Biology-Basel
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2026
·Vol. 15
·期 13
·999
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IF 4.3
Xiang Li,Bo Tian,Yuxin Chen,Huili Tong,Xiaoming Chen,Zhifeng Cheng
Simple SummaryType 2 diabetes (T2DM) often leads to skeletal muscle loss and weakness, a condition called sarcopenia, which worsens human health. This study explored whether carnosine, a natural dipeptide found in meat and present in human muscle, can help protect against muscle wasting. Using a T2DM sarcopenia mouse model and a high-glucose-treated C2C12 myotube in vitro model, the researchers found that carnosine levels were reduced in T2DM sarcopenia muscles. Oral carnosine supplementation in the mice helped alleviate skeletal muscle atrophy. Carnosine works by activating a cellular signaling pathway that boosts the number of mitochondria (the energy powerhouses of cells) and shifts muscle fibers toward a more oxidative type, leading to stronger and healthier muscles in T2DM sarcopenia mice. These findings suggest that carnosine supplementation could be a simple and promising nutritional strategy to help manage skeletal muscle loss in people with type 2 diabetes, though further studies in humans are needed to confirm its effectiveness.Type 2 diabetes mellitus (T2DM) accounts for over 90% of diabetes cases, and T2DM-related sarcopenia is a growing concern. Carnosine, abundant in human skeletal muscle, helps maintain muscle quality and function. This study investigated whether carnosine deficiency contributes to T2DM-related sarcopenia and whether exogenous carnosine supplementation alleviates muscle atrophy. A mouse model of T2DM sarcopenia was established using streptozotocin combined with a high-fat diet. LC-MS metabolomics revealed a significant reduction in carnosine content in the gastrocnemius muscle of model mice. A C2C12 myotube atrophy model was induced by high-glucose (HG), and qRT-PCR showed altered expression of carnosine metabolism-related enzymes, suggesting disrupted carnosine homeostasis under T2DM conditions. Mechanistic investigations using immunofluorescence, Western blotting, transcriptome sequencing, mitochondrial staining, and molecular docking indicated that carnosine may alleviate high-glucose-induced myotube atrophy through the PI3K/AMPK/PGC-1α signaling pathway. In vivo, carnosine supplementation increased the number of mitochondria and the proportion of slow muscle fibers in gastrocnemius muscle, ameliorating the atrophic phenotype. These findings suggest that carnosine has potential as a candidate for intervention in T2DM-related sarcopenia, though further validation of its direct molecular targets is required.
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Journal of Advanced Research
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2026
·
IF 17.1
Jiaxin Su,Lingcheng Wu,Huiru Zhu,Haoru Wang,Xiaoya He,Bing Liang,Jinhua Cai
Introduction Acute kidney injury (AKI) is a devastating global health burden. Its pathogenesis, particularly in ischemia/reperfusion (I/R) injury, centers on a vicious cycle between a reactive oxygen species (ROS)-driven inflammatory storm and severe mitochondrial dysfunction in renal tubular cells. While activation of the SIRT1/PGC-1α pathway is a promising therapeutic target for mitochondrial recovery, its potent agonist resveratrol (Rsv) suffers from poor bioavailability, and monotherapy fails to address the concomitant inflammatory pathology. Objective This study aimed to develop a kidney-targeted theranostic nanoplatform that synergistically breaks this pathological cycle. We hypothesized that a nanoplatform co-delivering Rsv and a ROS-scavenging component could concurrently suppress inflammation via direct ROS elimination and restore mitochondrial homeostasis via SIRT1/PGC-1α activation, with integrated magnetic resonance imaging (MRI) capability for monitoring. Methods We engineered a theranostic nanoplatform designated Rsv@HMnO 2 -HA (HMRH NPs). The platform was constructed by loading Rsv into hollow mesoporous manganese dioxide (HMnO 2 ) nanozymes, followed by surface coating with hyaluronic acid (HA) for active targeting to CD44 receptors over expressed on injured renal tubules. The system’s physicochemical properties were thoroughly characterized. Its therapeutic efficacy and theranostic performance were systematically evaluated in a well-established murine model of renal I/R-induced AKI, using a combination of biochemical assays, histological analysis, molecular biology techniques, and in vivo MRI. Results HMRH NPs successfully accumulated in injured kidneys and disassembled in situ. The HMnO 2 shell effectively scavenged excess ROS, attenuating the inflammatory response. The co-released Rsv activated the SIRT1/PGC-1α pathway, restored mitochondrial biogenesis, and improved cellular energy homeostasis. The released Mn 2+ ions enabled clear T 1 -weighted MRI contrast, allowing real-time visualization of renal targeting and therapeutic progression. Conclusion The results conclusively demonstrate that the HMRH NPs successfully implements a synergistic two-pronged therapeutic strategy. By co-delivering a ROS-scavenger and a mitochondrial-regenerative agent directly to the site of injury, the platform effectively disrupts the critical pathological crosstalk between inflammation and mitochondrial damage in AKI. This work presents a holistic, targeted, and image-guided nanomedicine strategy, offering a promising approach for the effective treatment and monitoring of AKI.
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Frontiers in Pharmacology
·
2021
·
IF 5.811
Yin Zhihui,Geng Xinyue,Zhang Zhengyi,Wang Ying,Gao Xiaoyan
Neuronal mitochondrial oxidative stress induced by β-amyloid (Aβ) is an early event of Alzheimer’s disease (AD). Emerging evidence has shown that antioxidant therapy represents a promising therapeutic strategy for the treatment of AD. In this study, we investigated the antioxidant activity of rhein against Aβ1-42 oligomer-induced mitochondrial oxidative stress in primary neurons and proposed a potential antioxidant pathway involved. The results suggested that rhein significantly reduced reactive oxygen species (ROS) level, reversed the depletion of mitochondrial membrane potential, and protected neurons from oxidative stress-associated apoptosis. Moreover, further study indicated that rhein activated mitochondrial biogenesis accompanied by increased cytochrome C oxidase (CytOx) and superoxide dismutase (SOD) activities. CytOx on the respiratory chain inhibited the production of ROS from electron leakage and SOD helped to eliminate excess ROS. Finally, western blot analysis confirmed that rhein remarkedly increased the protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) together with its upstream deacetylase sirtuin 1 (SIRT1), and activated downstream transcription factor nuclear respiratory factor 1, promoting mitochondrial biogenesis. In conclusion, our results demonstrate that rhein activates mitochondrial biogenesis regulated by the SIRT1/PGC-1α pathway as an antioxidant defense system against Aβ1-42 oligomer-induced oxidative stress. These findings broaden our knowledge of improving mitochondrial biogenesis as an approach for relieving neuronal oxidative stress in AD.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2021
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IF 4.932
Lu Wang,Xiaohui Wang,Lina Kong,Shuyuan Wang,Kai Huang,Jingjing Wu,Changyuan Wang,Huijun Sun,Kexin Liu,Qiang Meng
Acute liver failure (ALF) is a dramatic liver disease characterized by large areas of inflammation. However, there are no available effective targeted drugs for ALF treatment. In the study, serum biochemical index and H&E were used to explore the amelioration of the liver histopathological changes. The oxidative stress kits, quantitative real-time PCR, western blot, immunohistochemistry, immunofluorescence staining, reactive oxygen species (ROS), and siRNA were used to elucidate the mechanisms underlying isoliquiritigenin (ISL) protection. The results showed that ISL significantly improved the liver pathological changes. Furthermore, ISL reduced oxidative stress by altering the expression of PGC-1α, Nrf2, HO-1, NQO1, Keap1, GCLC, and GCLM in damaged hepatocytes. Moreover, the levels of inflammation-related genes including NLRP3 inflammasome, IL-1β, IL-6, TNF-α, iNOS, and Mip-2 were repressed by ISL. In addition, ISL alleviated LPS/D-GalN-induced hepatocytes apoptosis by increasing the Bcl-2/Bax ratio and suppressing the expression of cleaved caspase-3. Further in vivo and in vitro evidence proved the involvement of the PGC-1α/Nrf2 signaling pathway in ISL protection. In conclusion, ISL improves the ability of anti-oxidative stress, alleviates inflammatory reaction, apoptosis, and inhibits NLRP3 inflammasome to protect lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced ALF through activating the PGC-1α/Nrf2 pathway, which provides the possibility for the treatment of ALF.
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TOXICOLOGY
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2025
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IF 4.6
Mei-Ling Le,Jia-Yu Xue,Li-Hai Wu,Xin-Yuan Zhao,Jing Ding,Yang-Yang Yuan,Yi-Qi Wan,Da-Lei Zhang
Hexafluoropropylene oxide (HFPO) homologues (HFPOs), specifically HFPO-dimeric acid (DA), HFPO-trimeric acid (TA) and HFPO-tetrameric acid (TeA), have emerged as industrial replacements for phased-out perfluorooctanoic acid (PFOA), garnering considerable attention due to their environmental ubiquity and bioaccumulation potential. Nevertheless, the reproductive toxicity of HFPOs remains incompletely characterized, particularly regarding their endocrine-disrupting effect and the underlying mechanisms involving Leydig cell dysfunction. In this study, we investigated the cytotoxic influences of HFPOs on TM3 Leydig cells, focusing on mitochondrial function and dynamics, oxidative stress, and apoptosis. Our findings demonstrated that exposure to HFPOs significantly compromised mitochondrial function and fusion-fission dynamics by disrupting the SIRT1/PGC1α signaling pathway. The mitochondrial dysfunction further triggered excessive ROS production and apoptosis, ultimately impairing TM3 Leydig cell viability and testosterone secretion. However, supplementation with the SIRT1 agonist SRT1720 relieved the inhibitory effect of HFPOs on SIRT1/PGC1α signaling pathway and reversed the expression of apoptosis-associated proteins (BAX/BCL2), oxidative stress-associated proteins (SOD1/SOD2), as well as proteins associated with mitochondrial fusion (MFN2/OPA1) and fission (DRP1/FIS1). These results elucidated the involvement of the SIRT1/PGC1α pathway in mediating the cytotoxicity of HFPOs. Notably, the activation of SIRT1 mitigated HFPO-induced toxicity in the TM3 cells, uncovering its potential in safeguarding testicular cells from the damage caused by HFPOs exposure.
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Animal Nutrition
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2026
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IF 8.3
Anran Wang,Jie Xu,Haoyue Guo,Dongxu Luo,Zhen Zhang,Chao Ran,Shuyan Miao,Zhigang Zhou
Fish oil is an essential lipid source in aquafeed due to its high polyunsaturated fatty acid content. However, its susceptibility to oxidation can harm aquatic animal health and growth. This study investigated the effects of oxidized fish oil (OFO) diet on hepatopancreas health of Macrobrachium rosenbergii , and the mechanism by which Cetobacterium somerae protects against oxidative damage induced by OFO diet. A total of 240 juvenile prawns (3.36 ± 0.02 g) were randomly allocated to three dietary treatments with four replicates of 20 prawns each for 8 weeks: Control (control diet with fresh fish oil diet), OFO (OFO diet), and OFO + Cet (OFO diet supplemented with C. somerae at 1.52 × 10 7 CFU/g). Compared with the OFO group, C. somerae intervention significantly reduced the levels of lipid peroxidation-related markers, including malondialdehyde (MDA), 5-hydroperoxyeicosatetraenoic acid (5-HETE), leukotriene B4 (LTB4), prostaglandins (PGs), and thromboxanes (TXs), while increasing hepatopancreatic antioxidant indicators, including total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), and glutathione peroxidase (GSH-Px) ( P < 0.05). Moreover, it also reversed the OFO diet-induced alterations in the relative mRNA expression levels of ferroptosis-related genes ( acsl4 , tfr1 , gpx4 , and slc7a11 ) ( P < 0.05), potentially via the adenosine monophosphate (AMP)-activated protein kinase (AMPK)-sirtuin1 (SIRT1)-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signaling pathway. Serum acetic acid, a C. somerae metabolite, exhibited the most pronounced alteration in the C. somerae -treated group ( P = 0.004). Furthermore, 160 juvenile prawns (2.62 ± 0.12 g) were randomly divided into two groups with four replicates of 20 prawns in each for 4 weeks: OFO diet, OFO + 0.15% sodium acetate (0.15% NaAc). Supplementation with 0.15% NaAc in the OFO diet also effectively decreased the peroxides (MDA, 5-HETE, LTB4, and TXs) and reversed the OFO diet-induced alterations in the relative mRNA expression levels of ferroptosis-related genes ( acsl4 , tfr1 , gpx4 , and slc7a11 ) compared with OFO group ( P < 0.05), suggesting a contributory role of acetate in the functionality of C. somerae . Meanwhile, the elevated AMP/adenosine triphosphate (ATP) ratio and upregulated relative mRNA expression levels of acss1/2 , ampk, sirt1 , and pgc-1α ( P < 0.05) indicated that C. somerae- derived acetate activates AMP production, thereby activating the AMPK-SIRT1-PGC-1α signaling pathway . Overall, C. somerae protects against OFO diet-induced hepatopancreatic injury by mitigating ferroptosis via acetate-mediated activation of the AMPK-SIRT1-PGC-1α signaling pathway.
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Oxidative Medicine and Cellular Longevity
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2022
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IF 7.31
Zhihui Yin,Demin Gao,Ke Du,Chen Han,Yuhan Liu,Ying Wang,Xiaoyan Gao
Mitochondrial oxidative stress plays an important role in the pathogenesis of Alzheimer’s disease (AD). Recently, antioxidant therapy has been considered an effective strategy for the treatment of AD. Our previous work discovered that rhein relieved mitochondrial oxidative stress in β-amyloid (Aβ) oligomer-induced primary neurons by improving the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha- (PGC-1α-) regulated mitochondrial biogenesis. While encouraging results have been provided, mechanisms underlying the beneficial effect of rhein on AD are yet to be elucidated in vivo. In this study, we evaluated the therapeutic effect of rhein on an APP/PS1 transgenic (APP/PS1) mouse model of AD and explored its antioxidant mechanisms. As a result, rhein significantly reduced Aβ burden and neuroinflammation and eventually ameliorated cognitive impairment in APP/PS1 mice. Moreover, rhein reversed oxidative stress in the brain of APP/PS1 mice and protected neurons from oxidative stress-associated apoptosis. Further study revealed that rhein promoted mitochondrial biogenesis against oxidative stress by upregulating SIRT1 and its downstream PGC-1α as well as nuclear respiratory factor 1. Improved mitochondrial biogenesis not only increased the activity of superoxide dismutase to scavenge excess reactive oxygen species (ROS) but also repaired mitochondria by mitochondrial fusion to inhibit the production of ROS from the electron transport chain. Notably, the exposure of rhein in the brain analyzed by tissue distribution study indicated that rhein could permeate into the brain to exert its therapeutic effects. In conclusion, these findings drive rhein to serve as a promising therapeutic antioxidant for the treatment of AD. Our research highlights the therapeutic efficacy for AD through regulating mitochondrial biogenesis via the SIRT1/PGC-1α pathway.
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BIOCHEMICAL PHARMACOLOGY
·
2018
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IF 4.235
Zhihua Wang,Sheng Yuan,Yanbing Li,Zhe Zhang,Wei Xiao,Dan Tang,Kaihe Ye,Zhijun Liu,Congcong Wang,Yixiong Zheng,Hong Nie,Heru Chen
( R , E )- N -(3-(2-acetamido-3-(benzyloxy) propanamido)propyl)-2-cyano-3-(4-hydroxy phenyl)acrylamide ( hr5F ) was design-synthesized based on bioactivity focus strategy as a potential agent to treat diabetic complicates. With in vitro enzyme assay, it is confirmed that hr5F is an effective ALR2 inhibitor with IC 50 value of 2.60 ± 0.15 nM, and selectivity index of 86.0 over ALR1, which is a little bit better than the reference Epalrestat (Epa). hr5F inhibits the increase of ALR2 enzyme activity and expression in human lens epithelial cells (HLECs) induced by high glucose. By applying western blot , it was found that hr5F alleviates the high glucose-induced superoxide overproduction insults by regulating SIRT1-PGC-1α/Nrf2 pathway, together with regulating NRF-1, mtTFA , Bax/Bcl-2 to ameliorate cell apoptosis . The in vivo effects of hr5F on short term streptozocin (STZ)-induced diabetic mice confirm the same functions disclosed in vitro . All the evidences support that hr5F may serve as a promising agent in the treatment of diabetic complications with close efficacy and broader indication than the reference Epa.
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Scientific Reports
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2025
·Vol. 15
·期 1
·1-12
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IF 3.9
Wan Meixia,Li Qing,Xiao Yudie,Zhou Dan,Lei Qianya,Wang Shu
Mori Fructus, rich in polysaccharides and polyphenols, has long been used in East Asia as a functional food and medicinal agent. In traditional Chinese medicine, it is used to treat various ailments like wasting-thirst syndrome and constipation. Studies suggest its extract fractions may alleviate metabolic syndrome symptoms by affecting gut microbiota. To explore this, fecal microbiota transplantation (FMT) was used in an experiment. Pseudo-germ-free mice were created with antibiotics and given a high-fat, high-sugar diet (HFD) to induce metabolic syndrome. Then, fecal bacterial infusions were transplanted. Results showed significant improvement in metabolic syndrome parameters in the FMT-MFPS(fecal microbiota transplantation-Mori Fructus polyphenols plus polysaccharides) group. Dyslipidemia, liver, and kidney injuries were modulated in treated mice. The PPARα/PGC-1α signaling pathway was activated. These findings indicate Mori Fructus extract fractions prevent metabolic syndrome via gut microbiota modulation, with effects sustained through FMT, providing a reference for prevention.
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