Effects of industrial-scale pickling processes on the dynamic changes in the physicochemical indicators and microbial diversities of Yacai.

The effects of dry-salted and salt-fermented processing on the physicochemical characteristics and microbial communities of Yacai were systematically investigated. The results showed that the contents of total acid, amino acid nitrogen (AAN) and nitrite in the final products of dry-salted Yacai were greater than those in salt-fermented Yacai. Lactic acid was the dominant organic acid in the two types of Yacai. Dry-salted processing is more conducive to forming a high-quality reddish-brown color. During whole pickling process, the microbial diversity of dry-salted Yacai was higher than that of salt-fermented Yacai, particularly in the early and middle stages of fermentation. For dry-salted Yacai, 8 bacteria (Natribacillus, Chromohalobacter, Marinococcus, Lentibacillus, Nesterenkonia, Gracilibacillus, Oceanobacillus and Tetragenococcus) and 1 fungus (Zygosaccharomyces) showed a significant positive correlation with AAN. For salt-fermented Yacai, 8 bacteria (Gracilibacillus, Alkalibacillus, Oceanobacillus, Virgibacillus, Lentibacillus, Salibacterium, Chromohalobacter and Tetragenococcus) and 3 fungi (Zygosaccharomyces, Millerozyma, and Wickerhamomyces) exhibited significant positive correlations with AAN.

Design, synthesis and biological evaluation of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors bearing a heterocyclic-containing tail as potential anti-tumor agents.

A series of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors were designed and synthesized by heterocyclic-containing tail approach. The inhibitory activities against four human epidermal growth factor receptor (HER) isozymes (EGFR, HER-2, HER-3 and HER-4) of all new compounds so designed were investigated in vitro. Compound 12k was found to be the most effective and rather selective dual-target inhibitor of EGFR and HER-2 with inhibitory constant (IC50) values of 6.15 and 9.78 nM, respectively, which was more potent than the clinical used agent Lapatinib (IC50 = 8.41 and 9.41 nM). Meanwhile, almost all compounds showed excellent antiproliferative activities against four cancer cell models (A549, NCI-H1975, SK-BR-3 and MCF-7) and low damage to healthy cells. Among them, compound 12k also exhibited the most prominent antitumor activity. Moreover, the hit compound 12k could bind to EGFR and HER-2 stably in molecular docking and dynamics studies. The following wound healing assay revealed that compound 12k could inhibit the migration of SK-BR-3 cells. Further studies found that compound 12k could arrest cell cycle in the G0/G1 phase and induce SK-BR-3 cells apoptosis. Notably, compound 12k could effectively inhibit breast cancer growth with little toxicity in the SK-BR-3 cell xenograft model. Taken together, in vitro and in vivo results disclosed that compound 12k had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth.

Noninvasive Photothermal Therapy of Nasopharyngeal Cancer Guided by High Efficiency Optical-Absorption Nanomaterial Enhanced by NIR-II Photoacoustic Imaging.

Background: Photothermal therapy (PTT) guided by photoacoustic imaging (PAI) using nanoplatforms has emerged as a promising strategy for cancer treatment due to its efficiency and accuracy. This study aimed to develop and synthesize novel second near-infrared region (NIR-II) absorption-conjugated polymer acceptor acrylate-substituted thiadiazoloquinoxaline-diketopyrrolopyrrole polymers (PATQ-DPP) designed specifically as photothermal and imaging contrast agents for nasopharyngeal carcinoma (NPC). Methods: The PATQ-DPP nanoparticles were synthesized and characterized for their optical properties, including low optical band gaps. Their potential as PTT agents and imaging contrast agents for NPC was evaluated both in vitro and in vivo. The accumulation of nanoparticles at tumor sites was assessed post-injection, and the efficacy of PTT under near-infrared laser irradiation was investigated in a mouse model of NPC. Results: Experimental results indicated that the PATQ-DPP nanoparticles exhibited significant photoacoustic contrast enhancement and favorable PTT performance. Safety and non-toxicity evaluations confirmed the biocompatibility of these nanoparticles. In vivo studies showed that PATQ-DPP nanoparticles effectively accumulated at NPC tumor sites and demonstrated excellent tumor growth inhibition upon exposure to near-infrared laser irradiation. Notably, complete elimination of nasopharyngeal tumors was observed within 18 days following PTT. Discussion: The findings suggest that PATQ-DPP nanoparticles are a promising theranostic agent for NIR-II PAI and PTT of tumors. This innovative approach utilizing PATQ-DPP nanoparticles provides a powerful tool for the early diagnosis and precise treatment of NPC, offering a new avenue in the management of this challenging malignancy.

Environmental microbes alleviate antibiotic disturbance on plant endophytes in aquatic microcosms: Prospects for conferring fitness benefits.

Antibiotic pollution in water environment is an emerging threat to plant health. Developing efficient strategies to reassemble the antibiotic-tolerating endophytes will confer fitness benefits on host plants to alleviate antibiotic stress. Here, introducing environmental microbes was proved as a promising approach to reshape the antibiotic-tolerating plant endophytes under antibiotic stress in aquatic microcosms. The introduction of environmental microbes effectively relieved antibiotic-driven perturbation on plant endophytes, with reduced changes in bacterial diversity and differential bacterial taxa and functional genes. Moreover, introducing environmental microbes facilitated the enrichment of endophytic bacterial genera and functional genes related to drug metabolism, which possessed the potentials to degrade antibiotics. In addition, environmental microbes boosted antibiotic-reshaped endophytes to form more stable bacterial networks for stronger antibiotic tolerance. In consequence, the decreased growth inhibition of antibiotics on host plants and enhanced antibiotic removal from microcosms were achieved by introducing environmental microbes. These findings pursue environmental microbes as practical resources to assist plants in reshaping the stress-alleviating endophytes, potentially improving plant tolerance to water pollution.

Hemodynamic effects of pulsatile frequency of right ventricular assist device (RVAD) on pulmonary perfusion: a simulation study.

Right ventricular assist devices (RVADs) have been extensively used to provide hemodynamic support for patients with end-stage right heart (RV) failure. However, conventional in-parallel RVADs can lead to an elevation of pulmonary artery (PA) pressure, consequently increasing the right ventricular (RV) afterload, which is unfavorable for the relaxation of cardiac muscles and reduction of valve complications. The aim of this study is to investigate the hemodynamic effects of the pulsatile frequency of the RVAD on pulmonary artery. Firstly, a mathematical model incorporating heart, systemic circulation, pulmonary circulation, and RVAD is developed to simulate the cardiovascular system. Subsequently, the frequency characteristics of the pulmonary circulation system are analyzed, and the calculated results demonstrate that the pulsatile frequency of the RVAD has a substantive impact on the pulmonary artery pressure. Finally, to verify the analysis results, the hemodynamic effects of the pulsatile frequency of the RVAD on pulmonary artery are compared under diffident support modes. It is found that the pulmonary artery pressure decreases by approximately 6% when the pulsatile frequency changes from 1 to 3 Hz. The increased pulsatile frequency of RA-PA support mode may facilitate the opening of the pulmonary valve, while the RV-PA support mode can more effectively reduce the load of RV. This work provides a useful method to decrease the pulmonary artery pressure during the RVAD supports and may be beneficial for improving myocardial function in patients with end-stage right heart failure, especially those with pulmonary hypertension.

Widely targeted metabolomics and flavoromics reveal the effect of Wickerhamomyces anomalus fermentation on the volatile and nonvolatile metabolites of black garlic juice.

Black garlic has a variety of biological activities, but many consumers cannot accept it because of the garlic odor and the bitter taste. In this study, fermentation with yeast Wickerhamomyces anomalus was adopted to improve the flavor of black garlic juice. Although fermentation reduced antioxidant activities, the garlicky odor and bitter taste were weakened. Metabolomic analysis revealed 141 metabolites were significantly differentially regulated. The upregulated metabolites were mainly related to nucleotides, organic acids and their derivatives, while the downregulated metabolites were mainly related to amino acids, lipids and their derivatives. Flavoromics analysis revealed that 137 metabolites were significantly differentially regulated, particularly garlicky and pungent volatiles were significantly downregulated. Correlation analysis indicated that esters are most closely related to nonvolatile metabolites, and lipids degradation was significantly correlated with volatiles. The results indicated that W. anomalus fermentation is an effective strategy to improve the flavor of black garlic juice.

Copper-Catalyzed Vicinal Thiocyanosulfonylation of Alkenes and Alkynes.

Efficient copper-catalyzed radical thiocyanosulfonylation of alkenes and alkynes with potassium thiocyanate and sodium phenylsulfinate is described. The reactions provide general and convenient methods toward the synthesis of ß-thiocyanoalkyl sulfones and ß-thiocyanoalkenyl sulfones, respectively, in satisfactory yields. Based on conducted mechanistic experiments, a mechanism involving oxidative generation of sulfonyl radicals and subsequent addition to alkenes followed by Cu-assisted thiocyanation is proposed. Moreover, the practicability of the reaction is successfully demonstrated by its successful application on a gram scale.

Simultaneously Producing H2 and H2O2 by Photocatalytic Water Splitting: Recent Progress and Future.

The solar-driven overall water splitting (2H2O→2H2 + O2) is considered as one of the most promising strategies for reducing carbon emissions and meeting energy demands. However, due to the sluggish performance and high H2 cost, there is still a big gap for the current photocatalytic systems to meet the requirements for practical sustainable H2 production. Economic feasibility can be attained through simultaneously generating products of greater value than O2, such as hydrogen peroxide (H2O2, 2H2O→H2 + H2O2). Compared with overall water splitting, this approach is more kinetically feasible and generates more high-value products of H2 and H2O2. In several years, there has been an increasing surge in exploring the possibility and substantial progress has been achieved. In this review, a concise overview of the importance and underlying principles of PIWS is first provided. Next, the reported typical photocatalysts for PIWS are discussed, including commonly used semiconductors and cocatalysts, essential design features of these photocatalysts, and connections between their structures and activities, as well as the selected approaches for enhancing their stability. Then, the techniques used to quantify H2O2 and the operando characterization techniques that can be employed to gain a thorough understanding of the reaction mechanisms are summarized. Finally, the current existing challenges and the direction needing improvement are presented. This review aims to provide a thorough summary of the most recent research developments in PIWS and sets the stage for future advancements and discoveries in this emerging area.

Virus-Mimetic Extracellular-Vesicle Vaccine Boosts Systemic and Mucosal Immunity via Immune Recruitment.

Mucosal vaccines can prevent viruses from infecting the respiratory mucosa, rather than only curtailing infection and protecting against the development of disease symptoms. The SARS-CoV-2 spike receptor-binding domain (RBD) is a compelling vaccine target but is undermined by suboptimal mucosal immunogenicity. Here, we report a SARS-CoV-2-mimetic extracellular-vesicle vaccine developed using genetic engineering and dendritic cell membrane budding. After mucosal immunization, the vaccine recruits antigen-presenting cells rapidly initiating a strong innate immune response. Notably, it obviates the need for adjuvants and can induce germinal center formation through both intramuscular and intratracheal vaccination. It not only elicits high levels of RBD-specific antibodies but also stimulates extensive cellular immunity in the respiratory mucosa. A sequential immunization strategy, starting with an intramuscular injection followed by an intratracheal booster, significantly bolsters mucosal immunity with high levels of IgA and tissue-resident memory T cell responses, thereby establishing a formidable defense against pseudovirus infection.

Identification and bioactivity evaluation of twelve previously undescribed depsidone derivatives from Garcinia oligantha.

Phytochemical studies on the leaves and twigs of Garcinia oligantha Merr. led to the isolation of twelve previously undescribed depsidone derivatives (oliganthdepsidones A-L, 1-12). Their structures were elucidated by extensive spectroscopic analysis including 1H and 13C NMR, HSQC, HMBC and NOESY along with HRESIMS. The structures of oliganthdepsidones G and J were finally determined using DFT-NMR chemical shift calculations and DP4+ methods. Cytotoxicity test in four human cancer cell lines indicated that oliganthdepsidone F had relatively strong cytotoxic effect against A375 (melanoma), A549 (lung cancer), HepG2 (liver cancer), and MCF-7 (breast cancer) cell lines with IC50 of 18.71, 15.44, 10.92, and 15.90 µM, respectively. The dose- and time-dependent antiproliferative effects of oliganthdepsidone F on these cell lines were also observed by CCK-8 test. As determined by fluorescent microscopy and flow cytometry in these cell lines, oliganthdepsidone F could promote cell apoptosis, leading to the inhibition of cell proliferation. The results of wound healing assay and transwell assay showed that oliganthdepsidone F could inhibit the migration and invasion of A549 and MCF-7 cell lines in a concentration-dependent manner.

Risks associated with cognitive function and management strategies in the clinical use of ADT: a systematic review from clinical and preclinical studies.

Prostate cancer is one of the most common malignancies and a leading cause of death in men. Owing to its excellent anti-tumor effects, androgen deprivation therapy (ADT) is widely used in the treatment of prostate cancer. However, its use is controversial because of its potential for inducing cognitive decline. In this review, we summarized the findings of preclinical and clinical studies investigating the effects of ADT on cognitive function in prostate cancer. We discussed the methods used to assess cognitive function in these studies, elucidated the mechanisms through which ADT affects cognitive function, and highlighted recent advancements in cognitive assessment methods. The findings of this review serve as a valuable reference for examining the relationship between ADT and cognitive function in future studies. Besides, the findings may help clinicians understand the advantages and disadvantages of ADT and optimize the treatment plan so as to minimize the adverse effects of ADT.

The Characteristics of Gut Microbiota and Its Relation with Diet in Postmenopausal Osteoporosis.

The gut microbiome is linked to osteoporosis. Previous clinical studies showed inconsistent results. This study aimed to characterize the gut microbiota feature and reveal its relation with diet in postmenopausal osteoporosis. Fifty-five postmenopausal women with osteoporosis (Op group) and forty-four age-matched postmenopausal women (normal bone mineral density, Con group) were included in this study. Fecal microbiota was collected and analyzed by shallow shotgun sequencing. Food frequency questionnaires were collected from both groups, and Spearman analysis was used to clarify its correlation with gut microbiota. A total of 2671 species from 29 phyla, 292 families, 152 orders, 80 classes were detected in the study. The two groups had no significant difference in the α and ß diversity (p > 0.05). At the genus level, Anaerostipes was enriched in Op group (p < 0.05). At species level, Methanobrevibacter smithii, Bifidobacterium animalis, Rhodococcus defluvii, Lactobacillus plantarum, and Carnobacterium mobile were enriched in the Op group, while Bacillus luciferensis, Acetivibrio cellulolyticus, Citrobacter amalonaticus, and Bifidobacterium breve were differentially enriched in the Con group. Food frequency questionnaire showed that postmenopausal women with osteoporosis intaked more red meat, beer, white and red wine (p < 0.05), and the Con group had more yogurt, fruit, and tea consumption. Red meat consumption had a significant negative correlation with Streptosporangiales (p < 0.01) and Actinomadura (p < 0.05). Fruits intake negatively correlated with Nocardiaceae, Rhodococcus, and Rhodococcus defluvii (p < 0.05). More yogurt intake was consistently correlated with a greater abundance of Streptosporangiales. This study suggests that gut microbiota is significantly altered in the postmenopausal osteoporosis population at genus and species levels, and specific dietary intake might relate to these changes.

Alveolar Soft Tissue Sarcoma: Correlation of MRI Features With Histological Grading and Patient Prognosis.

BACKGROUND: Alveolar Soft Part Sarcoma (ASPS) is a rare, aggressive cancer whose diagnosis and treatment depend on histological grading. However, tumor variability can lead to underestimation, affecting treatment, and patient survival. OBJECTIVE: To evaluate MRI features associated with Grade III ASPS and to determine the relationship between MRI features and patient prognosis. STUDY TYPE: Retrospective analysis. SUBJECTS: Sixty-seven patients with ASPS were included with 37 males and 30 females (M/F = 1.23) follow-up and survival analysis on 50 patients. FIELD STRENGTH/SEQUENCE: A 3.0 T, T1WI-FSE, T2WI-FSE, DWI-EPI, DCE-MRI (gradient echo). ASSESSMENT: MRI features (margin, peritumoral oedema, peritumoral enhancement, necrosis, vascular flow void signal, heterogeneous signal intensity [SI] at T1WI and T2WI, ADCmean, time-intensity curve [TIC] type, distant metastasis, and bone invasion) and histological grading were independently evaluated by three radiologists and two pathologists, with Grade III considered high-grade. STATISTICAL TESTS: The chi-square or Fisher's exact test was used to assess the correlation between MRI features and histological grading. Multivariable binary logistic regression identified independent factors associated with high-grade tumors. The Kaplan-Meier method and Cox proportional hazards model were used to calculate hazard ratios for MRI features. RESULTS: Tumor necrosis, heterogeneous SI at T2WI ≥50%, and ADCmean were associated with high-grade ASPS. Tumor necrosis was an independent factors associated with local relapse-free survival (odds ratio [OR], 3.88). TIC type was associated with 5-year survival rate (OR, 2.80) and local relapse-free survival (OR, 2.69). Heterogeneous SI at T2WI ≥50% was associated with 5-year survival (OR, 4.00), local relapse-free survival (OR, 5.58), and local relapse-free survival (OR, 4.84). DATA CONCLUSION: MRI features including tumor necrosis, heterogeneity of SI at T2WI, ADCmean, and TIC type aid in assessing ASPS grading and prognosis. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 5.

Discovery of 4-(isopentyloxy)-3-nitrobenzamide derivatives as xanthine oxidase inhibitors through a non-anthraquinone exploration.

In our previous study, we reported a series of N-(9,10-anthraquinone-2-carbonyl) amino acid derivatives as novel inhibitors of xanthine oxidase (XO). Recognizing the suboptimal drug-like properties associated with the anthraquinone moiety, we embarked on a nonanthraquinone medicinal chemistry exploration in the current investigation. Through systematic structure-activity relationship (SAR) studies, we identified a series of 4-(isopentyloxy)-3-nitrobenzamide derivatives exhibiting excellent in vitro potency against XO. The optimized compound, 4-isopentyloxy-N-(1H-pyrazol-3-yl)-3-nitrobenzamide (6k), demonstrated exceptional in vitro potency with an IC50 value of 0.13 µM. Compound 6k showed favorable drug-like characteristics with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.41 and 3.73, respectively. In comparison to the initial compound 1d, 6k exhibited a substantial 24-fold improvement in IC50, along with a 1.6-fold enhancement in LE and a 3.7-fold increase in LLE. Molecular modeling studies provided insights into the strong interactions of 6k with critical amino acid residues within the active site. Furthermore, in vivo hypouricemic investigations convincingly demonstrated that 6k significantly reduced serum uric acid levels in rats. The MTT results revealed that compound 6k is nontoxic to healthy cells. The gastric and intestinal stability assay demonstrated that compound 6k exhibits good stability in the gastric and intestinal environments. In conclusion, compound 6k emerges as a promising lead compound, showcasing both exceptional in vitro potency and favorable drug-like characteristics, thereby warranting further exploration.

DHPS-Mediated Hypusination Regulates METTL3 Self-m6A-Methylation Modification to Promote Melanoma Proliferation and the Development of Novel Inhibitors.

Discovering new treatments for melanoma will benefit human health. The mechanism by which deoxyhypusine synthase (DHPS) promotes melanoma development remains elucidated. Multi-omics studies have revealed that DHPS regulates m6A modification and maintains mRNA stability in melanoma cells. Mechanistically, DHPS activates the hypusination of eukaryotic translation initiation factor 5A (eIF5A) to assist METTL3 localizing on its mRNA for m6A modification, then promoting METTL3 expression. Structure-based design, synthesis, and activity screening yielded the hit compound GL-1 as a DHPS inhibitor. Notably, GL-1 directly inhibits DHPS binding to eIF5A, whereas GC-7 cannot. Based on the clarification of the mode of action of GL-1 on DHPS, it is found that GL-1 can promote the accumulation of intracellular Cu2+ to induce apoptosis, and antibody microarray analysis shows that GL-1 inhibits the expression of several cytokines. GL-1 shows promising antitumor activity with good bioavailability in a xenograft tumor model. These findings clarify the molecular mechanisms by which DHPS regulates melanoma proliferation and demonstrate the potential of GL-1 for clinical melanoma therapy.

T-Cell Epitope Mapping of SARS-CoV-2 Reveals Coordinated IFN-γ Production and Clonal Expansion of T Cells Facilitates Recovery from COVID-19.

BACKGROUND: T-cell responses can be protective or detrimental during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, the underlying mechanism is poorly understood. METHODS: In this study, we screened 144 15-mer peptides spanning the SARS-CoV-2 spike, nucleocapsid (NP), M, ORF8, ORF10, and ORF3a proteins and 39 reported SARS-CoV-1 peptides in peripheral blood mononuclear cells (PBMCs) from nine laboratory-confirmed coronavirus disease 2019 (COVID-19) patients (five moderate and four severe cases) and nine healthy donors (HDs) collected before the COVID-19 pandemic. T-cell responses were monitored by IFN-γ and IL-17A production using ELISA, and the positive samples were sequenced for the T cell receptor (TCR) ß chain. The positive T-cell responses to individual SARS-CoV-2 peptides were validated by flow cytometry. RESULTS: COVID-19 patients with moderate disease produced more IFN-γ than HDs and patients with severe disease (moderate vs. HDs, p < 0.0001; moderate vs. severe, p < 0.0001) but less IL-17A than those with severe disease (p < 0.0001). A positive correlation was observed between IFN-γ production and T-cell clonal expansion in patients with moderate COVID-19 (r = 0.3370, p = 0.0214) but not in those with severe COVID-19 (r = -0.1700, p = 0.2480). Using flow cytometry, we identified that a conserved peptide of the M protein (Peptide-120, P120) was a dominant epitope recognized by CD8+ T cells in patients with moderate disease. CONCLUSION: Coordinated IFN-γ production and clonal expansion of SARS-CoV-2-specific T cells are associated with disease resolution in COVID-19. Our findings contribute to a better understanding of T-cell-mediated immunity in COVID-19 and may inform future strategies for managing and preventing severe outcomes of SARS-CoV-2 infection.

Dynamic characterization of vascular response and treatment in oral traumatic ulcer in mice via photoacoustic imaging.

Background: Dynamic surveillance of vasculature is essential for evaluating the healing of oral ulcer. Existing techniques used in vascular imaging face limitations, such as inadequate spatial resolution, restricted diagnostic depth, and the necessity of exogenous contrast agents. Therefore, this study aimed to use robust photoacoustic imaging (PAI) for the dynamic monitoring of vascular response during healing and the associated treatment process of oral ulcer. Methods: Kunming mice (male, 8 weeks old, 31-41 g) were treated with 50% acetic acid for 90 s on the tongue mucosa for induction of oral traumatic ulcer. Mice were randomly divided into three groups (n=12): the control, compound chamomile and lidocaine hydrochloride gel (CCLH), and phycocyanin (PC) groups. PAI was then conducted on days 0, 2, 3, 5, and 7 to obtain vessel parameters of the ulcer area, including vessel intensity, density, mean diameter, maximum diameter, and curvature. Immunohistochemical and hematoxylin and eosin (HE) staining were performed on days 3 and 7 to assess microvessel density and inflammation score. The ulcer healing rate and body weight changes were evaluated for clinical observation. Results: Beginning on the second day after ulcer induction, there was a progressive increase over time in blood intensity and vessel parameters, including vascular density and diameter. On day 7, the CCLH and PC groups demonstrated significantly higher measures than did the control group in terms of blood intensity (P<0.05 and P<0.01), vascular density (both P values <0.05), mean diameter (both P values <0.01), and maximum diameter (P<0.01 and P<0.05). Vessel curvature in the two treatment groups exhibited no significant differences compared to that in the control group (both P values >0.05). The effects of vascular morphological changes were further supported by the histological and clinical outcomes. On day 7, compared to that of the control group, the level of microvessel density was significantly higher in both the CCLH (P<0.01) and PC (P<0.05) groups. The histopathological score in PC group was significantly lower than that of the control group on day 7 (P<0.05). Additionally, compared to that of the control group, the healing rates of the CCLH (P<0.01) and PC groups (P<0.05) were superior on day 7. On day 3, the control group showed more weight loss than did the CCLH (P<0.05) and PC (P<0.01) groups. Conclusions: These findings indicate that PAI is a valuable strategy for the dynamic and quantitative analysis of vascular alterations in oral traumatic ulcers and support its prospective application in improving clinical treatment.

LDHA contributes to nicotine induced cardiac fibrosis through autophagy flux impairment.

Cardiac fibrosis is a typical feature of cardiac pathological remodeling, which is associated with adverse clinical outcomes and has no effective therapy. Nicotine is an important risk factor for cardiac fibrosis, yet its underlying molecular mechanism remains poorly understood. This study aimed to identify its potential molecular mechanism in nicotine-induced cardiac fibrosis. Our results showed nicotine exposure led to the proliferation and transformation of cardiac fibroblasts (CFs) into myofibroblasts (MFs) by impairing autophagy flux. Through the use of drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) technology, it was discovered that nicotine directly increased the stability and protein levels of lactate dehydrogenase A (LDHA) by binding to it. Nicotine treatment impaired autophagy flux by regulating the AMPK/mTOR signaling pathway, impeding the nuclear translocation of transcription factor EB (TFEB), and reducing the activity of cathepsin B (CTSB). In vivo, nicotine treatment exacerbated cardiac fibrosis induced in spontaneously hypertensive rats (SHR) and worsened cardiac function. Interestingly, the absence of LDHA reversed these effects both in vitro and in vivo. Our study identified LDHA as a novel nicotine-binding protein that plays a crucial role in mediating cardiac fibrosis by blocking autophagy flux. The findings suggest that LDHA could potentially serve as a promising target for the treatment of cardiac fibrosis.

Incidence and prognosis of olfactory and gustatory dysfunctions related to SARS-CoV-2 Omicron strain infection in China: A national multicenter survey of 35,566 individuals.

Objective: This cross-sectional study aimed to determine the epidemiology of olfactory and gustatory dysfunctions related to COVID-19 in China. Methods: This study was conducted by 45 tertiary Grade-A hospitals in China. Online and offline questionnaire data were obtained from patients infected with COVID-19 between December 28, 2022, and February 21, 2023. The collected information included basic demographics, medical history, smoking and drinking history, vaccination history, changes in olfactory and gustatory functions before and after infection, and other postinfection symptoms, as well as the duration and improvement status of olfactory and gustatory disorders. Results: Complete questionnaires were obtained from 35,566 subjects. The overall incidence of olfactory and taste dysfunction was 67.75%. Being female or being a cigarette smoker increased the likelihood of developing olfactory and taste dysfunction. Having received four doses of the vaccine or having good oral health or being a alcohol drinker decreased the risk of such dysfunction. Before infection, the average olfactory and taste VAS scores were 8.41 and 8.51, respectively; after infection, they decreased to 3.69 and 4.29 and recovered to 5.83 and 6.55 by the time of the survey. The median duration of dysosmia and dysgeusia was 15 and 12 days, respectively, with 0.5% of patients having symptoms lasting for more than 28 days. The overall self-reported improvement rate was 59.16%. Recovery was higher in males, never smokers, those who received two or three vaccine doses, and those that had never experienced dental health issues, or chronic accompanying symptoms. Conclusions: The incidence of dysosmia and dysgeusia following infection with the SARS-CoV-2 virus is high in China. Incidence and prognosis are influenced by several factors, including sex, SARS-CoV-2 vaccination, history of head-facial trauma, nasal and oral health status, smoking and drinking history, and the persistence of accompanying symptoms.