Yumeng Li

BACKGROUND: Cardiac aging involves progressive mitochondrial dysfunction, contributing to heart failure. Cardiolipin (CL), essential for mitochondrial function, is increasingly depleted in aging cardiomyocytes, promoting mitochondrial decline. Lysosomal degradation relies on v-ATPase (vacuolar-type H+-ATPase)–mediated acidification, and although lysosomes regulate phospholipid metabolism, their roles in CL homeostasis during aging remains unclear. This study examines whether v-ATPase dysfunction drives age-related cardiac changes by disrupting CL metabolism and mitochondrial function. METHODS: To investigate underlying mechanisms and causality, we use RNA sequencing, targeted lipidomics, immunofluorescence microscopy, (co)immunoprecipitation, proximity ligation assays, subcellular fractionation, mitochondrial respiration analysis and echocardiography, a cardiolipin synthase-1 ( Crsl1 ) knockout mouse model, and 2 v-ATPase knockout models. In addition, we assess whether a nutraceutical intervention targeting v-ATPase dysfunction can mitigate heart failure in aging mouse models and elderly people. RESULTS: Our present findings reveal a sequence of events driving age-related cardiomyopathy: declining cardiac nicotinamide adenine dinucleotide levels impair v-ATPase–mediated lysosomal acidification by weakening the interaction between nicotinamide adenine dinucleotide–dependent glycolytic enzyme aldolase and v-ATPase. This disruption increases lysosomal membrane permeability by reducing lysosomal acidification, allowing cathepsin B to leak into mitochondria. There, cathepsin B disrupts mitochondrial CRLS1 (cardiolipin synthase I), impairing CL synthesis and remodeling. The resulting CL deficiency causes mitochondrial oxidative stress and programmed cell death, leading to mitochondrial and cardiac dysfunction. Genetic or chemical inhibition of v-ATPase and of CRLS1 in mouse models reproduce these age-related defects, highlighting their central roles in cardiac aging. Restoring nicotinamide adenine dinucleotide levels rescues lysosomal acidification and CL metabolism, protecting against age-related cardiomyopathy in rodents and humans. CONCLUSIONS: Augmenting v-ATPase–mediated lysosomal acidification offers novel therapeutic strategies to combat age-related cardiomyopathy by rewiring CL homeostasis.

During aging, decreased intestinal barrier function and its ability to synthesize metabolites are closely associated with various age‐related diseases. However, the mechanism by which impaired intestinal synthesis contributes to gut–liver axis aging remains unclear. This study reveals that aging induces a mitochondrial energy crisis and defective membrane localization of ABCA1, significantly inhibiting the biosynthesis of high‐density lipoprotein 3 (HDL3) in the intestine. Exogenous supplementation with β‐nicotinamide mononucleotide (NMN) restores intestinal NAD ⁺ homeostasis, enhances oxidative phosphorylation efficiency, and promotes ATP‐dependent lipid transport, thereby rejuvenating the production of gut‐derived HDL3. Further investigations demonstrate that gut‐originated HDL3 neutralizes lipopolysaccharide (LPS) in the liver and attenuates TLR4‐mediated inflammatory cascades, ultimately ameliorating age‐related liver injury. These findings elucidate a novel mechanism whereby NMN modulates the NAD ⁺ –mitochondria–ABCA1–HDL3 axis to preserve gut–liver axis function, offering a promising therapeutic strategy for mitigating aging‐related pathologies in this metabolic cross‐talk.

Oxidative stress is one of the critical factors contributing to the rising prevalence of male infertility. Hydrolyzed peptides from Pichia pastoris (HPP), a major component of Pichia pastoris hydrolysate, have an underestimated impact on the male reproductive system. This study aimed to systematically evaluate the potential of HPP to improve sperm quality. Results revealed that HPP enhanced sperm quality and serum testosterone levels in rats, with no adverse impact on body weight or the genital weight index. HPP increased the diameter of seminiferous tubules, yet no significant changes were observed in the expression levels of blood-testis-barrier (BTB)-related genes (zonula occludens-1, Occludin, Connexin-43, and N-cadherin). Transcriptomics, non-target metabolomics, Western blotting, and Quantitative Real-time PCR analyses revealed that HPP-treated rats exhibited significantly upregulated antioxidant enzymes (nuclear factor erythroid-2-related factor 2 (Nrf2) and Heme Oxygenase-1 (HO-1)) expression, decreased reactive oxygen species (ROS) contents, and inhibited the PI3K/AKT signaling pathway. Moreover, we found that taurine and hypotaurine metabolism might be potential metabolic targets for improving sperm quality. Taken together, these results highlight HPP as a promising nutraceutical supplement for improving sperm quality. The antioxidant mechanism of HPP via the regulation of the PI3K/AKT signaling pathway lays a foundation for further research into nutrient-based interventions for male infertility.

With the increasing application of copper nanoparticles (CuNPs) as antibacterial agents, numerous studies have emerged in recent years focusing on their preparation and utilization. However, the existing physical and chemical processes for CuNPs synthesis are complex and environmentally hazardous, creating a demand for greener alternatives. Komagataella phaffii has been recognized as a cost-effective system for metal biosorption. Nevertheless, high concentrations of heavy metal particles inhibit cell growth and result in low biosorption efficiency of metal-based nanoparticles (NPs). To address this issue, we engineered the K. phaffii strain X-33-Cyb5R by expressing the cytochrome b-5 reductase (Cyb5R) enzyme, enhancing its tolerance to elevated heavy metal concentrations and promoting CuNPs biosorption. Through further optimization of biosorption conditions, CuNPs production reached 14.27 mg/g dry cell weight (DCW) after 36 h, utilizing 12 mmol/L CuSO₄ at 30 °C and pH 4. The adsorbed particles on the surface of the modified strain K. phaffii X-33-Cyb5R were confirmed to be CuNPs with diameters ranging from 40 to 80 nm. Notably, the CuNPs synthesized in this study exhibited potent antibacterial activity. This research not only provides a novel approach for the construction of highly metal-tolerant strains and efficient CuNPs production but also offers new insights for the development and utilization of environmentally friendly antibacterial agents.

Selenium (Se) is a trace element that is essential for health. Organic Se created by Se-enriched microorganisms has the characteristics of low toxicity, high bioavailability, and regulation of physiological functions. Here, the regulatory effect of Se-enriched Aspergillus oryzae A02 on the reproductive function of male mice and its potential molecular mechanism was studied. Specifically, twenty-four male mice were randomly divided into a control group and a Se-enriched A. oryzae A02 (Nano-Se) (daily gavage of 0.5 mg/kg, dissolved in saline) for an 8-week experiment. The results showed that Nano-Se intervention did not affect body weight and testicular index, but increased sperm concentration and seminiferous epithelium height in experimental mice, indicating that Nano-Se has the potential to improve the reproductive performance of male mice. Mechanistically, Nano-Se intervention increased the levels of antioxidant-related indicators catalase (CAT) and glutathione peroxidase (GSH-Px) in mouse serum, and increased the relative mRNA expression of GSH-Px, heme oxygenase-1 (HO-1), and NADPH quinine oxidoreductase-1 (NQO-1) in testicular tissues. We identified 9,10,13-trihydroxyoctadecenoic acids (TriHOMEs), stearidonic acid and selenomethionine linked with alpha-linolenic acid metabolism, selenocompound metabolism, folate biosynthesis, ubiquinone, and other terpenoid-quinone biosynthesis and biosynthesis of cofactors. In addition, Nano-Se did not influence the fecal bacterial alpha and beta diversity (P > 0.05), but increased the abundance of the Actinobacteriota and Proteobacteria phyla and the Staphylococcus and Corynebacterium genera, and lowered the abundance of the Bacteroidota phylum and the Lactobacillus and norank_f_Muribaculaceae genera. Nano-Se is considered a novel and promising nutritional regulator to improve reproductive function.

Nicotinamide mononucleotide (NMN), the direct precursor of nicotinamide adenine dinucleotide (NAD⁺), is involved in the regulation of many physiological and metabolic reactions in the body. NMN can indirectly affect cellular metabolic pathways, DNA repair, and senescence, while also being essential for maintaining tissues and dynamic metabolic equilibria, promoting healthy aging. Therefore, NMN has found many applications in the food, pharmaceutical, and cosmetics industries. At present, NMN synthesis strategies mainly include chemical synthesis and biosynthesis. Despite its potential benefits, the commercial production of NMN by organic chemistry approaches faces environmental and safety problems. With the rapid development of synthetic biology, it has become possible to construct microbial cell factories to produce NMN in a cost-effective way. In this review, we summarize the chemical and biosynthetic strategies of NMN, offering an overview of the recent research progress on host selection, chassis cell optimization, mining of key enzymes, metabolic engineering, and adaptive fermentation strategies. In addition, we also review the advances in the role of NMN in aging, metabolic diseases, and neural function. This review provides comprehensive technical guidance for the efficient biosynthesis of NMN as well as a theoretical basis for its application in the fields of food, medicine, and cosmetics.

β‐Nicotinamide mononucleotide (NMN) is a biologically active nucleotide that regulates the physiological metabolism of the body by rapidly increasing nicotinamide adenine dinucleotide (NAD⁺). To determine the safety and biological activity of NMN resources, we constructed a recombinant strain of P. pastoris that heterologously expresses nicotinamide‐phosphate ribosyltransferase (NAMPT), and subsequently catalyzed and purified the expressed product to obtain NMN. Consequently, this study established a high‐fat diet (HFD) obese model to investigate the lipid‐lowering activity of NMN. The findings showed that NMN supplementation directly increased the NAD⁺ levels, and reduced HFD‐induced liver injury and lipid deposition. NMN treatment significantly decreased total cholesterol (TC) and triglyceride (TG) in serum and liver, as well as alanine aminotransferase (ALT) and insulin levels in serum (p < .05 or p < .01). In conclusion, this study combined synthetic biology with nutritional evaluation to confirm that P. pastoris‐generated NMN modulated lipid metabolism in HFD mice, offering a theoretical framework and evidence for the application of microbially created NMN.

Under normal physiological conditions, reactive oxygen species (ROS) are produced through redox reactions as byproducts of respiratory and metabolic activities. However, due to various endogenous and exogenous factors, the body may produce excessive ROS, which leads to oxidative stress (OS). Numerous studies have shown that OS causes a variety of pathological changes in cells, including mitochondrial dysfunction, DNA damage, telomere shortening, lipid peroxidation, and protein oxidative modification, all of which can trigger apoptosis and senescence. OS also induces a variety of aging-related diseases, such as retinal disease, neurodegenerative disease, osteoarthritis, cardiovascular diseases, cancer, ovarian disease, and prostate disease. In this review, we aim to introduce the multiple internal and external triggers that mediate ROS levels in rodents and humans as well as the relationship between OS, aging, and aging-related diseases. Finally, we present a statistical analysis of effective antioxidant measures currently being developed and applied in the field of aging research.

BACKGROUND: Chronic overconsumption of lipids followed by their excessive accumulation in the heart leads to cardiomyopathy. The cause of lipid-induced cardiomyopathy involves a pivotal role for the proton-pump vacuolar-type H ⁺ -ATPase (v-ATPase), which acidifies endosomes, and for lipid-transporter CD36, which is stored in acidified endosomes. During lipid overexposure, an increased influx of lipids into cardiomyocytes is sensed by v-ATPase, which then disassembles, causing endosomal de-acidification and expulsion of stored CD36 from the endosomes toward the sarcolemma. Once at the sarcolemma, CD36 not only increases lipid uptake but also interacts with inflammatory receptor TLR4 (Toll-like receptor 4), together resulting in lipid-induced insulin resistance, inflammation, fibrosis, and cardiac dysfunction. Strategies inducing v-ATPase reassembly, that is, to achieve CD36 reinternalization, may correct these maladaptive alterations. For this, we used NAD ⁺ (nicotinamide adenine dinucleotide)-precursor nicotinamide mononucleotide (NMN), inducing v-ATPase reassembly by stimulating glycolytic enzymes to bind to v-ATPase. METHODS: Rats/mice on cardiomyopathy-inducing high-fat diets were supplemented with NMN and for comparison with a cocktail of lysine/leucine/arginine (mTORC1 [mechanistic target of rapamycin complex 1]-mediated v-ATPase reassembly). We used the following methods: RNA sequencing, mRNA/protein expression analysis, immunofluorescence microscopy, (co)immunoprecipitation/proximity ligation assay (v-ATPase assembly), myocellular uptake of [ ³ H]chloroquine (endosomal pH), and [ ¹⁴ C]palmitate, targeted lipidomics, and echocardiography. To confirm the involvement of v-ATPase in the beneficial effects of both supplementations, mTORC1/v-ATPase inhibitors (rapamycin/bafilomycin A1) were administered. Additionally, 2 heart-specific v-ATPase-knockout mouse models (subunits V ₁ G1/V ₀ d2) were subjected to these measurements. Mechanisms were confirmed in pharmacologically/genetically manipulated cardiomyocyte models of lipid overload. RESULTS: NMN successfully preserved endosomal acidification during myocardial lipid overload by maintaining v-ATPase activity and subsequently prevented CD36-mediated lipid accumulation, CD36-TLR4 interaction toward inflammation, fibrosis, cardiac dysfunction, and whole-body insulin resistance. Lipidomics revealed C18:1-enriched diacylglycerols as lipid class prominently increased by high-fat diet and subsequently reversed/preserved by lysine/leucine/arginine/NMN treatment. Studies with mTORC1/v-ATPase inhibitors and heart-specific v-ATPase-knockout mice further confirmed the pivotal roles of v-ATPase in these beneficial actions. CONCLUSION: NMN preserves heart function during lipid overload by preventing v-ATPase disassembly.

Background Syphilis is a chronic sexually transmitted disease caused by Treponema pallidum subspecies pallidum (T. pallidum), which is a public health problem that seriously affects human health worldwide. T. pallidum is characterized by early transmission and immune escape and is therefore termed an “invisible pathogen”. Methods This review systematically summarizes the host’s innate and adaptive immune responses to T. pallidum infection as well as the escape mechanisms of T. pallidum. Purpose To lay the foundation for assessing the pathogenic mechanism and the systematic prevention and treatment of syphilis. Conclusion The immune escape mechanism of T. pallidum plays an important role in its survival. Exploring the occurrence and development of these mechanisms has laid the foundation for the development of syphilis vaccine.