for improving damaged cartilage, offering a novel approach to cartilage regeneration.

PMID:39730885 | DOI:10.1038/s41598-024-82177-1

PLoS One. 2024 Dec 27;19(12):e0315245. doi: 10.1371/journal.pone.0315245. eCollection 2024.

ABSTRACT

The increasing utilization of deep learning models in drug repositioning has proven to be highly efficient and effective. In this study, we employed an integrated deep-learning model followed by traditional drug screening approach to screen a library of FDA-approved drugs, aiming to identify novel inhibitors targeting the TNF-α converting enzyme (TACE). TACE, also known as ADAM17, plays a crucial role in the inflammatory response by converting pro-TNF-α to its active soluble form and cleaving other inflammatory mediators, making it a promising target for therapeutic intervention in diseases such as rheumatoid arthritis. Reference datasets containing active and decoy compounds specific to TACE were obtained from the DUD-E database. Using RDKit, a cheminformatics toolkit, we extracted molecular features from these compounds. We applied the GraphConvMol model within the DeepChem framework, which utilizes graph convolutional networks, to build a predictive model based on the DUD-E datasets. Our trained model was subsequently used to predict the TACE inhibitory potential of FDA-approved drugs. From these predictions, Vorinostat was identified as a potential TACE inhibitor. Moreover, molecular docking and molecular dynamics simulation were conducted to validate these findings, using BMS-561392 as a reference TACE inhibitor. Vorinostat, originally an FDA-approved drug for cancer treatment, exhibited strong binding interactions with key TACE residues, suggesting its repurposing potential. Biological evaluation with RAW 264.7 cell confirmed the computational results, demonstrating that Vorinostat exhibited comparable inhibitory activity against TACE. In conclusion, our study highlights the capability of deep learning models to enhance virtual screening efforts in drug discovery, efficiently identifying potential candidates for specific targets such as TACE. Vorinostat, as a newly identified TACE inhibitor, holds promise for further exploration and investigation in the treatment of inflammatory diseases like rheumatoid arthritis.

PMID:39729480 | DOI:10.1371/journal.pone.0315245

Trop Med Infect Dis. 2024 Nov 25;9(12):288. doi: 10.3390/tropicalmed9120288.

ABSTRACT

Tuberculosis (TB) is a global health challenge associated with considerable levels of illness and mortality worldwide. The development of innovative therapeutic strategies is crucial to combat the rise of drug-resistant TB strains. DNA Gyrase A (GyrA) and serine/threonine protein kinase (PknB) are promising targets for new TB medications. This study employed techniques such as similarity searches, molecular docking analyses, machine learning (ML)-driven absolute binding-free energy calculations, and molecular dynamics (MD) simulations to find potential drug candidates. By combining ligand- and structure-based methods with ML principles and MD simulations, a novel strategy was proposed for identifying small molecules. Drugs with structural similarities to existing TB therapies were assessed for their binding affinity to GyrA and PknB through various docking approaches and ML-based predictions. A detailed analysis identified six promising compounds for each target, such as DB00199, DB01220, DB06827, DB11753, DB14631, and DB14703 for GyrA; and DB00547, DB00615, DB06827, DB14644, DB11753, and DB14703 for PknB. Notably, DB11753 and DB14703 show significant potential for both targets. Furthermore, MD simulations' statistical metrics confirm the drug-target complexes' stability, with MM-GBSA analyses underscoring their strong binding affinity, indicating their promise for TB treatment even though they were not initially designed for this disease.

PMID:39728815 | DOI:10.3390/tropicalmed9120288

Metabolites. 2024 Dec 20;14(12):719. doi: 10.3390/metabo14120719.

ABSTRACT

BACKGROUND: Paclitaxel is a widely used anticancer drug for ovarian, lung, breast, and stomach cancers; however, its clinical use is often limited by the side effects of peripheral neuropathy. This study evaluated the effects of Cyperus rotundus (C. rotundus) extract and its active metabolite, α-cyperone, on paclitaxel-induced neuropathic pain.

METHODS: The oral administration of C. rotundus extract at doses of 500 mg/kg and intraperitoneal administration of α-cyperone at doses of 480 and 800 μg/kg prevented both the development of cold and mechanical pain.

RESULTS: The gene and protein expressions of tyrosine hydroxylase and noradrenergic receptors (α1- and α2-adrenergic), which were upregulated by paclitaxel, were significantly downregulated in the C. rotundus extract-treated group. In the locus coeruleus region of the mouse brain, C. rotundus extract administration also reduced the elevated expression of tyrosine hydroxylase induced by paclitaxel. The concentration of α-cyperone in C. rotundus extract was quantified using high-performance liquid chromatography (HPLC). In the group treated with α-cyperone, at levels corresponding to its content in C. rotundus, both cold and mechanical allodynia were effectively prevented.

CONCLUSIONS: This study suggests that α-cyperone shows potential as a preventive agent for paclitaxel-induced neuropathic pain.

PMID:39728499 | DOI:10.3390/metabo14120719

J Fungi (Basel). 2024 Dec 15;10(12):871. doi: 10.3390/jof10120871.

ABSTRACT

This review explores current advancements and challenges in antifungal therapies amid rising fungal infections, particularly in immunocompromised patients. We detail the limitations of existing antifungal classes-azoles, echinocandins, polyenes, and flucytosine-in managing systemic infections and the urgent need for alternative solutions. With the increasing incidence of resistance pathogens, such as Candida auris and Aspergillus fumigatus, we assess emerging antifungal agents, including Ibrexafungerp, T-2307, and N'-Phenylhydrazides, which target diverse fungal cell mechanisms. Innovations, such as nanoparticles, drug repurposing, and natural products, are also evaluated for their potential to improve efficacy and reduce resistance. We emphasize the importance of novel approaches to address the growing threat posed by fungal infections, particularly for patients with limited treatment options. Finally, we briefly examine the potential use of artificial intelligence (AI) in the development of new antifungal treatments, diagnoses, and resistance prediction, which provides powerful tools in the fight against fungal pathogens. Overall, we highlight the pressing need for continued research to advance antifungal treatments and improve outcomes for high-risk populations.

PMID:39728367 | DOI:10.3390/jof10120871

In Silico Pharmacol. 2024 Dec 24;13(1):5. doi: 10.1007/s40203-024-00293-2. eCollection 2025.

ABSTRACT

Drug repurposing is necessary to accelerate drug discovery and meet the drug needs. This study investigated the possibility of using fluvoxamine to inhibit the cellular metabolizing enzyme NUDT5 in breast cancer. Computational and experimental techniques were used to evaluate the structural flexibility, binding stability, and chemical reactivity of the drugs. These findings indicated that fluvoxamine effectively suppressed the activity of NUDT5, as evidenced by a binding score of - 8.514 kcal/mol. Furthermore, the binding positions of fluvoxamine and NUDT5 were optimized. Fluvoxamine attachment to the active sites of Trp28, Trp46, Glu47, Arg51, Arg84, and Leu98 in NUDT5 has been shown to alter the metabolism of ADPr. These alterations play a role in ATP production in the breast cancer cells. In addition, an MTT assay conducted on the MCF-7 cell line using fluvoxamine revealed an IC50 value of 53.86 ± 0.05 µM. Fluvoxamine-induced apoptosis was confirmed as evidenced by AO/EtBr and DAPI staining.

GRAPHICAL ABSTRACT: Effect of fluvoxamine on breast cancer cells.

PMID:39726906 | PMC:PMC11668718 | DOI:10.1007/s40203-024-00293-2

Eur J Pharmacol. 2024 Dec 24:177231. doi: 10.1016/j.ejphar.2024.177231. Online ahead of print.

ABSTRACT

Multidrug resistance (MDR) remains a significant obstacle in cancer treatment, primarily attributable to the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2 within cancer cells. These transporters actively diminish the effectiveness of cytotoxic drugs by facilitating ATP hydrolysis-dependent drug efflux, thereby reducing intracellular drug accumulation. Given the absence of approved treatments for multidrug-resistant cancers and the established benefits of combining tyrosine kinase inhibitors (TKIs) with conventional anticancer drugs, we investigate the potential of vodobatinib, a potent c-Abl TKI presently in clinical trials, to restore sensitivity to chemotherapeutic agents in multidrug-resistant cancer cells overexpressing ABCB1 and ABCG2. Results indicate that vodobatinib, administered at sub-toxic concentrations, effectively restores the sensitivity of multidrug-resistant cancer cells to cytotoxic drugs in a concentration-dependent manner. Moreover, vodobatinib enhances drug-induced apoptosis in these cells by inhibiting the drug-efflux function of ABCB1 and ABCG2, while maintaining their expression levels. Moreover, we found that while vodobatinib enhances the ATPase activity of ABCB1 and ABCG2, the overexpression of these transporters does not induce resistance to vodobatinib. These results strongly suggest that increased levels of ABCB1 or ABCG2 are unlikely to play a significant role in the development of resistance to vodobatinib in cancer patients. Overall, our findings unveil an additional pharmacological facet of vodobatinib against ABCB1 and ABCG2 activity, suggesting its potential incorporation into combination therapy for a specific subset of patients with tumors characterized by high ABCB1 or ABCG2 levels. Further investigation is warranted to fully elucidate the clinical implications of this therapeutic approach.

PMID:39725134 | DOI:10.1016/j.ejphar.2024.177231

Arch Microbiol. 2024 Dec 26;207(1):18. doi: 10.1007/s00203-024-04205-y.

ABSTRACT

Klebsiella pneumoniae is a leading cause of anti-microbial resistance in healthcare-associated infections that have posed a severe threat to neonatal and wider community. The escalating crises of antibiotic resistance have compelled researchers to explore an innovative arsenal beginning from natural resources to chemical modifications in order to overcome the ever-increasing resistance issues. The present review highlights the drug discovery efforts with a special focus on cutting-edge strategies in the hunt for potential drug candidates against MDR/XDR Klebsiella pneumoniae. Nature's bounty constituting plant extracts, essential oils, fungal extracts, etc. holds promising anti-bacterial potential especially when combined with existing antibiotics. Further, enhancing these natural products with synthetic moieties has improved their effectiveness, creating a bridge between the natural and synthetic world. Conversely, the synthetically modified novel scaffolds have been also designed to meticulously target specific sites. Furthermore, we have also elaborated various emerging strategies for broad-spectrum infections caused by K. pneumoniae, which include anti-microbial peptides, nanotechnology, drug repurposing, bacteriophage, photodynamic, and multidrug therapies. This review further addresses the challenges confronted by the research community and the future way forward in the field of drug discovery against multi-resistant bacterial infections.

PMID:39724243 | DOI:10.1007/s00203-024-04205-y

Protein Sci. 2025 Jan;34(1):e70006. doi: 10.1002/pro.70006.

ABSTRACT

This study focuses on spastic paraplegia type 50 (SPG50), an adapter protein complex 4 deficiency syndrome caused by mutations in the adapter protein complex 4 subunit mu-1 (AP4M1) gene, and on the downstream alterations of the AP4M1 protein. We applied a battery of heterogeneous computational resources, encompassing two in-house tools described here for the first time, to (a) assess the druggability potential of AP4M1, (b) characterize SPG50-associated mutations and their 3D scenario, (c) identify mutation-tailored drug candidates for SPG50, and (d) elucidate their mechanisms of action by means of structural considerations on homology models of the adapter protein complex 4 core. Altogether, the collected results indicate R367Q as the mutation with the most promising potential of being corrected by small-molecule drugs, and the flavonoid rutin as best candidate for this purpose. Rutin shows promise in rescuing the interaction between the AP4M1 and adapter protein complex subunit beta-1 (AP4B1) subunits by means of a glue-like mode of action. Overall, this approach offers a framework that could be systematically applied to the investigation of mutation-wise molecular mechanisms in different hereditary spastic paraplegias, too.

PMID:39723768 | DOI:10.1002/pro.70006

Neurourol Urodyn. 2024 Dec 26. doi: 10.1002/nau.25651. Online ahead of print.

ABSTRACT

INTRODUCTION: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating pain condition of unknown etiology. Effective therapies for this condition could not have been developed in the last century. Drug repurposing is a practical strategy for enhancing patient access to successful therapies. It is an approach for discovering novel applications for licensed or investigational pharmaceuticals that extend beyond the initial medical indication. This work aims to identify repurposable medications through bioinformatics to discover potential drugs or compounds that can reverse the IC/BPS disease signature.

METHODS AND MATERIAL: The analysis involved examining the differentially expressed genes in IC/BPS patients with two distinct disease phenotypes (Hunner's lesion disease, non-Hunner's lesion disease) and controls using the datasets GSE11783, GSE28242, and GSE57560. The goal was to assess the reversal of the disease signature on the L1000CDS2 and cMAP platforms.

RESULTS: Twenty-one compounds were repurposed, consisting of 11 small molecules, 10 chemical compounds, 3 natural products, and 6 FDA-approved drugs, currently used for clinical indications such as cancer, myelofibrosis, and diabetes.

DISCUSSION: Bioinformatics can be useful for identifying therapeutic agents for IC/BPS by accessing and processing big data on molecular and cellular levels. Prospective in vivo experiments must validate repurposed drugs. The expansion of large-scale genome sequencing, gene expression studies, and clinical data for IC/BPS will improve successful drug selection.

PMID:39723619 | DOI:10.1002/nau.25651

Drug Des Devel Ther. 2024 Dec 19;18:6173-6184. doi: 10.2147/DDDT.S499068. eCollection 2024.

ABSTRACT

PURPOSE: Nitrofurantoin (NITRO), a long-standing antibiotic to treat urinary tract infections, is activated by Nitro reductases. This activation mechanism has led to its exploration for repositioning applications in controlling and treating breast cancer, which express a Nitro reductase gene.

METHODS: NITRO Cubosomes were developed using hot homogenization according to 23-full factorial design. The factors studied included the ratio of drug to oily phase (1:10 and 2:10), the ratio of oily to aqueous phase (1:10 and 1:5), and the ratio of Glyceryl mono-oleate (GMO) to Poloxamer 407 (PX407) (0.25:1 and 0.5:1). A total of 8 systems were proposed and evaluated by measuring particle size, zeta potential, polydispersity index, and percentage of entrapment efficiency.

RESULTS: S6 (1:10 drug: oily phase, 1:5 oily: aqueous phase and 0.5:1 GMO: PX407) with particle size 45.5 ±c1.1 nm and an entrapment efficiency of 98.6 ± 1.8% exhibited highest desirability and was selected for further analysis. The morphology of S6 was examined using TEM microscopy. The activation of NITRO from S6 reflected on intracellular viability of MCF-7 breast cancer cell line was investigated by an MTT assay. The findings indicated that S6 had the lowest IC50 value (83.99 ± 0.15 μg g/mL) compared to Free NITRO (174.54 ± 1.36 μg g/mL), suggesting enhanced efficacy compared to free NITRO.

CONCLUSION: Nitrofurantoin cubosomes can be candidates for repositioning in breast cancer management after encouraging further stability and in-vivo studies.

PMID:39722678 | PMC:PMC11668685 | DOI:10.2147/DDDT.S499068

Eur J Med Chem. 2024 Dec 13;284:117164. doi: 10.1016/j.ejmech.2024.117164. Online ahead of print.

ABSTRACT

Artificial Intelligence (AI) and Machine Learning (ML) are transforming drug discovery by overcoming traditional challenges like high costs, time-consuming, and frequent failures. AI-driven approaches streamline key phases, including target identification, lead optimization, de novo drug design, and drug repurposing. Frameworks such as deep neural networks (DNNs), convolutional neural networks (CNNs), and deep reinforcement learning (DRL) models have shown promise in identifying drug targets, optimizing delivery systems, and accelerating drug repurposing. Generative adversarial networks (GANs) and variational autoencoders (VAEs) aid de novo drug design by creating novel drug-like compounds with desired properties. Case studies, such as DDR1 kinase inhibitors designed using generative models and CDK20 inhibitors developed via structure-based methods, highlight AI's ability to produce highly specific therapeutics. Models like SNF-CVAE and DeepDR further advance drug repurposing by uncovering new therapeutic applications for existing drugs. Advanced ML algorithms enhance precision in predicting drug efficacy, toxicity, and ADME-Tox properties, reducing development costs and improving drug-target interactions. AI also supports polypharmacology by optimizing multi-target drug interactions and enhances combination therapy through predictions of drug synergies and antagonisms. In nanomedicine, AI models like CURATE.AI and the Hartung algorithm optimize personalized treatments by predicting toxicological risks and real-time dosing adjustments with high accuracy. Despite its potential, challenges like data quality, model interpretability, and ethical concerns must be addressed. High-quality datasets, transparent models, and unbiased algorithms are essential for reliable AI applications. As AI continues to evolve, it is poised to revolutionize drug discovery and personalized medicine, advancing therapeutic development and patient care.

PMID:39721292 | DOI:10.1016/j.ejmech.2024.117164

J Cell Mol Med. 2024 Dec;28(24):e70312. doi: 10.1111/jcmm.70312.

ABSTRACT

Polycystic ovary syndrome (PCOS), a major cause of female infertility, affects 4%-20% of reproductive-age women. Metabolic and hormonal alterations are key features of PCOS, potentially raising the risk of endometrial (EC) and ovarian (OVCA) cancers. This systematic review aims to summarise the proposed molecular mechanisms involved in the association between PCOS and EC or OVCA. This is achieved by conducting a thorough literature review and utilising specific search terms to identify all relevant studies published in English from 2010 to December 2022. PRISMA was followed, and the protocol was registered on PROSPERO (CRD42022375461). The QUADAS-2 tool and Review Manager Software were employed to evaluate study quality and risk of bias respectively. Forty-five eligible studies were selected with molecular signatures based on genomic, transcriptomic, metabolomic, proteomic and epigenetic analyses. Genes and their products deregulated in EC and/or OVCA were identified, including BRCA1, MLH1, NQO1 and ESR1, which were also deregulated in PCOS. Serum levels of IGF1, IGFBP1, SREBP1 and visfatin in women with PCOS were also identified as potential biomarkers of enhanced EC risk. Salusin-β serum levels in individuals with PCOS were identified as a potential biomarker for increased risk of OVCA. Gene signature-based drug repositioning identified several drug candidates: metformin, fenofibrate, fatostatin, melatonin, resveratrol and quercetin, some already established and prescribed for PCOS. In conclusion, this study provides a strong basis for further research to confirm the identified molecular signatures and associated causal links for potential therapeutic prevention strategies for EC and OVCA in women with PCOS.

PMID:39720923 | DOI:10.1111/jcmm.70312

Front Pharmacol. 2024 Dec 10;15:1516725. doi: 10.3389/fphar.2024.1516725. eCollection 2024.

ABSTRACT

Rare diseases affect over three hundred million individuals globally. Investment in research and development remains incommensurate with the challenges rare diseases pose. Further investment in information sharing platforms to promote common and standardized network technologies for rare disease is needed. Rare disease R&D generates information and assets that spill over in other ways, providing benefits that may not be apparent to investors ex ante. Analytical and computational methods recently applied at scale are promising. One important way of achieving efficiencies of scale in R&D is clustering rare diseases into groups with similar traits.

PMID:39720596 | PMC:PMC11666429 | DOI:10.3389/fphar.2024.1516725

Front Pharmacol. 2024 Dec 10;15:1507860. doi: 10.3389/fphar.2024.1507860. eCollection 2024.

ABSTRACT

Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly worldwide. Anti-vascular endothelial growth factor (anti-VEGF) injections remain the first-line therapy for AMD. However, their high cost and the need for frequent administration pose challenges to long-term adherence, highlighting the need for accessible and cost-effective preventive strategies. Emerging evidence suggests that traditional antidiabetic drugs, such as metformin, sulfonylureas, and thiazolidinediones, may offer neuroprotective benefits, opening new avenues for AMD prevention. Among these, metformin has emerged as the most promising candidate, demonstrating significant potential in reducing AMD risk, even at low cumulative doses, primarily through AMP-activated protein kinase (AMPK) activation. Sulfonylureas, although effective in stimulating insulin secretion, carry risks such as hypoglycemia, hyperinsulinemia, and a possible association with increased cancer risk. Similarly, thiazolidinediones, while improving insulin sensitivity, are associated with adverse effects, including cardiovascular risks and macular edema, limiting their broader application in AMD prevention. This paper explores the preventive potential and underlying mechanisms of these antidiabetic drugs in AMD and discusses the role of artificial intelligence in optimizing individualized prevention strategies. By advancing precision medicine, these approaches may improve public health outcomes and reduce the burden of aging-related vision loss.

PMID:39720591 | PMC:PMC11666363 | DOI:10.3389/fphar.2024.1507860

Commun Biol. 2024 Dec 24;7(1):1696. doi: 10.1038/s42003-024-07416-7.

ABSTRACT

Comorbidity among atopic diseases (ADs) and gastrointestinal diseases (GIDs) has been repeatedly demonstrated by epidemiological studies, whereas the shared genetic liability remains largely unknown. Here we establish an atlas of the shared genetic architecture between 10 ADs or related traits and 11 GIDs, comprehensively investigating the comorbidity-associated genomic regions, cell types, genes and genetically predicted causality. Although distinct genetic correlations between AD-GID are observed, including 14 genome-wide and 28 regional correlations, genetic factors of Crohn's disease (CD), ulcerative colitis (UC), celiac disease and asthma subtypes are converged on CD4+ T cells consistently across relevant tissues. Fourteen genes are associated with comorbidities, with three genes are known treatment targets, showing probabilities for drug repurposing. Lower expressions of WDR18 and GPX4 in PBMC CD4+ T cells predict decreased risk of CD and asthma, which could be novel drug targets. MR unveils certain ADs led to higher risk of GIDs or vice versa. Taken together, here we show distinct genetic correlations between AD-GID pairs, but the correlated genomic loci converge on the dysregulation of CD4+ T cells. Inhibiting WDR18 and GPX4 expressions might be candidate therapeutic strategies for CD and asthma. Estimated causality indicates potential guidance for preventing comorbidity.

PMID:39719505 | DOI:10.1038/s42003-024-07416-7

Mol Cell Endocrinol. 2024 Dec 22:112445. doi: 10.1016/j.mce.2024.112445. Online ahead of print.

ABSTRACT

Excessive consumption of saturated fatty acids creates a debilitating cellular environment that hinders the normal function and survival of osteoblasts, contributing to bone metabolic disorders such as osteoporosis. The FDA-approved polypeptide PTH 1-34 is a well-established therapy for post-menopausal osteoporosis, yet its protective effects in a palmitic acid (PA)-rich hyperlipidemic environment are not well understood. This study investigates the impact of PTH 1-34 on PA-induced cellular responses in osteoblasts. Experiments were conducted on mouse and human-derived osteoblasts as well as C57BL/6J male mice. PA was found to suppress osteoblast differentiation, increase apoptosis, and disrupt autophagy, and thereby impair cellular health. Conversely, PTH 1-34 enhanced cellular health by counteracting these effects. At the molecular level, PTH 1-34 exerted its bioactivity by modulating PTH signaling components such as cAMP and CREB. Impaired osteogenic differentiation was restored by modulating bone-anabolic genes. PTH 1-34 also improved mitochondrial health by preserving mitochondrial membrane potential and maintaining the Bax/Bcl2 ratio, thereby improving cellular viability. Additionally, PTH 1-34 regulated autophagic processes, as evidenced by balanced p62 and LC3 levels, further validated using the autophagy inhibitor Bafilomycin A1. In vivo studies in C57BL/6J male mice corroborated these findings. PTH reversed the PA action by maintaining osteoblast number and function. This study establishes the protective role of PTH 1-34 in safeguarding osteoblasts from lipotoxicity caused by excessive PA accumulation, highlighting its potential repurposing for patients with lipid-induced skeletal dysfunctions. The new data underscores the therapeutic versatility of the FDA-approved polypeptide PTH 1-34 in managing lipid-related bone health issues.

PMID:39719245 | DOI:10.1016/j.mce.2024.112445

J Control Release. 2024 Dec 22:S0168-3659(24)00906-4. doi: 10.1016/j.jconrel.2024.12.050. Online ahead of print.

ABSTRACT

Mertansine (DM1), a potent tumor-killing maytansinoid, requires conjugation to antibodies or incorporation into nanocarriers due to its high toxicity. However, these carriers often result in undesirable biodistribution, leading to rapid and long-term accumulation in the kidneys or liver and potentially increased toxicity. To overcome this limitation, we used the hydrophilic, biocompatible, and stealth properties of polyacrylamide (PAAm) as a scaffold to develop water-soluble PAAm-DM1 polymer prodrugs, leveraging PAAm's previous success in delivering paclitaxel via subcutaneous administration. To monitor distribution and predict efficacy, we have imparted Positron Emission Tomography (PET) imaging capabilities to well-defined PAAm-DM1 polymer prodrugs. Our studies demonstrated the same tumor accumulation and the same distribution of PAAm-DM1 in the main organs such as liver, kidneys muscle, regardless of delivery route (subcutaneous or intravenous). Interestingly, tumor accumulation of PAAm-DM1 was primarily driven by passive accumulation, as indicated by PET imaging, without significantly altering treatment efficacy. This suggests complex mechanisms, possibly involving immune system interactions by influencing notably the metabolism and clearance. To enhance therapeutic outcomes, we combined the polymer prodrug with immunotherapy, specifically anti-CTLA4. Our findings highlight the promising potential of PAAm-DM1, offering a novel formulation strategy for DM1 in cancer therapy.

PMID:39719212 | DOI:10.1016/j.jconrel.2024.12.050

AMB Express. 2024 Dec 24;14(1):141. doi: 10.1186/s13568-024-01809-x.

ABSTRACT

Antibiotic resistance by methicillin-resistant Staphylococcus aureus (MRSA) is an urgent threat to human health. The biofilm and persister cells formation ability of MRSA and Staphylococcus epidermidis often companied with extremely high antimicrobial resistance. Pinaverium bromide (PVB) is an antispasmodic compound mainly used for irritable bowel syndrome. Here we demonstrate that PVB could rapidly kill MRSA and S. epidermidis planktonic cells and persister cells avoiding resistance occurrence. Moreover, by crystal violet staining, viable cells counting and SYTO9/PI staining, PVB exhibited strong biofilm inhibition and eradication activities on the 96-well plates, glass surface or titanium discs. And the synergistic antimicrobial effects were observed between PVB and conventional antibiotics (ampicillin, oxacillin, and cefazolin). Mechanism study demonstrated the antimicrobial and antibiofilm effects by PVB were mainly mediated by proton motive force disrupting as well as reactive oxygen species inducing. Although, relatively poor pharmacokinetics were observed by systemic use, PVB could significantly reduce the viable bacterial cell loads and inflammatory infiltration in abscess in vivo caused by the biofilm forming strain ATCC 43,300. In all, our results indicated that PVB could be an alternative antimicrobial reagent for the treatment of MRSA, S. epidermidis and its biofilm related skin and soft tissue infections.

PMID:39718732 | DOI:10.1186/s13568-024-01809-x