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Methicillin-resistant Staphylococcus aureus (MRSA), a drug-resistant organism, can cause a spectrum of infections in the human host involving biofilm. Therefore, novel therapeutic approaches need to be explored to mitigate this persistent infection. This study investigated a combinatorial approach that incorporates cuminaldehyde (a phytochemical) alongside aminoglycoside antibiotics (gentamicin and tobramycin) to improve antibiofilm efficacy by addressing multiple targets. In this regard, to achieve precise dosing of the chosen compounds for effective biofilm management, different machine learning models, namely multiple linear regression (MLR), polynomial regression (PR), artificial neural network regression (ANNR), and support vector regression (SVR), were employed. The results suggested that ANNR exhibited a strong association between the predicted and experimental observations (R² = 98.07). Furthermore, the ANNR model, followed by genetic algorithm (GA), recommended that the combinatorial doses of the selected compounds [cuminaldehyde (40 μg/mL); gentamicin (0.5 μg/mL); and tobramycin (0.035 μg/mL)] could show the highest antibiofilm activity against MRSA. Additionally, this study revealed that the combination of the mentioned compounds at their recommended doses not only accumulated intracellular reactive oxygen species (ROS) but also increased the cell membrane permeability of MRSA. Thus, this study provides a promising foundation for developing novel therapeutic strategies against MRSA biofilm through an AI-driven approach.

Urinary tract infections (UTIs) are among the most common and serious global health concerns. The alarming rise of antibiotic resistance levels in uropathogens has further complicated the situation. This study aimed to determine the epidemiology, antibiotic resistance pattern, and associated risk factors of clinical isolates from patients suspected to have UTIs. A cross-sectional study was conducted at a tertiary-care hospital in North Kashmir, India, from June to December 2024. The samples were collected from the clinically suspected UTI patients and processed through standard procedures. Out of 513 urine samples, 190 (37%) showed significant growth on chrome agar, Escherchia coli followed by Entrococcus sp. were the most prevalent pathogens isolated. The isolates showed diverse resistance profiles, with 53% of pathogens showing multidrug resistance (resistance to three or more classes of antibiotics). The logistic regression and random forest models were applied to the dataset to determine the association between significant bacterial growth and the associated risk factors. The models were evaluated by AUC-ROC and F1-score. According to machine learning analysis, risk factors independently associated with the prevalence of UTIs were recurrent UTI, lower abdomen pain or hematuria, and urinary urgency. The findings in our study highlight that the unregulated use of antibiotics is encouraging the emergence of resistant strains, which need urgent attention due to their significant impact on community health.

Heat shock protein 22 (HSP22) is a molecular chaperone known to protect against tissue damage in ischemic conditions. However, its role in lung ischemia–reperfusion injury (LIRI) following pulmonary embolism (PE) remains unclear. This study aimed to investigate the protective effects and molecular mechanisms of HSP22 in LIRI, focusing on its regulation of the HIF-1α/NOX4 signaling pathway. We found that HSP22 expression was significantly downregulated in LIRI mouse lung tissues and hypoxia/reoxygenation (H/R)-exposed pulmonary microvascular endothelial cells (PMVECs). HSP22 overexpression improved pulmonary function, reduced lung edema, and alleviated apoptosis, inflammation, and oxidative stress in LIRI mice. Similarly, in PMVECs, HSP22 overexpression restored cell viability, suppressed apoptosis, and decreased TNF-α, IL-6, and ROS levels under H/R exposure. Mechanistically, HSP22 directly interacted with HIF-1α and promoted its ubiquitination, leading to proteasomal degradation and downregulation of NOX4 expression. Notably, NOX4 overexpression abolished the protective effects of HSP22, restoring apoptosis, inflammation, and oxidative stress both in vivo and in vitro. Collectively, our study demonstrates that HSP22 protects against LIRI by promoting HIF-1α ubiquitination and inhibiting the HIF-1α/NOX4 pathway, thereby reducing oxidative stress, inflammation, and apoptosis. These findings suggest that targeting HSP22 may represent a promising therapeutic strategy for preventing LIRI in PE patients undergoing reperfusion therapy.

Hospital- and community-acquired Staphylococcus aureus infections are dominated by their biofilms and cause difficult-to-treat persistent infections. As an alternative anti-biofilm agent, the efficacy of triphenylphosphonium (TPP)-conjugated curcumin (TPP-curcumin) was determined against S. aureus biofilms in comparison to that of curcumin and commercial antibiotics. TPP-curcumin elicited strong anti-staphylococcal activity with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values of 3.125 and 6.25 μM, respectively. The MIC and MBC values for curcumin and ampicillin were > 125 and > 286.2 μM (100 μg/mL), respectively. The MIC and MBC values were 25.7 μM (12.5 μg/mL) and 103 μM (50 μg/mL), respectively, for kanamycin. TPP-curcumin was multi-fold more effective than curcumin in inhibiting biofilm growth. Minimum biofilm inhibitory concentration (MBIC) values of TPP-curcumin, curcumin, ampicillin and kanamycin were 3.125, > 125, > 286 and 25 μM, respectively. Besides inhibiting biofilm formation, TPP-curcumin has effectively killed S. aureus cells in pre-formed or established biofilms. Treatment of biofilms with 25 μM TPP-curcumin achieved near-complete cell killing. Exposure to TPP-curcumin led to severe membrane damage and oxidative stress in S. aureus cells. The strong antimicrobial and antibiofilm activity of TPP-curcumin suggests its potential use for developing or augmenting antibacterial therapies for drug-resistant S. aureus infections.

Chronic Helicobacter pylori (H. pylori) infection leads to gastric carcinoma (GC), while aurora kinase A (AURKA) is known to be upregulated in several cancers. However, the direct association between AURKA and H. pylori remains largely unexplored. The significance of AURKA in H. pylori infection was investigated using an RNAi-mediated silencing method. The expression of downstream signaling genes and apoptotic markers was analyzed through qRT-PCR and western blot. Cancerous properties were evaluated through scratch wound assay, cell counting through trypan blue, and genomic instability assay. We used RNAi-mediated gene silencing to knock down AURKA expression and observed a reduction in the transcript levels of H. pylori pathogenic genes, signaling genes associated with H. pylori infection. We found that AURKA regulated STAT3 and c-Myc, which further enhanced the oncogenic potential of H. pylori. Moreover, AURKA knockdown led to the activation of apoptotic markers and alterations in mitochondrial biomass and membrane potential during H. pylori infection. Additionally, AURKA knockdown reduced cell proliferation, migration, and genomic instability in H. pylori-infected AGS cells. This study demonstrates that AURKA knockdown could abrogate H. pylori-induced expression of STAT3 and c-Myc in AGS, suggesting a functional signaling axis linking AURKA to H. pylori-mediated downstream effects.

Silver-based nanocomplexes are promising antibacterial agents because of their ability to break the bacterial cell membrane, enhance oxidative stress, and damage bacterial DNA, offering potential alternatives to conventional antibiotics. Recently, Prussian blue analogues nanocomposites have gained attention due to their unique advantages, including biocompatibility, low cost, and easy structural modification to induce bioactivity. Herein, we developed different metal analogues of Prussian blue@silver [M^IIPB@Ag, M^II = Cu, Co, and Mn] nanocomposites for antibacterial applications. In vitro assays confirmed the utility of these materials in inhibiting Gram-negative and Gram-positive bacteria. The antibiofilm property of CuIIPB@Ag and MnIIPB@Ag was assessed by coating them on PDMS disk surfaces. The results show that CuPB@Ag (at 1600 μM) and MnPB@Ag (at 4000 μM) achieve approximately an 85% reduction in biofilm formation. In vitro cytotoxicity studies assessed by using the MTT assay support the biocompatibility of Cu^IIPB@Ag (up to 80% cell viability in 60 μM) and Mn^IIPB@Ag (up to 70% cell viability in 150 μM). Moreover, Cu^IIPB@Ag (at 1600 μM) and Mn^IIPB@Ag (at 4000 μM) eliminated in vivo skin infections in the preclinical rat model. These results highlight the potential of these metal analogues of Prussian blue@silver nanocomposites for the treatment of bacterial infections.

Antimicrobial resistance (AMR) in ESKAPE pathogens presents a critical global health challenge, particularly in hospitals. The enzyme HisIE from A. baumannii was explored as a therapeutic target using structure-based drug design to combat bacterial infections. This study integrates various computational approaches, including homology modeling, molecular dynamics simulations (MDS), and structure-based virtual screening to identify the potent inhibitors with high binding affinity and favorable pharmacokinetic properties. High-throughput virtual screening of the COCONUT database identified lead compounds featuring strong binding affinities to protein targets along with favorable pharmacokinetic profiles. CNP0007442, CNP0007145, and CNP0007506 emerged as the most potent candidates based on MM/GBSA binding free energy calculations. They exhibited stable interactions with key active site residues (His98) of AbHisIE, primarily through Van der Waals and electrostatic forces, enabling enhanced enzyme inhibition. Furthermore, density functional theory analysis revealed optimal HOMO–LUMO energy gaps, indicating the selected compounds' potential reactivity and stability. The findings highlight these candidates for further experimental validation, offering a novel therapeutic approach by disrupting the essential bacterial metabolic pathways. This study identifies promising drug-like molecules targeting AbHisIE, offering a novel strategy to combat AMR infections.

Staphylococcus aureus (S. aureus)-induced osteomyelitis presents therapeutic challenges due to antibiotic resistance. Isoliquiritigenin (ISL), a licorice-derived chalcone, exhibits antibacterial and anti-inflammatory properties. This study evaluated vancomycin (VAN) combined with ISL against methicillin-resistant S. aureus (MRSA)-induced implant-related osteomyelitis. A rat model was established by tibial MRSA inoculation with simultaneous Kirschner wire implantation. Four weeks postinfection, rats were divided into five groups: normal, model, VAN (50 mg/kg), ISL (100 mg/kg), and VAN + ISL. After 14 days of treatment, combined therapy significantly reduced bone infection severity and histopathological scores versus monotherapies (p < 0.001), decreased serum inflammatory markers (IL-6, TNF-α, IL-1β, and CRP; p < 0.001), and reduced bacterial loads in bone/wire (p < 0.001). In vitro, ISL (50 μM) attenuated MRSA-induced inflammatory response in MC3T3-E1 osteoblasts by suppressing NF-κB and MAPK signaling, while promoting osteogenesis via increased Runx2/BMP2/ALP expression, activated BMP/Smad signaling, and enhanced mineralization. Overall, VAN + ISL combination therapy outperforms monotherapy by concurrently eradicating MRSA, suppressing inflammation, and promoting bone repair, representing a promising synergistic strategy for recalcitrant osteomyelitis.

Bacterial biofilms cause chronic infections by resisting the effectiveness of existing antibiotics. Staphylococcus aureus is a readily biofilm-forming pathogen that may cause severe health issues through its survival in indwelling medical devices. Salmonella enterica causes prevalent food poisoning and affects millions of people globally. Our study focused on the antibacterial, antibiofilm activities, and pharmacokinetic properties of the chemically synthesized flavonoids. A simple and effective protocol for synthesizing flavanones, flavones, O-propynyloxy aurones, and hydroxy aurones from O-propynyloxy chalcones was established. All the flavonoids except a few showed good zones of inhibition against both the above-mentioned bacterial pathogens. Flavonoids showed more than 50% inhibition in all the tested antibiofilm activities. Confocal images gave clear visual evidence for the decrease in cell density of the biofilms after flavonoids treatment. Among the synthesized compounds, compound 9h exhibited the highest antibacterial activity against S. aureus, while compound 8g was most effective against S. enterica. In terms of antibiofilm activity, compound 8g showed the strongest inhibition against S. aureus, whereas compound 10a demonstrated the highest activity against S. enterica. Pharmacokinetic studies suggest that these flavonoids, with appropriate structural modifications, could serve as promising candidates for the development of orally administrable agents targeting bacterial pathogens.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) represents a critical global public health challenge. Phages are regarded as promising alternatives to antibiotics. In this study, a novel lytic phage, HZJ33, was isolated from the clinical CRKP strain KP703. Transmission electron microscopy (TEM) revealed that HZJ33 possessed an icosahedral head and podovirus morphotype. HZJ33 achieved optimal infectivity at a multiplicity of infection (MOI) of 0.01, with a latent period of 10 min and a burst size of 4.65 × 10⁴ PFU/cell. It lysed 40% of tested clinical CRKP isolates (12/30). The endotoxin level released from bacterial lysis mediated by phage HZJ33 was well below the established safety threshold and exhibited no detectable cytotoxicity. Whole-genome analysis confirmed the absence of virulence and antibiotic resistance genes. In vitro, HZJ33 suppressed KP703 growth curves within 10 h. In the Galleria mellonella infection model, HZJ33 treatment at an MOI of 100 increased the larval survival rate to 75%, compared to 25% in the infected negative control group (1 × 10⁷ CFU/mL). These findings identify HZJ33 as a lytic phage with a broad host range, high stability, favorable safety, and strong antibacterial activity in vitro and in vivo, supporting its potential for CRKP therapy.