Resistance Pathways Research Articles

Gut microbiota may mediate the causality of statins on diabetic nephropathy: a mediation Mendelian randomization study.

Increasing evidence indicates that statins may increase the risk of developing diabetic nephropathy (DN). As the gut-kidney axis concept gains traction, it remains unclear whether statins contribute to the onset and progression of DN by modulating gut microbiota. To investigate the association between statins and DN and the proportion of this association mediated through gut microbiota. This study utilized a two-sample Mendelian randomization (MR) approach and a cross-sectional observational design to investigate the causal relationships among statins, 473 gut microbiota, and DN. Furthermore, mediation MR analysis was employed to explore the potential mediating effects of gut microbiota in the statins-DN relationship. HMGCR inhibitors were causally linked to the increased incidence of DN (odds ratio [OR]: 0.732, 95% confidence interval [CI] 0.647, 0.828, PFDR = 0.000004). Supporting results from a cross-sectional study based on the Medical Information Marketplace in Intensive Care (MIMIC-IV) database also indicated this association (OR: 0.74, 95% CI: 0.61, 0.91, P = 0.004). Among the 473 identified gut microbiota species, 13 (PFDR < 0.05) were causally associated with DN. The mediation MR analysis revealed that 10 gut microbiota mediated the relationship between statins and DN, acting as either protective or risk factors (P < 0.05). In addition, HMGCR and related proteins may be involved in lipid metabolism, insulin resistance, and AMPK signaling pathway. Statins may become a risk factor for DN by increasing or decreasing the abundance of specific gut microbiota. These specific gut bacteria have the potential to become a new indicator for guiding the clinical use of statins in diabetic patients.

The Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer

Lung cancer has emerged as a highly aggressive malignancy posing a significant global health hazard, with a particular concern for the rising incidence and mortality of gene-altered non-small cell lung cancer (NSCLC). As the prevalence of NSCLC rises, the investigation and selection of tumor treatment techniques are gaining significance. The treatment of individuals with genetic mutations in advanced NSCLC has emphasized the application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Early and subsequent generations of EGFR-TKIs have demonstrated clinical efficacy in NSCLC patients carrying select genetic alterations. Osimertinib, a third-generation EGFR-TKI, has been sanctioned as the standard first-line therapy and is also utilized as a second-line option for individuals who develop the T790M resistance mutation following prior EGFR-TKI treatment. Approximately 10 to 30 percent of patients diagnosed with NSCLC exhibit EGFR mutations. This leads to abnormal activation of cancer genes and inactivation of tumor suppressor genes, resulting in poor prognosis for patients. This paper aims to analyze the development and resistance processes of EGFR inhibitors, thereby enhancing the comprehension of the resistance pathways to EGFR-TKIs.

Transgenic expression of SeCYP9A186 and PxFMO2 confers resistance to emamectin benzoate in Plutella xylostella.

The overexpression of metabolic enzymes constitutes a crucial mechanism for insects to detoxify xenobiotics and metabolic pesticides. A flavin-containing monooxygenase gene (PxFMO2) from Plutella xylostella and a P450 gene (SeCYP9A186, F116V mutant allele) from Spodoptera exigua have been reported to be involved in insecticide resistance. In this study, we aim to utilize transgenic technology to validate their in vivo detoxification functions in Plutella xylostella. We established two transgenic strains of Plutella xylostella with expressing an endogenous PxFMO2 gene from Plutella xylostella and an exogenous SeCYP9A186 gene from S. exigua, respectively. Bioassays demonstrated that the transgenic Plutella xylostella strain (IPP-FMO2) expressing PxFMO2 exhibited a 12-fold resistance to emamectin benzoate and a 6.4-fold resistance to chlorantraniliprole compared to the background strain (IPP-S). In contrast, the transgenic Plutella xylostella strain (IPP-9A186) expressing SeCYP9A186 displayed a 235-fold resistance to emamectin benzoate and a 115-fold resistance to abamectin. Moreover, resistance to emamectin benzoate in the IPP-9A186 strain of Plutella xylostella was inherited as an incompletely dominant trait and was genetically linked to the transgene locus. Our results not only elucidated the in vivo contribution of the PxFMO2 and SeCYP9A186 to the insecticide resistance phenotype in Plutella xylostella, but also provided a genetic engineering toolkit to manipulate resistance pathways. These insights and methodologies could further aid in developing sustainable pest management strategies in Plutella xylostella. © 2024 Society of Chemical Industry.

Advances in Understanding Drug Resistance Mechanisms and Innovative Clinical Treatments for Melanoma.

Melanoma, a highly invasive skin cancer resulting from melanocyte malignant transformation, is the third most common skin malignancy. Despite accounting for only 4% to 5% of all skin malignancies, it is responsible for 80% of skin cancer-related deaths. Targeted therapies and immune checkpoint inhibitors have improved survival rates, yet drug resistance remains a major challenge. In this review, I explore the latest research progress on melanoma drug resistance mechanisms and clinical treatment methods. This aims to provide insights for more effective treatment strategies and improve patient prognosis and quality of life. I also discuss potential strategies to overcome drug resistance based on the latest scientific findings, with a particular focus on the complex and multi-factorial drug resistance mechanisms of melanomas, including genetic mutations, epigenetic changes, and tumor microenvironment factors. Understanding these mechanisms is crucial for developing new drugs and combination therapies targeting drug-resistant tumors. Analyzing complex drug resistance pathways paves the way for personalized medical approaches, which is expected to provide enlightenment on breaking through drug resistance barriers and enhancing the effectiveness of melanoma treatment.

Exploration of the key active ingredients and mechanisms of Sparganii Rhizoma-Curcumae Rhizoma compatible formulation against human colorectal cancer through network pharmacology and in vitro experiments

IntroductionSparganii Rhizoma-Curcumae Rhizoma (SR-CR) formulation may offer an effective treatment for human colorectal cancer (CRC). However, the active ingredients and underlying mechanisms of this herbal formulation remain unclear. MethodsThis study integrates network pharmacology, molecular docking and experimental verification to identify key active ingredients and elucidate the mechanisms of SR-CR in CRC treatment. ResultsTwenty-three active components of SR-CR were identified using the TCMSP, UniProt and Gene Cards databases. These components were associated with 178 targets, of which 118 are directly related to CRC. Protein-protein interaction (PPI) network analysis identified protein kinase B (AKT) 1, epidermal growth factor receptor (EGFR), SRC, Bcl2 and CASP3 as core anti-CRC targets. Gene Ontology (GO) and KEGG pathway analyses were performed on these 178 intersecting targets, and the results showed that these targets are involved in EGFR tyrosine kinase inhibitor resistance and AGE-RAGE signaling pathway in diabetic complications. At the same time, five compounds, including bisdemethoxycurcumin, formononetin, β-sitosterol, stigmasterol and hederagenin, were selected based on the target number of effective components and tested for cytotoxicity against human CRC cell lines HT-29, HCT-8 and HCT-116 in vitro. The results showed that bisdemethoxycurcumin exhibited significant anti-proliferative activity against HCT-116 cells. Molecular docking results indicated that bisdemethoxycurcumin effectively binds with AKT, EGFR, Bcl-2 and CASP3. Further pharmacological experiments demonstrated that bisdemethoxycurcumin inhibits HCT-116 cell proliferation and migration via inhibiting EGFR-AKT pathway, and induces apoptosis by up-regulating Bcl-2 expression. DiscussionBased on our study, inhibiting the EGFR-AKT pathway and upregulating Bcl2 may be one of the mechanisms by which SR-CR inhibits the growth of CRC. The main active ingredients of SR-CR include bisdemethoxycurcumin, formononetin, β-sitosterol, stigmasterol and hederagenin, which may exert anti-colon cancer activity by targeting the regulation of AKT, EGFR, Bcl-2 and CASP3. However, we need more in vitro and in vivo evidence to confirm this conclusion. This study lays the foundation for further research on the pharmacological mechanism of SR-CR in the treatment of CRC.

Transcriptome Comparison between Resistant and Susceptible Soybean Cultivars in Response to Inoculation of Phytophthora sojae.

Phytophthora root and stem rot, caused by Phytophthora sojae, considerably reduces soybean yield worldwide. Our previous study identified two genomic regions on chromosome 18 (2.1-2.6 and 53.1-53.3 Mbp) that confer resistance to the P. sojae isolate 2457, through linkage analysis using progenies derived from the Daepung × Socheong2 population. These two regions contained 51 and 19 annotated genes, respectively. However, the specific gene responsible for resistance to P. sojae isolate 2457 has yet to be identified. In this study, we performed a comparative transcriptomic analysis of Socheong2 and Daepung, two Korean soybean varieties identified as resistant and susceptible to P. sojae isolate 2457, respectively. RNA sequencing was conducted on tissue samples collected at 0, 6, and 12 hours after inoculation (HAI), and significant differences in the expression of defense-related genes were observed across time points and between the two cultivars. Genes associated with the jasmonic acid, salicylic acid, ethylene, and systemic acquired resistance pathways were upregulated in both cultivars at 6 and 12 HAI compared to 0 HAI, with these biological processes were more strongly upregulated in Socheong2 compared to Daepung at 6 and 12 HAI. A comparison of differentially expressed genes (DEGs) and candidate genes within the previously identified QTL regions revealed an ortholog of the HS1 PRO-1 2 gene from Arabidopsis thaliana among the upregulated DEGs in Socheong2, particularly at 12 HAI compared to 0 HAI. This study will aid in targeted breeding efforts to develop soybean varieties with improved resistance to P. sojae.

Investigation of TSRP reverses imatinib resistance through the PI3K / Akt pathway in chronic myeloid leukemia.

Chronic myelogenous leukemia (CML) is a malignant tumor of the blood system, so far there is no effective cure. Imatinib (IM), as the first-line drug for the clinical targeted treatment of CML, has some limiting factors such as drug resistance and relapse, and drug resistance has also emerged in combination with other drugs. At present, traditional Chinese medicine combined with targeted drugs in the treatment of tumor is a research hotspot. The total saponin of L. (TSRP) has an effective anti-tumor activity. Our previous in vitro experiments showed that TSRP can effectively inhibit the proliferation and promote apoptosis of CML cells K562, suggesting that TSRP can effectively reverse the drug resistance of IM, but the mechanism of drug resistance remains unclear. Studies have shown that the PI3K/AKT pathway is the main activation pathway of IM secondary resistance, and is considered to be an innovative therapeutic strategy for targeted cancer treatment, which may be an important mechanism of IM resistance. This project aims to reveal the possible mechanism of TSRP reversing IM resistance through PI3K/AKT signaling pathway through both in vitro and in vivo experiments, providing experimental basis for TSRP combined with IM treatment of CML.

Next-generation combination approaches for immune checkpoint therapy.

Immune checkpoint therapy has revolutionized cancer treatment, leading to dramatic clinical outcomes for a subset of patients. However, many patients do not experience durable responses following immune checkpoint therapy owing to multiple resistance mechanisms, highlighting the need for effective combination strategies that target these resistance pathways and improve clinical responses. The development of combination strategies based on an understanding of the complex biology that regulates human antitumor immune responses has been a major challenge. In this Review, we describe the current landscape of combination therapies. We also discuss how the development of effective combination strategies will require the integration of small, tissue-rich clinical trials, to determine how therapy-driven perturbation of the human immune system affects downstream biological responses and eventual clinical outcomes, reverse translation of clinical observations to immunocompetent preclinical models, to interrogate specific biological pathways and their impact on antitumor immune responses, and novel computational methods and machine learning, to integrate multiple datasets across clinical and preclinical studies for the identification of the most relevant pathways that need to be targeted for successful combination strategies.

Metabolomic profiles of stony coral species from the Dry Tortugas National Park display inter- and intraspecies variation.

Previous research profiling gene expression, proteins, and metabolites produced during thermal stress have reported the importance of endosymbiont-derived pathways in coral bleaching resistance. However, our understanding of interspecies variation in these pathways among healthy corals and their role in diseases is limited. We surveyed the metabolomes of four species of healthy corals with differing susceptibilities to the devastating stony coral tissue loss disease and applied advanced annotation approaches in untargeted metabolomics to determine the interspecies variation in host and endosymbiont-derived pathways. Using this approach, we propose the survey of immune markers such as vitamin E family compounds, acylcarnitines, and other metabolites to infer their role in resilience to coral diseases. As time-resolved multi-omics datasets are generated for disease-impacted corals, our approach and findings will be valuable in providing insight into the mechanisms of disease resistance.

Are we there yet? CAR-T therapy in multiple myeloma.

The last few years have seen a revolution in cellular immunotherapies for multiple myeloma (MM) with novel antigen targets. The principle new target is B-cell maturation antigen (BCMA). Autologous chimeric antigen receptor T-cell (CAR-T) therapy directed against BCMA was first approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2021, although approval by the National Institute for Health and Care Excellent (NICE) is awaited. Initial response rates in patients with heavily pretreated MM have been impressive, but patients are still relapsing. Furthermore, CAR-T manufacturing is expensive and time-consuming, and T-cell fitness is impaired by prior MM treatment. Numerous strategies to improve outcomes and delivery of cellular immunotherapy are under investigation, including next-generation CARs, allogeneic 'off-the-shelf' CARs and targeting of other MM antigens including G protein-coupled receptor, class C, group 5, member D (GPRC5D), Fc receptor homologue 5 (FcRH5), cluster of differentiation (CD)19, signalling lymphocyte activation molecule family member 7 (SLAMF7) and several others. In this exciting and rapidly evolving treatment landscape, this review evaluates the most recent clinical and preclinical data pertaining to these new cellular immunotherapies and explores strategies to overcome resistance pathways. On the protracted journey to a long-term cure, we outline the challenges that lie ahead and ask, 'Are we there yet?'

Multilevel Mechanisms of Cancer Drug Resistance.

Cancer drug resistance represents one of the most significant challenges in oncology and manifests through multiple interconnected molecular and cellular mechanisms. Objective: To provide a comprehensive analysis of multilevel processes driving treatment resistance by integrating recent advances in understanding genetic, epigenetic, and microenvironmental factors. This is a systematic review of the recent literature focusing on the mechanisms of cancer drug resistance, including genomic studies, clinical trials, and experimental research. Key findings include the following: (1) Up to 63% of somatic mutations can be heterogeneous within individual tumors, contributing to resistance development; (2) cancer stem cells demonstrate enhanced DNA repair capacity and altered metabolic profiles; (3) the tumor microenvironment, including cancer-associated fibroblasts and immune cell populations, plays a crucial role in promoting resistance; and (4) selective pressure from radiotherapy drives the emergence of radioresistant phenotypes through multiple adaptive mechanisms. Understanding the complex interplay between various resistance mechanisms is essential for developing effective treatment strategies. Future therapeutic approaches should focus on combination strategies that target multiple resistance pathways simultaneously, guided by specific biomarkers.

Advances in research on the relationship between mitochondrial function and colorectal cancer: a bibliometric study from 2013 to 2023.

The study provides a thorough examination of literature from 2013 to 2023, delving into the intricate relationship between mitochondrial function and colorectal cancer (CRC). It offers a concise overview of the current landscape and emerging trends in this rapidly evolving research area. The findings indicate a consistent rise in annual publications, reflecting growing interest and significant potential in the field. China emerges as the leading contributor, followed by the United States and India. However, despite China's dominance in output, its average citation rate is lower than that of the US, which leads in citations per publication, highlighting a noticeable disparity. In the realm of research institutions, Shanghai Jiao Tong University and China Medical University are identified as major contributors, yet the potential for inter-institutional collaboration remains largely untapped, suggesting avenues for future synergy. Internationally, China-US collaborations are particularly robust, fostering cross-border knowledge exchange. Hyun Jin Won and Li Wei are recognized as prolific authors, while Ahmedin Jemal is an influential co-cited scholar, noted for his seminal contributions. Keyword analysis reveals research focus areas, such as the complex CRC tumor microenvironment, molecular mechanisms of oxidative stress, and key multidrug resistance pathways. It also highlights the promising potential of mitochondria-targeted therapies and nanomolecular technologies in clinical practice, signaling their growing significance in addressing complex health challenges. The study underscores the imperative to validate complex mitochondrial mechanisms and signaling pathways in CRC, with a particular emphasis on translating these insights into drug targets for clinical trials. Advancing this research is expected to refine and enhance CRC treatment strategies. Additionally, it highlights the urgency of validating mitochondrial complexities in CRC, advocating for collaborative efforts to link these mechanisms with tailored therapeutic interventions for clinical testing. This integrated approach promises significant advancements in developing effective, targeted CRC treatments, ultimately improving patient outcomes.

Phyllanthi Fructus ameliorates hyperuricemia and kidney injure via inhibiting uric acid synthesis, modulating urate transporters, and alleviating inflammation

Phyllanthi Fructus, known as Yuganzi (YGZ), is a unique medicine and food homologous fruit with both medicinal and nutritional properties. Its historical use in treating hyperuricemia (HUA) and gout is well-documented. However, the precise therapeutic effects and potential molecular mechanisms remain unclear. In this study, an experimental rat modelling by a high-fat/high-sugar diet and potassium oxonate/adenine oral administration was used to evaluate the pharmacodynamic effects of YGZ. Network pharmacology, molecular docking and molecular dynamics simulation were utilized to elucidate the potential mechanisms. Supplementation with YGZ effectively ameliorated HUA by inhibiting xanthine oxidase activity, and enhancing uric acid excretion through up-regulating of OAT1 and ABCG2, while down-regulating of URAT1. Furthermore, YGZ supplementation enhanced superoxide dismutase activity, reduced malondialdehyde content, and inhibited the secretion of IL1B, IL6, TNFα, ICAM1, VCAM1, TGFβ1, and NF-κB protein expression. Network pharmacology analysis indicated that YGZ influences 138 targets, modulating the disease network via lipid and atherosclerosis, insulin resistance, HIF-1, TNF, IL-17, TLRS, and NF-κB signaling pathways. Molecular docking analysis suggested that organic acids (e.g. ellagic acid, gallic acid) and flavonoids (e.g. quercetin, delphinidin, luteolin, epigallocatechin gallate) exhibited superior binding abilities to key targets (e.g. XDH, ABCG2, URAT1, OAT1, IRS1, PTGS2, TLR4). Noteworthy, molecular dynamics simulations confirmed that epigallocatechin gallate binds to URAT1 with the greatest stability. These results provide substantial evidence for the therapeutic efficacy of YGZ and establish a theoretical foundation for the development of natural products in treating hyperuricemia.

DDDR-42. LEVERAGING GENOME-WIDE CRISPR/CAS9 KNOCKOUT DRUG SCREENS TO IDENTIFY SENSITIZERS FOR PROTEOSOME INHIBITORS IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis despite aggressive treatment. Patient outcomes remain abysmal with 95% of patients relapsing and a median overall survival of 15 months. This necessitates the rapid search for personalized therapeutics and agents to enhance current treatments. One pathway that demonstrates dysregulated functioning is the ubiquitin-proteasome pathway (UPP). Literature has shown that UPP dependent proteolysis remains constitutively upregulated in cancer cells leading to the rapid degradation of proteins that regulate oncogenic pathways. Despite robust preclinical evaluations for the usage of proteasome inhibitors against GBM, most proteasome inhibitors failed in clinical trials, indicating resistance. We conducted an unbiased genome wide CRISPR-Cas9 screen in HAP1 cells treated with the proteasome inhibitor, Bortezomib (BTZ), to identify genes leading to a BTZ-resistant phenotype. We identified several genes that when perturbed, sensitized cells to BTZ including N-glycanase-1 (NGLY-1), Nuclear factor Erythroid 2-Like-1 (NFE2L1), and DNA damage inducible 1 homolog 2 (DDI2). Herein, we sought to evaluate the effects of perturbing these identified genes in our patient derived GBM cell lines by utilizing CRISPR/Cas9 knockout technology in vitro and in vivo. The generation of NGLY-1, DDI2, and NFE2L1 KO cell lines demonstrated functional sensitivity to the proteasome inhibitor Marizomib (MZB) as observed through a significant reduction of the IC50 in the KO cell lines compared to an adeno-associated virus integration site 1 (AAVS1) control. Functional evaluation also demonstrated reduced proliferation capacity and sphere formation in our KO GBM lines. Ongoing in vivo work will aim to evaluate the mitigation of this resistant pathway in our NSG mouse models orthotopically transplanted with our patient derived KO cell lines. In an ongoing collaborative effort, we aim to functionally assess a novel small molecule NGLY-1 inhibitor for preclinical sensitivity to MZB in our in vitro and in vivo models.

Network Pharmacology and Molecular Dynamics Simulations Reveal the Mechanism of Total Alkaloid Components in Anisodus Tanguticus (Maxim.) Pascher in Treating Inflammation and Pain.

This study aimed to elucidate the mechanism that total alkaloids in Anisodus tanguticus (AT)(Maxim.) Pascher played anti-inflammatory and analgesic effects. In this paper, the anti-inflammatory effect in the total alkaloids of AT was confirmed via lipopolysaccharide (LPS)-induced inflammation model in RAW 264.7 cells and the main components of AT were immediately analyzed by UPLC/MS. Disease targets were obtained in GeneCards and DisGeNET. Targets of major compounds were searched in ETCM, TCMSP and other databases. The protein-protein interaction (PPI) network was constructed using STRING database, and Cytoscape was used for core targets screening. GO and KEGG enrichment analysis were performed using Daivid database. Sailvina was used for molecular docking. Molecular dynamics simulation analysis was performed using the Amber 20 program. The results showed that the main components in AT were anisodamine, atropine, fabiatrin, scopolamine, scopoletin and scopolin, possibly exerting anti-inflammatory and analgesic effects through pathways such as EGFR tyrosine kinase inhibitor resistance and IL-17 signaling pathway. Fabiatrin and scopolin could be potential drugs with good anti-inflammatory and analgesic effects.

The engagement of Ras/Raf/MEK/ERK and PLCγ1/PKC pathways regulated by TrkB receptor in resistance of glioma cells to elimination upon apoptosis induction

The most aggressive tumors of human central nervous system are anaplastic astrocytoma (AA, III grade) and glioblastoma multiforme (GBM, IV grade) with an extremely bad prognosis. Their malignant character and resistance to standard therapy are correlated to the over-expression of survival pathways such as Ras/Raf/MEK/ERK and PLCγ1/PKC regulated by TrkB receptor. Therefore, the aim of this study was to investigate the engagement of those pathways in human glioma cells resistance for apoptosis induction by Temozolomide treatment. Two cancer MOGGCCM (AA) and T98G (GBM) and normal human astrocytes (NHA) cell lines were utilized. The tested inhibitors single and simultaneous action with Temozolomide affection on apoptosis induction was analyzed by MTT, microscopic observations and flow cytometry. Bcl-2:beclin-1 complexes occurrence was also assessed. siRNAs were used for direct proof of tested pathways engagement in gliomas resistance to apoptosis elimination. The most effective in eliminating gliomas with minimal astrocyte damage was 5 μM PLCγ1 inhibitor (U-73122) for MOGGCCM and 15 μM for T98G cells, and 1 μM LOXO-101 for all cancer cells. Sorafenib, Temozolomide, U-73122, and LOXO-101 effectively eliminate cancer cells. Single applications of sorafenib and Temozolomide were effective, but had lower efficiency than U-73122 and LOXO-101. These drugs induced apoptosis, affecting mitochondrial membrane potential and caspases 3, 8, and 9 activity. The study found that a Bcl-2:beclin-1 complex formation was observed when apoptosis was dominant. Inhibiting the pathways regulated by TrkB receptor combined with Temozolomide action, led to successful gliomas elimination. Those results might serve as basis for modern targeted treatment development.

Metabolite Profiling and Integrated Network Pharmacology Based Mechanism of Benincasa hispida (Thunb.) Cogn. Fruit Against Non-insulin-Dependent Diabetes Mellitus.

Benincasa hispida (Thunb.) Cogn. (Cucurbitaceae) is an essential food plant in India possessing antihyperglycemic and antihyperlipidemic activities. The objective included comparative estimation of α-glucosidase and α-amylase enzyme inhibition potential of B. hispida fractions prepared by microwave-assisted extraction and prediction of metabolite interaction against non-insulin-dependent diabetes mellitus by metabolite profiling based network pharmacology analysis. A validated microwave-assisted extraction method was employed to obtain different fractions of B. hispida fruits. The invitro enzyme assay was done with p-nitrophenyl-α-D-glucopyranoside and acarbose as standard to evaluate antidiabetic potential. The phytomolecules present in the active fraction wereidentified by UHPLC-QToF-MS/MS analysis. Network pharmacology analysis gave possible gene and disease association, combination synergy network, and predicted probable mechanism of action. The highest enzyme inhibition potential (IC50) was shown by the ethyl acetate fraction (0.546 ± 0.17 mg/mL and 1.134 ± 0.42 mg/mL) compared to acarbose (0.298 ± 0.08 mg/mL and 0.532 ± 0.38 mg/mL), respectively, for α-glucosidase and α-amylase addressing the potential role in ameliorating non-insulin-dependent diabetes mellitus. Metabolite profiling resulted in the identification of 17 metabolites, and a synergy between the identified molecules suggested multimolecule action in the amelioration of non-insulin-dependent diabetes mellitus through insulin resistance pathway, AMPK signaling pathway, PPAR signaling pathway, and PI3K-Akt signaling pathway. Combination synergy of identified molecules was observed through a multitarget approach to manage non-insulin-dependent diabetes mellitus. Polyphenol-enriched fraction of B. hispida fruits and identified phytocompounds ameliorate non-insulin-dependent diabetes mellitus. Thus, enriched extract of B. hispida can be further investigated in order to develop high-quality, safe, and effective products for the management of non-insulin-dependent diabetes mellitus.

Dual Transcriptome Analysis Reveals the Changes in Gene Expression in Both Cotton and Verticillium dahliae During the Infection Process.

Cotton is often threatened by Verticillium wilt caused by V. dahliae. Understanding the molecular mechanism of V. dahlia-cotton interaction is important for the prevention of this disease. To analyze the transcriptome profiles in V. dahliae and cotton simultaneously, the strongly pathogenic strain Vd592 was inoculated into cotton, and the infected cotton roots at 36 h and 3 d post infection were subjected to dual RNA-seq analysis. For the V. dahliae, transcriptomic analysis identified 317 differentially expressed genes (DEGs) encoding classical secreted proteins, which were up-regulated at least at one time point during infection. The 317 DEGs included 126 carbohydrate-active enzyme (CAZyme) and 108 small cysteine-rich protein genes. A pectinesterase gene (VDAG_01782) belonging to CAZyme, designated as VdPE1, was selected for functional validation. VdPE1 silencing by HIGS (host-induced gene silencing) resulted in reduced disease symptoms and the increased resistance of cotton to V. dahliae. For the cotton, transcriptomic analysis found that many DEGs involved in well-known disease resistance pathways (flavonoid biosynthesis, plant hormone signaling, and plant-pathogen interaction) as well as PTI (pattern-triggered immunity) and ETI (effector-triggered immunity) processes were significantly down-regulated in infected cotton roots. The dual RNA-seq data thus potentially connected the genes encoding secreted proteins to the pathogenicity of V. dahliae, and the genes were involved in some disease resistance pathways and PTI and ETI processes for the susceptibility of cotton to V. dahliae. These findings are helpful in the further characterization of candidate genes and breeding resistant cotton varieties via genetic engineering.

Data-Driven Approaches in Antimicrobial Resistance: Machine Learning Solutions.

Background/Objectives: The emergence of antimicrobial resistance (AMR) due to the misuse and overuse of antibiotics has become a critical threat to global public health. There is a dire need to forecast AMR to understand the underlying mechanisms of resistance for the development of effective interventions. This paper explores the capability of machine learning (ML) methods, particularly unsupervised learning methods, to enhance the understanding and prediction of AMR. It aims to determine the patterns from AMR gene data that are clinically relevant and, in public health, capable of informing strategies. Methods: We analyzed AMR gene data in the PanRes dataset by applying unsupervised learning techniques, namely K-means clustering and Principal Component Analysis (PCA). These techniques were applied to identify clusters based on gene length and distribution according to resistance class, offering insights into the resistance genes' structural and functional properties. Data preprocessing, such as filtering and normalization, was conducted prior to applying machine learning methods to ensure consistency and accuracy. Our methodology included the preprocessing of data and reduction of dimensionality to ensure that our models were both accurate and interpretable. Results: The unsupervised learning models highlighted distinct clusters of AMR genes, with significant patterns in gene length, including their associated resistance classes. Further dimensionality reduction by PCA allows for clearer visualizations of relationships among gene groupings. These patterns provide novel insights into the potential mechanisms of resistance, particularly the role of gene length in different resistance pathways. Conclusions: This study demonstrates the potential of ML, specifically unsupervised approaches, to enhance the understanding of AMR. The identified patterns in resistance genes could support clinical decision-making and inform public health interventions. However, challenges remain, particularly in integrating genomic data and ensuring model interpretability. Further research is needed to advance ML applications in AMR prediction and management.

Cefiderocol in Combating Carbapenem-Resistant Acinetobacter baumannii: Action and Resistance.

Acinetobacter baumannii (A. baumannii) has emerged as a prominent multidrug-resistant (MDR) pathogen, significantly complicating treatment strategies due to its formidable resistance mechanisms, particularly against carbapenems. Reduced membrane permeability, active antibiotic efflux, and enzymatic hydrolysis via different β-lactamases are the main resistance mechanisms displayed by A. baumannii, and they are all effective against successful treatment approaches. This means that alternate treatment approaches, such as combination therapy that incorporates beta-lactams, β-lactamase inhibitors, and novel antibiotics like cefiderocol, must be investigated immediately. Cefiderocol, a new catechol-substituted siderophore cephalosporin, improves antibacterial activity by allowing for better bacterial membrane penetration. Due to its unique structure, cefiderocol can more efficiently target and destroy resistant bacteria by using iron transport systems. Through its inhibition of peptidoglycan formation through binding to penicillin-binding proteins (PBPs), cefiderocol avoids conventional resistance pathways and induces bacterial cell lysis. The possibility of resistance development due to β-lactamase synthesis and mutations in PBPs, however, emphasizes the need for continued investigation into cefiderocol's efficacy in combination treatment regimes. Cefiderocol's siderophore mimic mechanism is especially important in iron-limited conditions because it can use ferric-siderophore transporters to enter cells. Additionally, its passive diffusion through bacterial porins increases its intracellular concentrations, making it a good option for treating carbapenem-resistant A. baumannii, especially in cases of severe infections and ventilator-associated diseases (IVACs). Cefiderocol may reduce MDR infection morbidity and mortality when combined with customized antimicrobial treatments, but further investigation is needed to improve patient outcomes and address A. baumannii resistance issues.