Search Results (417)

Mitochondria, pivotal organelles in cellular metabolism and energy production, have emerged as critical players in the pathogenesis of cancer. This review outlines the progress in mitochondrial profiling through mass spectrometry-based metabolomics and its applications in cancer research. We provide unprecedented insights into the mitochondrial metabolic rewiring that fuels tumorigenesis, metastasis, and therapeutic resistance. The purpose of this review is to provide a comprehensive guide for the implementation of mitochondrial metabolomics, integrating advanced methodologies—including isolation, detection, and data integration—with insights into cancer-specific metabolic rewiring. We first summarize current methodologies for mitochondrial sample collection and pretreatment. Furthermore, we then discuss the recent advancements in mass spectrometry-based methodologies that facilitate the detailed profiling of mitochondrial metabolites, unveiling significant metabolic reprogramming associated with tumorigenesis. We emphasize how recent technological advancements have addressed longstanding challenges in the field and explore the role of mitochondrial metabolism-driven cancer development and progression for novel drug discovery and translational research applications in cancer. Collectively, this review delineates emerging opportunities for therapeutic discovery and aims to establish a foundation for future investigations into the therapeutic modulation of mitochondrial pathways in cancer, thereby paving the way for innovative diagnostic and therapeutic approaches targeting mitochondrial pathways. Full article

Background: Intravenous vancomycin remains a key agent in the treatment of complex orthopedic infections, particularly those involving methicillin-resistant Staphylococcus aureus (MRSA). However, its use is associated with significant risks, most notably nephrotoxicity. Despite guideline recommendations, standardized dosing and monitoring protocols are often absent in orthopedic settings, leading to inconsistent therapeutic drug exposure and preventable adverse events. This study evaluated the clinical impact of implementing a structured standard operating procedure (SOP) for intravenous vancomycin therapy in orthopedic inpatients. Methods: We conducted a single-center, pre-post cohort study at a university orthopedic department. The intervention consisted of a standard operating procedure (SOP) for intravenous vancomycin therapy, which mandated weight-based loading doses, renal function-adjusted maintenance dosing, trough level monitoring, and defined dose adjustments. Patients treated before SOP implementation (n = 58) formed the control group; those treated under the SOP (n = 56) were prospectively included. The primary outcome was the incidence of vancomycin-associated acute kidney injury (VA-AKI) defined by KDIGO Stage 1 criteria. Secondary outcomes included therapeutic trough level attainment and infusion-related or ototoxic adverse events. Results: All patients in the post-SOP group received a loading dose (100% vs. 31% pre-SOP, p < 0.001). The range of measured vancomycin trough levels narrowed substantially after SOP implementation (7.1–36.2 mg/L vs. 4.0–80.0 mg/L). The proportion of patients reaching therapeutic trough levels increased, although this was not statistically significant. Most notably, VA-AKI occurred in 17.2% of patients in the control group, but in none of the patients after SOP implementation (0%, p = 0.0013). No cases of ototoxicity were observed in either group. Infusion-related reactions decreased after the implementation of the SOP, though not significantly. Conclusions: The introduction of a structured vancomycin protocol significantly reduced adverse drug events and improved dosing control in orthopedic inpatients. Incorporating such protocols into routine practice represents a feasible and effective strategy to strengthen antibiotic stewardship and clinical quality in surgical disciplines. Full article

Background and Objectives: Colorectal cancer (CRC) is one of the most frequently diagnosed malignancies worldwide. Although chemotherapy is an effective treatment for colorectal cancer (CRC), its effectiveness is frequently hindered by the emergence of resistant cancer cells. Studies have demonstrated a linkage between drug resistance and the pregnane X receptor (PXR), which influences the metabolism and the transport of chemotherapeutic agents. Likewise, autophagy is also a well-established mechanism that contributes to chemotherapy resistance, and it is closely tied to tumor progression. This pre-clinical study aims to investigate the role of mtKRAS-dependent autophagy with PXR expression after treatment with Irinotecan in colorectal cancer. Methods: CRC lines were treated with specific inhibitors, such as 3-methyladeninee, hydroxychloroquine PI-103, and irinotecan hydrochloride, and subjected to various assays, including MTT for cell viability, Western blot for protein expression, siRNA-mediated PXR knock-out, and confocal microscopy for autophagic vacuole visualization. Protein quantification, gene knockdown, and subcellular localization studies were performed under standardized conditions to investigate treatment effects on autophagy and apoptosis pathways. Conclusions: Our experiments showed that PXR knockdown does not alter autophagy levels following Irinotecan treatment, but it promotes apoptotic cell death despite elevated autophagy. Moreover, late-stage autophagy inhibition reduces PXR expression, whereas induction through PI3K/AKT/mTOR inhibition leads to increased expression of PXR. Our experiments uncover a mechanism by which autophagy facilitates the nuclear translocation of the PXR, thereby promoting resistance to Irinotecan across multiple cell lines. Full article

Worldwide, several million people are infected with mycobacteria such as Mycobacterium tuberculosis (M. tb) or non-tuberculous mycobacteria (NTM). In 2023, 10.8 million cases and 1.25 million deaths due to M. tb were recorded. In Europe and North America, the emergence of NTM is tending to outstrip that of M. tb. Among pulmonary NTM, Mycobacterium avium complex (MAC) is the most common, accounting for 80% of NTM infections. First-line treatment requires the combination of at least three antibiotics over a long period and with different mechanisms of action to limit cross-resistance. The challenge is to discover more effective new anti-MAC molecules to reduce the duration of treatment and to overcome resistant strains. The aim of this review is to present an overview of the challenges posed by MAC infection such as side effects, reinfections and resistance mechanisms. The latest therapeutic options such as the optimized combination therapy, drug repurposing and the development of new formulations, as well as new anti-MAC compounds currently in (pre)clinical trials will also be discussed. Full article

Background/Objectives: Clostridium perfringens is a normal inhabitant of the intestinal tract of poultry, and it has the potential to induce cholangiohepatitis and necrotic enteritis (NE). The poultry industry suffers significant financial losses because of NE, and treatment becomes more challenging due to resistant C. perfringens strains. Methods: The antimicrobial and antibiofilm activities of cellulose nanocrystals/zinc oxide nanocomposite (CNCs/ZnO) were assesses against pan drug-resistant (PDR) C. perfringens isolated from chickens and turkeys using phenotypic and molecular assays. Results: The overall prevalence rate of C. perfringens was 44.8% (43.75% in chickens and 58.33% in turkeys). Interestingly, the antimicrobial susceptibility testing of C. perfringens isolates revealed the alarming PDR (29.9%), extensively drug-resistant (XDR, 54.5%), and multidrug-resistant (MDR, 15.6%) isolates, with multiple antimicrobial resistance (MAR) indices ranging from 0.84 to 1. All PDR C. perfringens isolates could synthesize biofilms; among them, 21.7% were strong biofilm producers. The antimicrobial potentials of CNCs/ZnO against PDR C. perfringens isolates were evaluated by the agar well diffusion and broth microdilution techniques, and the results showed strong antimicrobial activity of the green nanocomposite with inhibition zones’ diameters of 20–40 mm and MIC value of 0.125 µg/mL. Moreover, the nanocomposite exhibited a great antibiofilm effect against the pre-existent biofilms of PDR C. perfringens isolates in a dose-dependent manner [MBIC50 up to 83.43 ± 1.98 for the CNCs/ZnO MBC concentration (0.25 μg/mL)]. The transcript levels of agrB quorum sensing gene and pilA2 type IV pili gene responsible for biofilm formation were determined by the quantitative real time-PCR technique, pre- and post-treatment with the CNCs/ZnO nanocomposite. The expression of both genes downregulated (0.099 ± 0.012–0.454 ± 0.031 and 0.104 ± 0.006–0.403 ± 0.035, respectively) when compared to the non-treated isolates. Conclusions: To the best of our knowledge, this is the first report of CNCs/ZnO nanocomposite’s antimicrobial and antibiofilm activities against PDR C. perfringens isolated from chickens and turkeys. Full article

We developed a novel biodegradable poly(lactic-co-glycolic acid) (PLGA) polymer chemically modified with paclitaxel (PTX) to form a PLGA-PTX hybrid. Pre-modification of PTX enhanced its loading in PLGA-PTX nanoparticles (NPs). Background/Objectives: PTX is one of the most effective chemotherapy agents used in cancer therapy. The primary mode of PTX’s action is the hyperstabilization of microtubules leading to cell growth arrest. Although highly potent, the drug is water insoluble and requires the Cremophor EL excipient. The toxic effects of the free drug (e.g., neurotoxicity) as well as its solubilizing agent are well established. Thus, there is strong clinical rationale and need for exploring alternative PTX delivery approaches, retaining biological activity and minimizing systemic effects. Methods: The PTX modification method features reacting the C-2′ and C-7 residues with a linker (succinic anhydride) to produce easily accessible carboxyl groups on the PTX for enhanced coupling to the hydroxyl group of PLGA. The PLGA-PTX hybrid, formed via esterification reaction, was used to formulate lipid-coated PLGA-PTX NPs. As proof of concept, the PLGA-PTX NPs were tested in ovarian cancer (OvCA) models, including several patient-derived cell lines (PDCLs), one of which was generated from a platinum-resistant patient. Results: The PLGA-PTX NPs critically remained stable in water and serum while enabling slow drug release. Importantly, PLGA-PTX NPs demonstrated biological activity. Conclusions: We suggest that this approach offers both a new and effective PTX formulation and a possible path towards the development of a new generation of OvCA treatment. Full article

Background/Objectives: Philadelphia has experienced a surge in illicit fentanyl adulterated with alpha-2 agonist sedatives. Initially, xylazine (“tranq”) was the predominant adulterant, and a novel multimodal withdrawal protocol was effective at mitigating symptoms. However, since mid-2024, medetomidine—a more potent sedative—has largely supplanted xylazine. Clinicians have reported more severe, treatment-resistant opioid withdrawal during this transition. To assess whether a previously effective withdrawal management protocol retained efficacy after the emergence of medetomidine as the primary fentanyl adulterant in a community. Methods: We conducted a retrospective cohort study of patients receiving protocol-based opioid withdrawal treatment at two emergency departments in Philadelphia between September 2022 and April 2025. Patients were divided into the xylazine era (September 2022–July 2024) and medetomidine era (August 2024–April 2025). The primary outcome was a change in Clinical Opioid Withdrawal Scale (COWS) score from pre- to post-treatment. Secondary outcomes included rates of discharge against medical advice (AMA) and ICU admission, as well as the impact of a revised treatment protocol. Results: Among 1269 encounters with full data, 616 occurred during the xylazine era and 770 during the medetomidine era. Median COWS reduction was greater in the xylazine group (−9.0 vs. −4.0 points, p < 0.001), with more patients achieving symptom relief (COWS ≤ 4: 65.6% vs. 14.2%, p < 0.001). ICU admission occurred in 8.5% of xylazine era patients and 16.8% of medetomidine era patients (p < 0.001). Rates of AMA were higher during the medetomidine era as well (6.5% vs. 3.6%) (p = 0.038). Revision of treatment protocols showed promise. Conclusions: The protocol was significantly less effective during the medetomidine era, though a protocol change may be helping. Findings highlight the need to adapt withdrawal treatment protocols in response to changes in the illicit drug supply. Full article

Hearing loss (HL) is a major global health concern, with drug-induced ototoxicity contributing significantly, particularly in patients undergoing treatment for drug-resistant tuberculosis (DR-TB). In South Africa, where both TB and HIV are prevalent, the risk of treatment-related auditory damage is especially high. This study aimed to assess the prevalence and predictors of hearing impairment among DR-TB patients in rural Eastern Cape, South Africa. A retrospective analysis was conducted on 438 DR-TB patients treated between 2018 and 2020, using pure tone audiometry (PTA) to assess hearing status post-treatment. Demographic, clinical, and lifestyle data were extracted from patient records and analyzed using logistic regression. The overall prevalence of hearing loss was 37.2%. Risk was significantly associated with an older age, a male gender, DR-TB classification (MDR, pre-XDR, and XDR), unsuccessful treatment outcomes, and substance use. Prevalence of HL increased notably in patients aged 70 and older. Lifestyle factors, particularly combined use of tobacco, alcohol, and drugs, were linked to higher odds of HL. These findings underscore the need for routine audiometric screening and personalized treatment monitoring in DR-TB care, especially for high-risk populations. Early identification of ototoxicity risk factors can inform safer treatment regimens and improve patient outcomes in resource-limited settings. Full article

Bacterial antimicrobial resistance (AMR) represents a critical public health threat, with increasing resistance compromising the effectiveness of treatments worldwide. Resistance trends, such as fluctuating benzylpenicillin resistance in Staphylococcus aureus, highlight the growing urgency, with projections indicating a rise in resistance to various antibiotics, including complete resistance to gentamicin and tetracycline by 2027. Despite substantial efforts to develop new antibiotics and drug delivery systems, these approaches must undergo rigorous clinical evaluation to ensure their safety and efficacy. In parallel, alternative therapies, such as phytotherapy and apitherapy, have garnered attention for their potential in combating infections. Natural substances like tea tree essential oils and propolis, which exhibit antimicrobial properties, are being increasingly incorporated into novel drug delivery systems. However, much of the research on these materials is not new, with several studies already exploring their effectiveness. To address the escalating AMR crisis, combining advanced therapies with alternative medicine could offer a promising solution. Advanced therapy products could target bacterial genomes and enhance the effectiveness of antibiotics and natural substances. This integrated approach remains underexplored in pre-clinical and clinical trials, presenting future research opportunities to develop more effective strategies in combating AMR. Given the rapid spread of resistant infections, there is an urgent need for innovative antimicrobial agents to overcome emerging resistance mechanisms and improve diagnoses and treatments. Full article

Background: Acinetobacter baumannii is a significant pathogen and a major contributor to healthcare-associated infections, particularly in intensive care units. Its high potential for developing multiple drug resistance (MDR) makes it a challenging pathogen to manage. This study investigates the prevalence and resistance patterns of MDR A. baumannii isolates over a six-year period at a university hospital in Southern Italy. Objective: The aims of this study are to evaluate recent trends in the prevalence of MDR A. baumannii, analyze resistance patterns, and assess the impact of the antimicrobial diagnostic stewardship program implemented in 2018. Methods: This retrospective cohort study was conducted at the University Hospital of Campania “Luigi Vanvitelli” from 2018 to 2023. A total of 191 A. baumannii isolates from blood, urine, and wound samples were analyzed. Antimicrobial susceptibility testing was performed following EUCAST guidelines. The prevalence of MDR strains was assessed across three periods: pre-pandemic (2018–2019), during the pandemic (2020–2021), and post-pandemic (2022–2023) Results: Among the 191 isolates, 89.5% were classified as MDR. The highest number of isolates occurred in 2020, with blood cultures and urine samples increasing by 40.9% and 62.5%, respectively, while wound isolates decreased by 34.2%. The implementation of antimicrobial diagnostic stewardship programs correlated with a reduction in carbapenem resistance in 2020 and 2022. However, resistance to meropenem and colistin persisted. A 60.4% decline in total isolation from 2020 to 2023 suggests effective infection control measures. Conclusions: MDR A. baumannii remains a significant threat to healthcare. Although there have been slight reductions in resistance following antimicrobial stewardship interventions, persistent resistance to last-line antibiotics underscores the urgent need for alternative treatments, enhanced surveillance, and stricter infection control strategies. Full article

The integration of artificial intelligence and personalized medicine is transforming HIV management by enhancing diagnostics, treatment optimization, and disease monitoring. Advances in machine learning, deep neural networks, and multi-omics data analysis enable precise prognostication, tailored antiretroviral therapy, and early detection of drug resistance. AI-driven models analyze vast genomic, proteomic, and clinical datasets to refine treatment strategies, predict disease progression, and pre-empt therapy failures. Additionally, AI-powered diagnostic tools, including deep learning imaging and natural language processing, improve screening accuracy, particularly in resource-limited settings. Despite these innovations, challenges such as data privacy, algorithmic bias, and the need for clinical validation remain. Successful integration of AI into HIV care requires robust regulatory frameworks, interdisciplinary collaboration, and equitable technology access. This review explores both the potential and limitations of AI in HIV management, emphasizing the need for ethical implementation and expanded research to maximize its impact. AI-driven approaches hold great promise for a more personalized, efficient, and effective future in HIV treatment and care. Full article

Seasonal outbreaks and occasional pandemics triggered by influenza viruses annually impose considerable burdens on public health and finances. The continual evolution of viral strains with drug resistance emphasizes the urgency of discovering novel agents for influenza viruses. This study investigated a set of innovative substances derived from Morinda officinalis with antiviral potential against influenza virus strains. The top candidate, anthraquinone-2-carboxylic acid (A2CA), presented antiviral activity against diverse influenza virus strains, including those resistant to oseltamivir. In an influenza mouse model, the pre-administration of A2CA dose-dependently ameliorated influenza A virus (IAV)-mediated weight loss as well as protected mice from a lethal IAV infection. In addition, lung injury and cytokine dysregulation were mitigated. Further investigation revealed that IAV-induced activation of the RIG-I/STAT1 signaling pathway did not occur after A2CA treatment. A time-of-addition assay revealed that A2CA targeted the final phase of intracellular replication, which was further determined by molecular docking between A2CA and the IAV RdRp protein. Finally, transcriptome analysis revealed that the TP53TG3C, CFAP57 and SNX30-DT genes may be involved in the antiviral effects of A2CA. These results play a part in achieving a thorough comprehension of the capacity of A2CA to inhibit influenza virus infection. Full article

Cancer is biologically diverse, highly heterogeneous, and associated with molecular alterations, significantly contributing to mortality worldwide. Currently, cancer patients are subjected to single or combination treatments comprising chemotherapy, surgery, immunotherapy, radiation therapy, and targeted therapy. Chemotherapy remains the first line of treatment in cancer but faces a major obstacle in the form of chemoresistance. This obstacle has resulted in relapses and poor patient survival due to decreased treatment efficacy. Aberrant pre-mRNA alternative splicing can significantly modulate gene expression and function involved in the resistance mechanisms, potentially shaping the intricate landscape of tumour chemoresistance. Thus, novel strategies targeting abnormal pre-mRNA alternative splicing and understanding the molecular mechanisms of chemotherapy resistance could aid in overcoming the chemotherapeutic challenges. This review first highlights drug targets, drug pumps, detoxification mechanisms, DNA damage response, and evasion of apoptosis and cell death as key molecular mechanisms involved in chemotherapy resistance. Furthermore, the review discusses the progress of research on the dysregulation of alternative splicing and molecular targets involved in chemotherapy resistance in major cancer types. Full article

The human gut microbiota—an intricate and dynamic ecosystem—plays a pivotal role in metabolic regulation, immune modulation, and the maintenance of intestinal barrier integrity. Although antibiotic therapy is indispensable for managing bacterial infections, it profoundly disrupts gut microbial communities. Such dysbiosis is typified by diminished diversity and shifts in community structure, especially among beneficial bacterial genera (e.g., Bifidobacterium and Eubacterium), and fosters antibiotic-resistant strains and the horizontal transfer of resistance genes. These alterations compromise colonization resistance, increase intestinal permeability, and amplify susceptibility to opportunistic pathogens like Clostridioides difficile. Beyond gastrointestinal disorders, emerging evidence associates dysbiosis with systemic conditions, including chronic inflammation, metabolic syndrome, and neurodegenerative diseases, underscoring the relevance of the microbiota–gut–brain axis. The recovery of pre-existing gut communities post-antibiotic therapy is highly variable, influenced by drug spectrum, dosage, and treatment duration. Innovative interventions—such as fecal microbiota transplantation (FMT), probiotics, synbiotics, and precision microbiome therapeutics—have shown promise in counteracting dysbiosis and mitigating its adverse effects. These therapies align closely with antibiotic stewardship programs aimed at minimizing unnecessary antibiotic use to preserve microbial diversity and curtail the spread of multidrug-resistant organisms. This review emphasizes the pressing need for microbiota-centered strategies to optimize antibiotic administration, promote long-term health resilience, and alleviate the disease burden associated with antibiotic-induced dysbiosis. Full article

Background/Objectives: Pulmonary hypertension is a progressive disease leading to right heart failure. One treatment strategy is to induce vasodilation via the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate (NO–sGC–cGMP) signaling pathway. There are currently two soluble guanylate cyclase stimulators on the market: Riociguat and vericiguat, with vericiguat having a longer half-life and needing to be taken only once a day. This study investigated whether the pharmacological differences between the drugs affect pulmonary vessels and airways. Methods: The effects of vericiguat and riociguat on pulmonary arteries, veins, and airways were studied using rat precision-cut lung slices (PCLS). Vessels were pretreated with endothelin-1 and airways with serotonin. In isolated perfused lungs (IPL), the effects of sGC stimulation on pulmonary artery pressure (PAP), airway resistance, inflammatory cytokine, and chemokine release were quantified. Results: Riociguat and vericiguat caused pulmonary artery dilation in PCLS. During IPL, riociguat was more effective than vericiguat in reducing PAP with a statistically significant reduction of 10%. Both drugs were potent bronchodilators in preconstricted airways (p < 0.001). Only vericiguat reduced airway resistance during IPL, as shown here for the first time. Both drugs significantly reduced IL-6 and IL-1ß levels, while riociguat also reduced VEGF-A and KC-GRO levels. Conclusions: Riociguat and vericiguat had three main effects in the two rat ex-vivo models: They dilated the pulmonary arteries, induced bronchodilation, and reduced inflammation. These properties could make sGC stimulators useful for treating diseases associated with endothelial dysfunction. In the future, vericiguat may provide an alternative treatment to induce bronchodilation in respiratory diseases. Full article