Exploring the conformational dynamics and key amino acids in the CD26-caveolin-1 interaction and potential therapeutic interventions.

This study aimed to decipher the interaction between CD26 and caveolin-1, key proteins involved in cell signaling and linked to various diseases. Using computational methods, we predicted their binding conformations and assessed stability through 100 ns molecular dynamics (MD) simulations. We identified two distinct binding conformations (con1 and con4), with con1 exhibiting superior stability. In con1, specific amino acids in CD26, namely GLU237, TYR241, TYR248, and ARG147, were observed to engage in interactions with the F-J chain of Caveolin-1, establishing hydrogen bonds and cation or π-π interactions. Meanwhile, in con4, CD26 amino acids ARG253, LYS250, and TYR248 interacted with the J chain of Caveolin-1 via hydrogen bonds, cation-π interactions, and π-π interactions. Virtual screening also revealed potential small-molecule modulators, including Crocin, Poliumoside, and Canagliflozin, that could impact this interaction. Additionally, predictive analyses were conducted on the potential bioactivity, drug-likeness, and ADMET properties of these three compounds. These findings offer valuable insights into the binding mechanism, paving the way for new therapeutic strategies. However, further validation is required before clinical application. In summary, we provide a detailed understanding of the CD26 and caveolin-1 interaction, identifying key amino acids and potential modulators, essential for developing targeted therapies.

Real-world study on the efficacy and safety of different treatment regimens in treatment-naïve CHB patients with high viral load.

Evaluate the real-world effectiveness and safety of different treatment regimens for treatment-naïve high viral load chronic hepatitis B (CHB) patients. Between January 2021 and August 2022, CHB patients with HBV DNA ≥ 107 IU/mL were collected from four medical centers in Shenzhen. Patients treated with mono or combine antiviral therapy. The primary endpoint was the cumulative incidence of virological response at 48 weeks, and other endpoints included changes in HBsAg, HBeAg, ALT, and eGFR at 48 weeks. We used propensity score-based inverse probability of treatment weighting (IPTW) to balance the bias. Weighted logistics regression was used to estimate the factors affecting virological response. A total of 391 patients were included in the study, with 296 patients undergoing statistical analysis after IPTW. The patients were distributed into four groups: ETV (n = 62), TDF (n = 89), TAF (n = 36), TDF + LdT/ETV (n = 109). The 48-week cumulative incidence of virological response was significantly lower in ETV group (52.3%) compared to TDF (71.7%), TAF (74.2%), and TDF + LdT/ETV groups (77.9%) (P < 0.05). There were no significant differences in HBsAg loss among the four groups, but the HBeAg seroconversion rate was significantly higher in the TAF group. The ALT normalization rate was significantly higher in the TAF group (72.2%) compared to the others at 48 weeks (P < 0.05). In treatment-naïve CHB patients with high viral load, combination therapy was not superior to TDF or TAF monotherapy in virological response. Patients treated with TDF or TAF showed superior virological response compared to those treated with ETV. The TAF group demonstrated superiority in terms of ALT normalization and HBeAg seroconversion.

Insights into the antifungal mechanism of Bacillus subtilis cyclic lipopeptide iturin A mediated by potassium ion channel.

Fungal infections pose severe and potentially lethal threats to plant, animal, and human health. Ergosterol has served as the primary target for developing antifungal medications. However, many antifungal drugs remain highly toxic to humans due to similarity in cell membrane composition between fungal and animal cells. Iturin A, lipopeptide produced by Bacillus subtilis, efficiently inhibit various fungi, but demonstrated safety in oral administration, indicating the existence of targets different from ergosterol. To pinpoint the exact antifungal target of iturin A, we used homologous recombination to knock out and overexpress erg3, a key gene in ergosterol synthesis. Saccharomyces cerevisiae and Aspergillus carbonarius were transformed using the LiAc/SS-DNNPEG and Agrobacterium-mediated transformation (AMT), respectively. Surprisingly, increasing ergosterol content did not augment antifungal activity. Furthermore, iturin A's antifungal activity against S. cerevisiae was reduced while it pre-incubation with voltage-gated potassium (Kv) channel inhibitor, indicating that Kv activation was responsible for cell death. Iturin A was found to activate the Kv protein, stimulating K+ efflux from cell. In vitro tests confirmed interaction between iturin A and Kv protein. This study highlights Kv as one of the precise targets of iturin A in its antifungal activity, offering a novel target for the development of antifungal medications.

Transcutaneous Auricular Vagus Nerve Stimulation Ameliorates Preeclampsia-Induced Apoptosis of Placental Trophoblastic Cells Via Inhibiting the Mitochondrial Unfolded Protein Response.

Preeclampsia is a serious obstetric complication. Currently, there is a lack of effective preventive approaches for this disease. Recent studies have identified transcutaneous auricular vagus nerve stimulation (taVNS) as a potential novel non-pharmaceutical therapeutic modality for preeclampsia. In this study, we investigated whether taVNS inhibits apoptosis of placental trophoblastic cells through ROS-induced UPRmt. Our results showed that taVNS promoted the release of acetylcholine (ACh). ACh decreased the expression of UPRmt by inhibiting the formation of mitochondrial ROS (mtROS), presumably through M3AChR. This reduced the release of pro-apoptotic proteins (cleaved caspase-3, NF-κB-p65, and cytochrome C) and helped preserve the morphological and functional integrity of mitochondria, thus reducing the apoptosis of placental trophoblasts, improving placental function, and relieving preeclampsia. Our study unravels the potential pathophysiological mechanism of preeclampsia. In-depth characterization of the UPRmt is essential for developing more effective therapeutic strategies for preeclampsia targeting mitochondrial function.

Multifunctional Gold Nanozyme-Engineered Amphotericin B for Enhanced Antifungal Infection Therapy.

Chronic wounds of significant severity and acute injuries are highly vulnerable to fungal infections, drastically impeding the expected wound healing trajectory. The clinical use of antifungal therapeutic drug is hampered by poor solubility, high toxicity and adverse reactions, thereby necessitating the urgent development of novel antifungal therapy strategy. Herein, this study proposes a new strategy to enhance the bioactivity of small-molecule antifungal drugs based on multifunctional metal nanozyme engineering, using amphotericin B (AmB) as an example. AmB-decorated gold nanoparticles (AmB@AuNPs) are synthesized by a facile one-pot reaction strategy, and the AmB@AuNPs exhibit superior peroxidase (POD)-like enzyme activity, with maximal reaction rates (Vmax) 3.4 times higher than that of AuNPs for the catalytic reaction of H2O2. Importantly, the enzyme-like activity of AuNPs significantly enhanced the antifungal properties of AmB, and the minimum inhibitory concentrations of AmB@AuNPs against Candida albicans (C. albicans) and Saccharomyces cerevisiae (S. cerevisiae) W303 are reduced by 1.6-fold and 50-fold, respectively, as compared with AmB alone. Concurrent in vivo studies conducted on fungal-infected wounds in mice underscored the fundamentally superior antifungal ability and biosafety of AmB@AuNPs. The proposed strategy of engineering antifungal drugs with nanozymes has great potential for enhanced therapy of fungal infections and related diseases.

Overview of mechanisms of Fe-based catalysts for the selective catalytic reduction of NOx with NH3 at low temperature.

With the increasingly stringent control of NOx emissions, NH3-SCR, one of the most effective de-NOx technologies for removing NOx, has been widely employed to eliminate NOx from automobile exhaust and industrial production. Researchers have favored iron-based catalysts for their low cost, high activity, and excellent de-NOx performance. This paper takes a new perspective to review the research progress of iron-based catalysts. The influence of the chemical form of single iron-based catalysts on their performance was investigated. In the section on composite iron-based catalysts, detailed reviews were conducted on the effects of synergistic interactions between iron and other elements on catalytic performance. Regarding loaded iron-based catalysts, the catalytic performance of iron-based catalysts on different carriers was systematically examined. In the section on iron-based catalysts with novel structures, the effects of the morphology and crystallinity of nanomaterials on catalytic performance were analyzed. Additionally, the reaction mechanism and poisoning mechanism of iron-based catalysts were elucidated. In conclusion, the paper delved into the prospects and future directions of iron-based catalysts, aiming to provide ideas for the development of iron-based catalysts with better application prospects. The comprehensive review underscores the significance of iron-based catalysts in the realm of de-NOx technologies, shedding light on their diverse forms and applications. The hope is that this paper will serve as a valuable resource, guiding future endeavors in the development of advanced iron-based catalysts.

Therapeutic effect of iturin A on Candida albicans oral infection and its pathogenic factors.

Candida albicans is responsible for conditions ranging from superficial infections such as oral or vaginal candidiasis to potentially fatal systemic infections. It produces pathogenic factors contributing to its virulence. Iturin A, a lipopeptide derived from Bacillus sp., exhibits a significant inhibitory effect against C. albicans. However, its exact mechanism in mitigating the pathogenic factors of C. albicans remains to be elucidated. This study aimed to explore the influence of iturin A on several pathogenic attributes of C. albicans, including hypha formation, cell membrane permeability, cell adhesion, biofilm formation, and therapeutic efficacy in an oral C. albicans infection model in mice. The minimal inhibitory concentration of iturin A against C. albicans was determined to be 25 µg/mL in both YEPD and RPMI-1640 media. Iturin A effectively inhibited C. albicans hyphal formation, decreased cell viability within biofilms, enhanced cell membrane permeability, and disrupted cell adhesion in vitro. Nonetheless, iturin A did not significantly affect the phospholipase activity or hydrophobicity of C. albicans. A comparative study with nystatin demonstrated the superior therapeutic efficacy of iturin A in a mouse model of oral C. albicans infection, significantly decreasing C. albicans count and inhibiting both fungal hypha formation and tongue surface adhesion. High-dose iturin A treatment (25 µg/mL) in mice had no significant effects on blood indices, tongue condition, or body weight, indicating the potential for iturin A in managing oral infections. This study confirmed the therapeutic potential of iturin A and provided valuable insights for developing effective antifungal therapies targeting C. albicans pathogenic factors.

Human dendritic cell subsets in the glioblastoma-associated microenvironment.

Glioblastoma (GBM) is the most aggressive type of glioma (Grade IV). The presence of cytotoxic T lymphocyte (CTLs) has been associated with improved outcomes in patients with GBM, and it is believed that the activation of CTLs by dendritic cells may play a critical role in controlling the growth of GBM. DCs are professional antigen-presenting cells (APC) that orchestrate innate and adaptive anti-GBM immunity. DCs can subsequently differentiate into plasmacytoid DCs (pDC), conventional DC1 (cDC1), conventional (cDC2), and monocyte-derived DCs (moDC) depending on environmental exposure. The different subsets of DCs exhibit varying functional capabilities in antigen presentation and T cell activation in producing an antitumor response. In this review, we focus on recent studies describing the phenotypic and functional characteristics of DC subsets in humans and their respective antitumor immunity and immunotolerance roles in the GBM-associated microenvironment. The critical components of crosstalk between DC subsets that contribute significantly to GBM-specific immune responses are also highlighted in this review with reference to the latest literature. Since DCs could be prime targets for therapeutic intervention, it is worth summarizing the relevance of DC subsets with respect to GBM-associated immunologic tolerance and their therapeutic potential.

A review of regeneration mechanism and methods for reducing soot emissions from diesel particulate filter in diesel engine.

With the global emphasis on environmental protection and the proposal of the climate goal of "carbon neutrality," countries around the world are calling for reductions in carbon dioxide, nitrogen oxide, and particulate matter pollution. These pollutants have severe impacts on human lives and should be effectively controlled. Engine exhaust is the most serious pollution source, and diesel engine is an important contributor to particulate matter. Diesel particulate filter (DPF) technology has proven to be an effective technology for soot control at the present and in the future. Firstly, the exacerbating effect of particulate matter on human infectious disease viruses is discussed. Then, the latest developments in the influence of key factors on DPF performance are reviewed at different observation scales (wall, channel, and entire filter). In addition, current soot catalytic oxidant schemes are presented in the review, and the significance of catalyst activity and soot oxidation kinetic models are highlighted. Finally, the areas that need further research are determined, which has important guiding significance for future research. Current catalytic technologies are focused on stable materials with high mobility of oxidizing substances and low cost. The challenge of DPF optimization design is to accurately calculate the balance between soot and ash load, DPF regeneration control strategy, and exhaust heat management strategy.

Energy metabolic mechanisms for high altitude sickness: Downregulation of glycolysis and upregulation of the lactic acid/amino acid-pyruvate-TCA pathways and fatty acid oxidation.

Hypobaric hypoxia is often associated with the plateau environment and can lead to altitude sickness or death. The underlying cause is a lack of oxygen, which limits energy metabolism and leads to a compensatory stress response. Although glycolysis is commonly accepted as the primary energy source during clinical hypoxia, our preliminary experiments suggest that hypobaric hypoxia may depress glycolysis. To provide a more comprehensive understanding of energy metabolism under short-term hypobaric hypoxia, we exposed mice to a simulated altitude of 5000 m for 6 or 12 h. After the exposure, we collected blood and liver tissues to quantify the substrates, enzymes, and metabolites involved in glycolysis, lactic acid metabolism, the tricarboxylic acid cycle (TCA), and fatty acid ß-oxidation. We also performed transcriptome and enzymatic activity analyses of the liver. Our results show that 6 h of hypoxic exposure significantly increased blood glucose, decreased lactic acid and triglyceride concentrations, and altered liver enzyme activities of mice exposed to hypoxia. The key enzymes in the glycolytic, TCA, and fatty acid ß-oxidation pathways were primarily affected. Specifically, the activities of key glycolytic enzymes, such as glucokinase, decreased significantly, while the activities of enzymes in the TCA cycle, such as isocitrate dehydrogenase, increased significantly. Lactate dehydrogenase, pyruvate carboxylase, and alanine aminotransferase were upregulated. These changes were partially restored when the exposure time was extended to 12 h, except for further downregulation of phosphofructokinase and glucokinase. This study demonstrates that acute high altitude hypoxia upregulated the lactic acid/amino acid-pyruvate-TCA pathways and fatty acid oxidation, but downregulated glycolysis in the liver of mice. The results obtained in this study provide a theoretical framework for understanding the mechanisms underlying the pathogenesis of high-altitude sickness in humans. Additionally, these findings have potential implications for the development of prevention and treatment strategies for altitude sickness.

Hyperglycosylated N-Linked Site 339 of gp120 Appears to Be Unique and May Contribute to CRF01_AE Transmission Among Men Who Have Sex with Men in China and Thailand.

Human immunodeficiency virus (HIV)-1 CRF01_AE is one of the most important genotypes in China, especially in the population of men who have sex with men (MSM). It has become the most prevalent strain among them. Describing the variant characterization of CRF01_AE will help to reveal the reason behind its predominance in MSM. In this study, the complete DNA sequences (CDSs) for gp120 from the envelope protein (env) gene of CRF01_AE in China and Thailand were retrieved from the Los Alamos HIV database. The CDSs for gp120 were divided into three subgroups according to the risk factors for HIV-1 transmission in a variety of populations, such as intravenous drug users (IDU), heterosexual contacts (HC), and MSM. The N-linked CDS glycosylation sites for gp120 in CRF01_AE were analyzed. The results showed a unique hyperglycosylation site N-339 (refer to Hxb2) in the gp120 of CRF01_AE in MSM compared with the IDU and HC groups from China. The result was the same in the MSM group from Thailand, which suggests that the hyperglycosylation site N-339 may explain the widespread CRF01_AE genotype in MSM.

High homocysteine is associated with idiopathic normal pressure hydrocephalus in deep perforating arteriopathy: a cross-sectional study.

BACKGROUND AND OBJECTIVE: The pathogenesis and pathophysiology of idiopathic normal pressure hydrocephalus (iNPH) remain unclear. Homocysteine may reduce the compliance of intracranial arteries and damage the endothelial function of the blood-brain barrier (BBB), which may be the underlying mechanism of iNPH. The overlap cases between deep perforating arteriopathy (DPA) and iNPH were not rare for the shared risk factors. We aimed to investigate the relationship between serum homocysteine and iNPH in DPA. METHODS: A total of 41 DPA patients with iNPH and 49 DPA patients without iNPH were included. Demographic characteristics, vascular risk factors, laboratory results, and neuroimaging data were collected. Multivariable logistic regression analysis was performed to investigate the relationship between serum homocysteine and iNPH in DPA patients. RESULTS: Patients with iNPH had significantly higher homocysteine levels than those without iNPH (median, 16.34 mmol/L versus 14.28 mmol/L; P = 0.002). There was no significant difference in CSVD burden scores between patients with iNPH and patients without iNPH. Univariate logistic regression analysis demonstrated that patients with homocysteine levels in the Tertile3 were more likely to have iNPH than those in the Tertile1 (OR, 4.929; 95% CI, 1.612-15.071; P = 0.005). The association remained significant after multivariable adjustment for potential confounders, including age, male, hypertension, diabetes mellitus, atherosclerotic cardiovascular disease (ASCVD) or hypercholesterolemia, and eGFR level. CONCLUSION: Our study indicated that high serum homocysteine levels were independently associated with iNPH in DPA. However, further research is needed to determine the predictive value of homocysteine and to confirm the underlying mechanism between homocysteine and iNPH.

Modifications of Ganoderma lucidum spores into digestive-tissue highly adherent porous carriers with selective affinity to hydrophilic or hydrophobic drugs.

Ganoderma lucidum spores (GLSs) have been suggested to provide optimal structures for transporting orally bioavailable drugs. However, the double-layer wall and cavities of GLSs are naturally closed. This study aimed to modify GLSs into porous carriers by opening the layers and internal cavity with iturin A (IA) followed by potassium hydroxide (KOH) or hydrochloric acid (HCl). The (IA + KOH)- and (IA + HCl)-treated GLS carriers exhibited a high loading rate of 301.50 ± 2.33 and 268.18 ± 7.72 mg/g for the hydrophilic methylene blue (MB) and hydrophobic rifampicin (RF), respectively. The mechanisms underlying the modification involved the enhancement of the specific surface area with IA and the exposure of hydrophilic groups or hydrophobic groups of the GLSs with KOH or HCl. The sustained 48-h molecule-release profiles of the MB- and RF-loaded GLS carriers were best fitted using a first-order kinetics model in simulated gastric (or intestinal) fluid compared with other models. In mice, the designed GLS carriers had high adhesion capacities onto the mucosa of the digestive tract and long retention times (120 h), and even promoted the secretion of mucus and expression of several key intestinal barrier proteins. This study provided a new method to modify GLSs into oral carriers with selective drug affinity, high loading capacity, sustained drug release, and high adhesion to the digestive tract.

Preventive and therapeutic effects of an exopolysaccharide produced by Lacticaseibacillus rhamnosus on alcoholic gastric ulcers.

Crude exopolysaccharides produced by Lacticaseibacillus rhamnosus SHA113 were previously found to exhibit anti-alcoholic gastric ulcer activity in mice, but their major active fraction, structural characteristics, and underlying mechanisms remain unknown. Here, LRSE1 was identified as the active exopolysaccharide fraction produced by L. rhamnosus SHA113 responsible for the above effects. Purified LRSE1 had a molecular weight of 4.9 × 104 Da and was comprised of L-fucose, D-mannose, D-glucuronic acid, d-glucose, D-galactose, and L-arabinose in the molar ratio of 2.4:6.5:1.2:1.00:0.3:0.6, respectively. The oral administration of LRSE1 resulted in a significant protective and therapeutic effect on alcoholic gastric ulcers in mice. These effects were identified to involve a reduction in reactive oxygen species, apoptosis, and the inflammatory response, increases in antioxidant enzyme activities, and increases in the phylum Firmicutes and decreases in the genera Enterococcus, Enterobacter, and Bacteroides in the gastric mucosa of mice. In vitro experiments showed that the administration of LRSE1 both inhibited apoptosis in GEC-1 cells via the TRPV1-P65-Bcl-2 pathway and inhibited the inflammatory response in RAW264.7 cells via the TRPV1-PI3K pathway. For the first time, we have identified the active exopolysaccharide fraction produced by Lacticaseibacillus that protects against alcoholic gastric ulcers and determined that its effect involves TRPV1-mediated pathways.

A novel probability integral method segmental modified model for subsidence prediction applicable to thick loose layer mining areas.

In response to the problem that the actual extent of coal mining impacts on the surface in thick loose layer mines significantly exceeds the theoretical predictions, based on the literature study, the form of influence of thick loose layer on the predicted parameters of the probability integral method is summarized and analyzed; taking into account the influence of the subsidence coefficient, the sine modification formula of the major influence radius and the logistic modification formula of the subsidence coefficient are established, respectively, and based on the characteristics of the major influence radius, a new subsidence basin demarcation point is proposed and a novel probability integral method segmental parameter modified prediction model is constructed. The simulated experiment and real data experiment results prove that the constructed probability integral method segmented parameter modified model can both reduce the convergence of surface subsidence basin edge better and take into account the predicted accuracy inside the subsidence basin. The research achievements provide scientific data support for disaster warning, pollution management, ecological restoration, and coordination between coal mining and surface city construction in thick loose layer mining areas.

Microgravity and immune cells.

The microgravity environment experienced during spaceflight severely impaired immune system, making astronauts vulnerable to various diseases that seriously threaten the health of astronauts. Immune cells are exceptionally sensitive to changes in gravity and the microgravity environment can affect multiple aspects of immune cells through different mechanisms. Previous reports have mainly summarized the role of microgravity in the classification of innate and adaptive immune cells, lacking an overall grasp of the laws that microgravity effects on immune cells at different stages of their entire developmental process, such as differentiation, activation, metabolism, as well as function, which are discussed and concluded in this review. The possible molecular mechanisms are also analysed to provide a clear understanding of the specific role of microgravity in the whole development process of immune cells. Furthermore, the existing methods by which to reverse the damage of immune cells caused by microgravity, such as the use of polysaccharides, flavonoids, other natural immune cell activators etc. to target cell proliferation, apoptosis and impaired function are summarized. This review will provide not only new directions and ideas for the study of immune cell function in the microgravity environment, but also an important theoretical basis for the development of immunosuppression prevention and treatment drugs for spaceflight.

Potential role of selenium in alleviating obesity-related iron dyshomeostasis.

Obesity is a serious health problem in modern life and increases the risk of many comorbidities including iron dyshomeostasis. In contrast to malnourished anemia, obesity-related iron dyshomeostasis is mainly caused by excessive fat accumulation, inflammation, and disordered gut microbiota. In obesity, iron dyshomeostasis also induces disorders associated with gut microbiota, neurodegenerative injury, oxidative damage, and fat accumulation in the liver. Selenium deficiency is often accompanied by obesity or iron deficiency, and selenium supplementation has been shown to alleviate obesity and overcome iron deficiency. Selenium inhibits fat accumulation and exhibits anti-inflammatory activity. It regulates gut microbiota, prevents neurodegenerative injury, alleviates oxidative damage to the body, and ameliorates hepatic fat accumulation. These effects theoretically meet the requirements for the inhibition of factors underlying obesity-related iron dyshomeostasis. Selenium supplementation may have a potential role in the alleviation of obesity-related iron dyshomeostasis. This review verifies this hypothesis in theory. All the currently reported causes and results of obesity-related iron dyshomeostasis are reviewed comprehensively, together with the effects of selenium. The challenges and strategies of selenium supplementation are also discussed. The findings demonstrate the possibility of selenium-containing drugs or functional foods in alleviating obesity-related iron dyshomeostasis.