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ObjectiveNontyphoidal Salmonella is a significant public health concern due to its ability to cause foodborne illnesses worldwide. This study aims to characterize the nontyphoidal Salmonella strains isolated from patients in China.MethodsA total of 19 nontyphoidal Salmonella strains were characterized through serovar identification, antimicrobial susceptibility testing (AST), biofilm formation assessment. Genetic relatedness was determined using pulsed-field gel electrophoresis (PFGE). WGS was employed to decipher the resistance mechanism and to contextualize the S. serovar Mbandaka strains among previously sequenced isolates in China. The biofilm associated mrkA gene was examined by PCR.ResultsThe predominant serovar identified was S. Enteritidis, followed by S. Mbandaka, S. Thompson, S. Livingston, S. Alachua, and S. Infantis. PFGE analysis indicated a notable genetic similarity among the S. Mbandaka isolates. Phylogenetic analysis suggested that these strains were likely derived from a single source that had persisted in China for over five years. One multidrug resistance (MDR) S. Enteritidis isolate carried a highly transferable IncB/O/K/Z plasmid with blaCTX-M-15. One S. Thompson strain, harboring the mrkABCDF operon in an IncX1 plasmid, isolated from cutaneous lesions, demonstrated robust biofilm formation. However, no mrkABCDF loci were detected in other strains.ConclusionOur study emphasizes the importance of persisted surveillance and prompt response to Salmonella infections to protect public health. The dissemination of blaCTX-M-15-harboring IncB/O/K/Z plasmid and the spread of virulent mrkABCDF operon among Salmonella in China and other global regions warrant close monitoring.

Invasive fungal infections are an emerging problem worldwide, which bring huge health challenges. Candida albicans, the most common opportunistic fungal pathogen, can cause bloodstream infections with high mortality in susceptible hosts. At present, available antifungal agents used in clinical practice are limited, and most of them also have some serious adverse effects. The emergence of drug resistance because of the wide use of antifungal agents is a new limitation to successful patient therapy. Drug combination therapy is increasingly becoming a way to enhance antifungal efficacy, and reduce drug resistance and potential toxicity. Panobinostat, as a pan-histone deacetylase inhibitor, has been approved by the United States Food and Drug Administration as novel antitumor agents. In this study, the antifungal effects and mechanisms of panobinostat combined with fluconazole (FLC) against C. albicans were explored for the first time. The results indicated that panobinostat could work synergistically with FLC against resistant C. albicans, the minimal inhibitory concentration (MIC) of panobinostat could decrease from 128 to 0.5–2 μg/ml and the MIC of FLC could decrease from >512 to 0.25–0.5 μg/ml, and the fractional inhibitory concentration index (FICI) value ranged from 0.0024 to 0.0166. It was not only synergized against planktonic cells but also against C. albicans biofilms performed ≤8 h when panobinostat is combined with fluconazole; the sessile MIC (sMIC) of panobinostat could decrease from >128 to 0.5–8 μg/ml and the sMIC of FLC from >1024 to 0.5–2 μg/ml, and the FICI value was 0.05). These findings might provide novel insights into the antifungal drug discovery and the treatment of candidiasis caused by C. albicans.

ObjectiveThe emergence of carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-hvKp) strains poses a significant public threat, and effective antimicrobial therapy is urgently needed. Recent studies indicated that apramycin is a potent antibiotic with good activity against a range of multi-drug resistant pathogens. In this study, we evaluated the in vitro activity of apramycin against clinical CR-hvKp along with carbapenem-resistant non-hvKp (CR-non-hvKp) isolates.MethodsBroth microdilution method was used to evaluate the in vitro activities of apramycin, gentamicin, amikacin, imipenem, meropenem, doripenem, ertapenem and other comparator “last-resort” antimicrobial agents, including ceftazidime-avibactam, colistin and tigecycline, against eighty-four CR-hvKp and forty CR-non-hvKp isolates collected from three Chinese hospitals. Multilocus Sequence typing (MLST), molecular capsule typing (wzi sequencing) and antimicrobial resistance genes were examined by PCR and Sanger sequencing. Pulsed-field gel electrophoresis and next generation sequencing were conducted on selected isolates.ResultsAmong the 84 CR-hvKp isolates, 97.6, 100, 97.6, and 100% were resistant to imipenem, meropenem, doripenem and ertapenem, respectively. Apramycin demonstrated an MIC50/MIC90 of 4/8 μg/mL against the CR-hvKp isolates. In contrast, the MIC50/MIC90 for amikacin and gentamicin were >64/>64 μg/mL. All CR-hvKp isolates were susceptible to ceftazidime-avibactam, colistin and tigecycline with the MIC50/MIC90 values of 0.5/1, 0.25/0.5, 1/1, respectively. For CR-non-hvKp, The MIC50/90 values for apramycin, gentamicin and amikacin were 2/8, >64/>64, and >64/>64 μg/mL, respectively. There were no statistical significance in the resistance rates of antimicrobial agents between CR-hvKp and CR-non-hvKp groups (p > 0.05). Genetic analysis revealed that all CR-hvKp isolates harbored blaKPC–2, and 94% (n = 79) belong to the ST11 high-risk clone. 93.6% (44/47) of amikacin or gentamicin resistant strains carried 16S rRNA methyltransferases gene rmtB.ConclusionApramycin demonstrated potent in vitro activity against CR-hvKp isolates, including those were resistant to amikacin or gentamicin. Further studies are needed to evaluate the applicability of apramycin to be used as a therapeutic antibiotic against CR-hvKp infections.

ObjectivesTo compare the sensitivity of identification of penile plaques in the erect and flaccid penises by ultrasound in patients with Peyronie’s disease (PD).Materials and MethodsA total of 75 PD patients were screened by palpation and ultrasonography for penile lesions in both flaccid and erect penises induced by prostaglandin E1 (PG-1) injection.ResultsA total of 138 lesions were identified by ultrasound in the erect penises induced by injection of PG-1. However, only 74.6% of the lesions (103) were detectable by the palpation of the flaccid penises, and 84.1% (116) by ultrasound of the flaccid penises. The ultrasound confirmed 99 of the palpated lesions in the flaccid penises. The detection rate of lesions in drug-induced erect penises by ultrasound was significantly higher than those in the flaccid penises by the ultrasound (P < 0.01) or palpation (P < 0.0005) The type of penile lesions identified by ultrasonography included tunical thickening, calcifications, septal fibrosis, and intracavernosal fibrosis. The ratios of these lesions confirmed by ultrasound were 52.6, 33.6, 6.0, and 7.8%, respectively, in the flaccid penises, and 55.8, 28.3, 8.7, and 7.2%, respectively, in the erect penises.ConclusionDrug-induced erection can be used in suspicious PD patients when penile lesion is not identified by palpation or ultrasound in the flaccid penis.

Cognitive dysfunction is one of the serious complications induced by status epilepticus (SE), which has a significant negative impact on patients’ quality of life. Previous studies demonstrated that the pathophysiological changes after SE such as oxidative stress, inflammatory reaction contribute to neuronal damage. A recent study indicated that preventive astaxanthin (AST) alleviated epilepsy-induced oxidative stress and neuronal apoptosis in the brain. In the present study, rats were treated with vehicle or AST 1 h after SE onset and were injected once every other day for 2 weeks (total of seven times). The results showed that the cognitive function in SE rats was significantly impaired, and AST treatment improved cognitive function in the Morris water maze (MWM). Magnetic resonance imaging (MRI), hematoxylin-eosin (HE) staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining showed obvious damage in the hippocampus of SE rats, and AST alleviated the damage. Subsequently, we evaluated the effect of AST on relative pathophysiology to elucidate the possible mechanisms. To evaluate the oxidative stress, the expression of malondialdehyde (MDA) and superoxide dismutase (SOD) in plasma were detected using commercially available kits. NADPH oxidase-4 (Nox-4), p22phox, NF-E2-related factor 2 (Nrf-2), heme oxygenase 1 (Ho-1) and sod1 in the parahippocampal cortex and hippocampus were detected using western blot and real-time polymerase chain reaction (RT-PCR). The levels of MDA in plasma and Nox-4 and p22phox in the brain increased in SE rats, and the levels of SOD in plasma and Nrf-2, Ho-1 and sod1 in the brain decreased. Treatment with AST alleviated these changes. We also detected the levels of inflammatory mediators like cyclooxygenase-2 (cox-2), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and NF-κB phosphorylation p65 (p-p65)/p65 in the brain. The inflammatory reaction was significantly activated in the brain of SE rats, and AST alleviated neuroinflammation. We detected the levels of p-Akt, Akt, B-cell lymphoma-2 (Bcl-2), Bax, cleaved caspase-3, and caspase-3 in the parahippocampal cortex and hippocampus using western blot. The levels of p-Akt/Akt and Bcl-2 decreased in SE rats, Bax and cleaved caspase-3/caspase-3 increased, while AST alleviated these changes. The present study indicated that AST exerted an reobvious neuroprotective effect in pilocarpine-induced SE rats.

Currently, there are no effective treatments for diabetes-related cognitive dysfunction. Astaxanthin (AST), the most powerful antioxidant in nature, exhibits diverse biological functions. In this study, we tried to explore whether AST would ameliorate cognitive dysfunction in chronic type 2 diabetes mellitus (T2DM) rats. The T2DM rat model was induced via intraperitoneal injection of streptozotocin. Forty Wistar rats were divided into a normal control group, an acute T2DM group, a chronic T2DM group, and an AST group (treated with AST at a dose of 25 mg/kg three times a week). The Morris water maze test showed that the percentage of time spent in the target quadrant of the AST group was identical to that of the chronic T2DM group, while the escape latency of the AST group was decreased in comparison to that of the chronic T2DM group. Histology of the hippocampus revealed that AST ameliorated the impairment in the neurons of diabetic rats. Western blot showed that AST could upregulate nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) expression and inhibit nuclear transcription factor kappa B (NF-κB) p65 activation in the hippocampus. We found that AST increased the level of superoxide dismutase (SOD) and decreased the level of malondialdehyde (MDA) in the hippocampus. In addition, the levels of interleukin 1 beta (IL-1β) and interleukin 6 (IL-6) were reduced in the AST group compared with those in the chronic T2DM group. The findings of this research imply that AST might inhibit oxidative stress and inflammatory responses by activating the Nrf2-ARE signaling pathway.

Objective: It was demonstrated that inflammation and oxidative stress induced by hyperglycemia were closely associated with alteration of miR-146a. Here, we investigated the role of miR-146a in mediating inflammation and oxidative stress in the brain of chronic T2DM rats.Methods: The chronic T2DM (cT2DM) models were induced by intraperitoneal administration of STZ (35 mg/kg) after being fed a high-fat, high-sugar diet for 6 weeks. H&E staining was conducted to observe the morphological impairment of the rat hippocampus. The expressions of inflammatory mediators (COX-2, TNF-α, IL-1β) and antioxidant proteins (Nrf2, HO-1) were measured by western blot. The levels of MDA and SOD were detected by the respective activity assay kit. The levels of p22phox and miR-146a were examined by quantitative real-time PCR (qRT-PCR). The expressions of IRAK1, TRAF6 and NF-κB p65 were measured by western blot and qRT-PCR. Pearson correlation analysis was performed to investigate the correlations between miR-146a and inflammatory mediators as well as oxidative stress indicators.Results: The expression of miR-146a was negatively correlated with inflammation and oxidative stress status. In the brain tissues of cT2DM rats, it was observed that the expressions of inflammatory mediators (COX-2, TNF-α, IL-1β) and oxidative stress indicators including MDA and p22phox were elevated, which were negatively correlated with the expression of miR-146a. While, the antioxidant proteins (Nrf2, HO-1, SOD) levels decreased in the brain of cT2DM rats, which were positively correlated with the miR-146a level. The expressions of NF-κB p65 and its specific modulators (IRAK1&TRAF6) were elevated in the brain of cT2DM rats, which might be inhibited by miR-146a.Conclusion: Our results implied that increased inflammation and oxidative stress status were associated with brain impairment in cT2DM rats, which were negatively correlated with miR-146a expression. Thus, miR-146a may serve as a negative comprehensive indicator of inflammation and oxidative stress status in the brain of chronic T2DM rats.

The SARS-CoV-2 pandemic and particularly the emerging variants have deepened the need for widely available therapeutic options. We have demonstrated that hexamer-enhancing mutations in the Fc region of anti-SARS-CoV IgG antibodies lead to a noticeable improvement in IC50 in both pseudo and live virus neutralization assay compared to parental molecules. We also show that hexamer-enhancing mutants improve C1q binding to target surface. To our knowledge, this is the first time this format has been explored for application in viral neutralization and the studies provide proof-of-concept for the use of hexamer-enhanced IgG1 molecules as potential anti-viral therapeutics.