Acetate ameliorates ovarian mitochondrial dysfunction in letrozole-induced polycystic ovarian syndrome rat model by improving mitofusin-2.

Androgen excess and metabolic abnormality largely contribute to the pathogenesis of polycystic ovarian syndrome (PCOS), which primarily precipitates ovarian dysfunction and infertility in reproductive-age women. Impaired mitochondrial function and epigenetic alteration have been linked to the development of PCOS. However, it is unknown whether acetate would exert a therapeutic effect on ovarian mitochondrial dysfunction in PCOS. Herein, the study hypothesized that acetate reverses ovarian mitochondrial dysfunction in experimental PCOS rat model, possibly through modulation of mitofusin-2 (MFn2). Eight-week-old female Wistar rats were randomized into four groups (n = 5). Induction of PCOS was performed by 1 mg/kg letrozole (p.o.), administered for 21 days. Thereafter, the rats were treated with acetate (200 mg/kg; p.o.) for 6 weeks. The PCOS rats demonstrated androgen excess, multiple ovarian cysts, elevated anti-mullerian hormone and leptin and decreased SHBG, adiponectin and 17-ß estradiol with corresponding increase in ovarian transforming growth factor-ß1. Additionally, inflammation (tumor growth factor and nuclear factor-kB), elevated caspase-6, decreased hypoxia-inducible factor-1α and elevated histone deacetylase-2 (HDAC2) were observed in the ovaries of PCOS rats, while mitochondrial abnormality with evidence of decreased adenosine triphosphate synthase and MFn2 was observed in rats with PCOS. Treatment with acetate reversed the alterations. The present results collectively suggest that acetate ameliorates ovarian mitochondrial abnormality, a beneficial effect that is accompanied by MFn2 with consequent normalization of reproductive-endocrine profile and ovarian function. Perhaps, the present data provide hope for PCOS individuals that suffer infertility.

Reinforcing the Evidence of Mitochondrial Dysfunction in Long COVID Patients Using a Multiplatform Mass Spectrometry-Based Metabolomics Approach.

Despite the recent and increasing knowledge surrounding COVID-19 infection, the underlying mechanisms of the persistence of symptoms for a long time after the acute infection are still not completely understood. Here, a multiplatform mass spectrometry-based approach was used for metabolomic and lipidomic profiling of human plasma samples from Long COVID patients (n = 40) to reveal mitochondrial dysfunction when compared with individuals fully recovered from acute mild COVID-19 (n = 40). Untargeted metabolomic analysis using CE-ESI(+/-)-TOF-MS and GC-Q-MS was performed. Additionally, a lipidomic analysis using LC-ESI(+/-)-QTOF-MS based on an in-house library revealed 447 lipid species identified with a high confidence annotation level. The integration of complementary analytical platforms has allowed a comprehensive metabolic and lipidomic characterization of plasma alterations in Long COVID disease that found 46 relevant metabolites which allowed to discriminate between Long COVID and fully recovered patients. We report specific metabolites altered in Long COVID, mainly related to a decrease in the amino acid metabolism and ceramide plasma levels and an increase in the tricarboxylic acid (TCA) cycle, reinforcing the evidence of an impaired mitochondrial function. The most relevant alterations shown in this study will help to better understand the insights of Long COVID syndrome by providing a deeper knowledge of the metabolomic basis of the pathology.

Clinical and genetic analysis of essential hypertension with mitochondrial tRNAMet 4435A>G and YARS2 mutation. / 携带线粒体tRNAMet 4435A>Gå’Œæ ¸åŸºå› YARS2çªå˜çš„åŽŸå‘æ€§é«˜è¡€åŽ‹å®¶ç³»é—ä¼ å­¦åˆ†æž.

OBJECTIVES: To investigate the role of m.4435A>G and YARS2 c.572G>T (p.G191V) mutations in the development of essential hypertension. METHODS: A hypertensive patient with m.4435A>G and YARS2 p.G191V mutations was identified from the mitochondrial genome and exon sequencing data previously collected. Clinical data were collected, and the molecular genetic study was conducted in the proband and his family members. Peripheral venous blood was collected, and immortalized lymphocyte lines were constructed. The mitochondrial tRNA, mitochondrial protein, ATP, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) in the constructed lymphocyte cell lines were detected. RESULTS: Mitochondrial genome sequencing results showed that all maternal members carried a highly conserved m.4435A>G mutation. The m.4435A>G mutation might affect the secondary structure and folding free energy of mitochondrial tRNA and change its stability, which would affect the anticodon ring structure. Compared with the control group, the cell lines carrying m.4435A>G and YARS2 p.G191V mutations had decreased mitochondrial tRNA homeostasis, partial mitochondrial protein expression, ATP production, and MMP levels, and increased ROS levels. The differences were statistically significant (P<0.05). CONCLUSIONS: The YARS2 p.G191V mutation aggravates the changes in mitochondrial translation and mitochondrial function caused by m.4435A>G by affecting the steady-state level of mitochondrial tRNA and further leads to cell dysfunction, indicating that YARS2 p.G191V and m.4435A>G mutations have a synergistic effect in this family and jointly participate in the occurrence and development of essential hypertension.

Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review).

Chronic neuroinflammation serves a key role in the onset and progression of neurodegenerative disorders. Mitochondria serve as central regulators of neuroinflammation. In addition to providing energy to cells, mitochondria also participate in the immunoinflammatory response of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis and epilepsy, by regulating processes such as cell death and inflammasome activation. Under inflammatory conditions, mitochondrial oxidative stress, epigenetics, mitochondrial dynamics and calcium homeostasis imbalance may serve as underlying regulatory mechanisms for these diseases. Therefore, investigating mechanisms related to mitochondrial dysfunction may result in therapeutic strategies against chronic neuroinflammation and neurodegeneration. The present review summarizes the mechanisms of mitochondria in chronic neuroinflammatory diseases and the current treatment approaches that target mitochondrial dysfunction in these diseases.

Mapping the Research of Ferroptosis in Parkinson's Disease from 2013 to 2023: A Scientometric Review.

Methods: Related studies on PD and ferroptosis were searched in Web of Science Core Collection (WOSCC) from inception to 2023. VOSviewer, CiteSpace, RStudio, and Scimago Graphica were employed as bibliometric analysis tools to generate network maps about the collaborations between authors, countries, and institutions and to visualize the co-occurrence and trends of co-cited references and keywords. Results: A total of 160 original articles and reviews related to PD and ferroptosis were retrieved, produced by from 958 authors from 162 institutions. Devos David was the most prolific author, with 9 articles. China and the University of Melbourne had leading positions in publication volume with 84 and 12 publications, respectively. Current hot topics focus on excavating potential new targets for treating PD based on ferroptosis by gaining insight into specific molecular mechanisms, including iron metabolism disorders, lipid peroxidation, and imbalanced antioxidant regulation. Clinical studies aimed at treating PD by targeting ferroptosis remain in their preliminary stages. Conclusion: A continued increase was shown in the literature within the related field over the past decade. The current study suggested active collaborations among authors, countries, and institutions. Research into the pathogenesis and treatment of PD based on ferroptosis has remained a prominent topic in the field in recent years, indicating that ferroptosis-targeted therapy is a potential approach to halting the progression of PD.

Leaky gut, circulating immune complexes, arthralgia, and arthritis in IBD: coincidence or inevitability?

Most host-microbiota interactions occur within the intestinal barrier, which is essential for separating the intestinal epithelium from toxins, microorganisms, and antigens in the gut lumen. Gut inflammation allows pathogenic bacteria to enter the blood stream, forming immune complexes which may deposit on organs. Despite increased circulating immune complexes (CICs) in patients with inflammatory bowel disease (IBD) and discussions among IBD experts regarding their potential pathogenic role in extra-intestinal manifestations, this phenomenon is overlooked because definitive evidence demonstrating CIC-induced extra-intestinal manifestations in IBD animal models is lacking. However, clinical observations of elevated CICs in newly diagnosed, untreated patients with IBD have reignited research into their potential pathogenic implications. Musculoskeletal symptoms are the most prevalent extra-intestinal IBD manifestations. CICs are pivotal in various arthritis forms, including reactive, rheumatoid, and Lyme arthritis and systemic lupus erythematosus. Research indicates that intestinal barrier restoration during the pre-phase of arthritis could inhibit arthritis development. In the absence of animal models supporting extra-intestinal IBD manifestations, this paper aims to comprehensively explore the relationship between CICs and arthritis onset via a multifaceted analysis to offer a fresh perspective for further investigation and provide novel insights into the interplay between CICs and arthritis development in IBD.

Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders.

The oxytosis/ferroptosis regulated cell death pathway is an emerging field of research owing to its pathophysiological relevance to a wide range of neurological disorders, including Alzheimer's and Parkinson's diseases and traumatic brain injury. Developing novel neurotherapeutics to inhibit oxytosis/ferroptosis offers exciting opportunities for the treatment of these and other neurological diseases. Previously, we discovered cannabinol (CBN) as a unique, potent inhibitor of oxytosis/ferroptosis by targeting mitochondria and modulating their function in neuronal cells. To further elucidate which key pharmacophores and chemical space are essential to the beneficial effects of CBN, we herein introduce a fragment-based drug discovery strategy in conjunction with cell-based phenotypic screens using oxytosis/ferroptosis to determine the structure-activity relationship of CBN. The resulting information led to the development of four new CBN analogs, CP1-CP4, that not only preserve the sub-micromolar potency of neuroprotection and mitochondria-modulating activities seen with CBN in neuronal cell models but also have better druglike properties. Moreover, compared to CBN, the analog CP1 shows improved in vivo efficacy in the Drosophila model of mild traumatic brain injury. Together these studies identify the key molecular scaffolds of cannabinoids that contribute to neuroprotection against oxytosis/ferroptosis. They also highlight the advantageous approach of combining in vitro cell-based assays and rapid in vivo studies using Drosophila models for evaluating new therapeutic compounds.

From powerhouse to regulator: The role of mitoepigenetics in mitochondrion-related cellular functions and human diseases.

Beyond their crucial role in energy production, mitochondria harbor a distinct genome subject to epigenetic regulation akin to that of nuclear DNA. This paper delves into the nascent but rapidly evolving fields of mitoepigenetics and mitoepigenomics, exploring the sophisticated regulatory mechanisms governing mitochondrial DNA (mtDNA). These mechanisms encompass mtDNA methylation, the influence of non-coding RNAs (ncRNAs), and post-translational modifications of mitochondrial proteins. Together, these epigenetic modifications meticulously coordinate mitochondrial gene transcription, replication, and metabolism, thereby calibrating mitochondrial function in response to the dynamic interplay of intracellular needs and environmental stimuli. Notably, the dysregulation of mitoepigenetic pathways is increasingly implicated in mitochondrial dysfunction and a spectrum of human pathologies, including neurodegenerative diseases, cancer, metabolic disorders, and cardiovascular conditions. This comprehensive review synthesizes the current state of knowledge, emphasizing recent breakthroughs and innovations in the field. It discusses the potential of high-resolution mitochondrial epigenome mapping, the diagnostic and prognostic utility of blood or tissue mtDNA epigenetic markers, and the promising horizon of mitochondrial epigenetic drugs. Furthermore, it explores the transformative potential of mitoepigenetics and mitoepigenomics in precision medicine. Exploiting a theragnostic approach to maintaining mitochondrial allostasis, this paper underscores the pivotal role of mitochondrial epigenetics in charting new frontiers in medical science.

Mitofilin in cardiovascular diseases: Insights into the pathogenesis and potential pharmacological interventions.

The impact of mitochondrial dysfunction on the pathogenesis of cardiovascular disease is increasing. However, the precise underlying mechanism remains unclear. Mitochondria produce cellular energy through oxidative phosphorylation while regulating calcium homeostasis, cellular respiration, and the production of biosynthetic chemicals. Nevertheless, problems related to cardiac energy metabolism, defective mitochondrial proteins, mitophagy, and structural changes in mitochondrial membranes can cause cardiovascular diseases via mitochondrial dysfunction. Mitofilin is a critical inner mitochondrial membrane protein that maintains cristae structure and facilitates protein transport while linking the inner mitochondrial membrane, outer mitochondrial membrane, and mitochondrial DNA transcription. Researchers believe that mitofilin may be a therapeutic target for treating cardiovascular diseases, particularly cardiac mitochondrial dysfunctions. In this review, we highlight current findings regarding the role of mitofilin in the pathogenesis of cardiovascular diseases and potential therapeutic compounds targeting mitofilin.

Salidroside induces mitochondrial dysfunction and ferroptosis to inhibit melanoma progression through reactive oxygen species production.

Reactive oxygen species (ROS) induces necroptotic and ferroptosis in melanoma cells. Salidroside (SAL) regulates ROS in normal cells and inhibits melanoma cell proliferation. This study used human malignant melanoma cells treated with SAL either alone or in combination with ROS scavenger (NAC) or ferroptosis inducer (Erastin). Through cell viability, wound healing assays, and a Seahorse analyze found that SAL inhibited cell proliferation, migration, extracellular acidification rate, and oxygen consumption rate. Metabolic flux analysis, complexes I, II, III, and IV activity of the mitochondrial respiratory chain assays, mitochondrial membrane potential assay, mitochondrial ROS, and transmission electron microscope revealed that SAL induced mitochondrial dysfunction and ultrastructural damage. Assessment of malondialdehyde, lipid ROS, iron content measurement, and Western blot analysis showed that SAL activated lipid peroxidation and promoted ferroptosis in A-375 cells. These effects were abolished after NAC treatment. Additionally, SAL and Erastin both inhibited cell proliferation and promoted cell death; SAL increased the Erastin sensitivity of cells while NAC antagonized it. In xenograft mice, SAL inhibited melanoma growth and promoted ROS-dependent ferroptosis. SAL induced mitochondrial dysfunction and ferroptosis to block melanoma progression through ROS production, which offers a scientific foundation for conducting SAL pharmacological research in the management of melanoma.

Olesoxime protects against cisplatin-induced acute kidney injury by attenuating mitochondrial dysfunction.

BACKGROUND: Mitochondrial dysfunction is a critical factor in the pathogenesis of acute kidney injury (AKI). Agents that ameliorate mitochondrial dysfunction hold potential for AKI treatment. The objective of this study was to investigate the impact of olesoxime, a novel mitochondrial-targeted agent, on cisplatin-induced AKI. METHODS: In vivo, a cisplatin-induced AKI mouse model was established by administering a single intraperitoneal dose of cisplatin (25 mg/kg) to male C57BL/6 mice for 72 hours, followed by gavage of either olesoxime or a control solution. In vitro, human proximal tubular HK2 cells were cultured and subjected to treatments with cisplatin, either in the presence or absence of olesoxime. RESULTS: In vivo, our findings demonstrated that olesoxime administration significantly mitigated the nephrotoxic effects of cisplatin in mice, as evidenced by reduced blood urea nitrogen (BUN) and serum creatinine (SCr) levels, improved renal histopathology, and decreased expression of renal tubular injury markers such as kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, olesoxime administration markedly reduced cisplatin-induced apoptosis, inflammation, and oxidative stress in the kidneys of AKI mice. Additionally, olesoxime treatment effectively restored mitochondrial function in the kidneys of AKI mice. In vitro, our results indicated that olesoxime treatment protected against cisplatin-induced apoptosis and mitochondrial dysfunction in cultured HK2 cells. Notably, cisplatin's anticancer effects were unaffected by olesoxime treatment in human cancer cells. CONCLUSION: The results of this study suggest that olesoxime is a viable and efficient therapeutic agent in the treatment of cisplatin-induced acute kidney injury presumably by alleviating mitochondrial dysfunction.

Types of memory, dementia, Alzheimer's disease, and their various pathological cascades as targets for potential pharmacological drugs.

Alzheimer's disease (AD) is the most common type of dementia accounting for 90% of cases; however, frontotemporal dementia, vascular dementia, etc. prevails only in a minority of populations. The term dementia is defined as loss of memory which further takes several other categories of memories like working memory, spatial memory, fear memory, and long-term, and short-term memory into consideration. In this review, these memories have critically been elaborated based on context, duration, events, appearance, intensity, etc. The most important part and purpose of the review is the various pathological cascades as well as molecular levels of targets of AD, which have extracellular amyloid plaques and intracellular hyperphosphorylated tau protein as major disease hallmarks. There is another phenomenon that either leads to or arises from the above-mentioned hallmarks, such as oxidative stress, mitochondrial dysfunction, neuroinflammation, cholinergic dysfunction, and insulin resistance. Several potential drugs like antioxidants, anti-inflammatory drugs, acetylcholinesterase inhibitors, insulin mimetics or sensitizers, etc. studied in various previous preclinical or clinical reports were put as having the capacity to act on these pathological targets. Additionally, agents directly or indirectly targeting amyloid and tau were also discussed. This could be further investigated in future research.

Deficiency of the BKCa potassium channel displayed significant implications for the physiology of the human bronchial epithelium.

Plasma membrane large-conductance calcium-activated potassium (BKCa) channels are important players in various physiological processes, including those mediated by epithelia. Like other cell types, human bronchial epithelial (HBE) cells also express BKCa in the inner mitochondrial membrane (mitoBKCa). The genetic relationships between these mitochondrial and plasma membrane channels and the precise role of mitoBKCa in epithelium physiology are still unclear. Here, we tested the hypothesis that the mitoBKCa channel is encoded by the same gene as the plasma membrane BKCa channel in HBE cells. We also examined the impact of channel loss on the basic function of HBE cells, which is to create a tight barrier. For this purpose, we used CRISPR/Cas9 technology in 16HBE14o- cells to disrupt the KCNMA1 gene, which encodes the α-subunit responsible for forming the pore of the plasma membrane BKCa channel. Electrophysiological experiments demonstrated that the disruption of the KCNMA1 gene resulted in the loss of BKCa-type channels in the plasma membrane and mitochondria. We have also shown that HBE ΔαBKCa cells exhibited a significant decrease in transepithelial electrical resistance which indicates a loss of tightness of the barrier created by these cells. We have also observed a decrease in mitochondrial respiration, which indicates a significant impairment of these organelles. In conclusion, our findings indicate that a single gene encodes both populations of the channel in HBE cells. Furthermore, this channel is critical for maintaining the proper function of epithelial cells as a cellular barrier.

Ginsenoside Re protects against kainate-induced neurotoxicity in mice by attenuating mitochondrial dysfunction through activation of the signal transducers and activators of transcription 3 signaling.

It was demonstrated that ginsenosides exert anti-convulsive potentials and interleukin-6 (IL-6) is protective from excitotoxicity induced by kainate (KA), a model of temporal lobe epilepsy. Ginsenosides-mediated mitochondrial recovery is essential for attenuating KA-induced neurotoxicity, however, little is known about the effects of ginsenoside Re (GRe), one of the major ginsenosides. In this study, GRe significantly attenuated KA-induced seizures in mice. KA-induced redox changes were more evident in mitochondrial fraction than in cytosolic fraction in the hippocampus of mice. GRe significantly attenuated KA-induced mitochondrial oxidative stress (i.e. increases in reactive oxygen species, 4-hydroxynonenal, and protein carbonyl) and mitochondrial dysfunction (i.e. the increase in intra-mitochondrial Ca2+ and the decrease in mitochondrial membrane potential). GRe or mitochondrial protectant cyclosporin A restored phospho-signal transducers and activators of transcription 3 (STAT3) and IL-6 levels reduced by KA, and the effects of GRe were reversed by the JAK2 inhibitor AG490 and the mitochondrial toxin 3-nitropropionic acid (3-NP). Thus, we used IL-6 knockout (KO) mice to investigate whether the interaction between STAT3 and IL-6 is involved in the GRe effects. Importantly, KA-induced reduction of manganese superoxide dismutase (SOD-2) levels and neurodegeneration (i.e. astroglial inhibition, microglial activation, and neuronal loss) were more prominent in IL-6 KO than in wild-type (WT) mice. These KA-induced detrimental effects were attenuated by GRe in WT and, unexpectedly, IL-6 KO mice, which were counteracted by AG490 and 3-NP. Our results suggest that GRe attenuates KA-induced neurodegeneration via modulating mitochondrial oxidative burden, mitochondrial dysfunction, and STAT3 signaling in mice.

Dysregulated Ca2+ signaling, fluid secretion, and mitochondrial function in a mouse model of early Sjögren's syndrome.

Saliva is essential for oral health. The molecular mechanisms leading to physiological fluid secretion are established, but factors that underlie secretory hypofunction, specifically related to the autoimmune disease Sjögren's syndrome (SS) are not fully understood. SS-like disease was induced by the treatment with 5,6-Dimethyl-9-oxo-9H-xanthene-4-acetic acid (DMXAA), an activator of the stimulator of the interferon gene (STING) pathway. This mouse model mimics exposure to foreign cytoplasmic ribonucleotides occurring following viral and bacterial infection and thought to be an initiating event in SS. Neurotransmitter-stimulated increases in cytoplasmic [Ca2+] are central to stimulating fluid secretion, primarily by increasing the activity of the Ca2+-activated Cl- channel, TMEM16a. Paradoxically, in DMXAA-treated mice in vivo imaging demonstrated that neural-stimulation resulted in greatly enhanced Ca2+ levels when a significant reduction in fluid secretion was observed. Notably, in the disease model, the spatiotemporal characteristics of the Ca2+ signals were altered to result in global rather than largely apically confined Ca2+ rises observed physiologically. Notwithstanding the augmented Ca2+ signals, muscarinic stimulation resulted in reduced activation of TMEM16a, although there were no changes in channel abundance or absolute sensitivity to Ca2+. However, super-resolution microscopy revealed a disruption in the localization of Inositol 1,4,5-trisphosphate receptor Ca2+ release channels in relation to TMEM16a. Appropriate Ca2+ signaling is also pivotal for mitochondrial morphology and bioenergetics and secretion is an energetically expensive process. Disrupted mitochondrial morphology, a depolarized mitochondrial membrane potential, and reduced oxygen consumption rate were observed in DMXAA-treated animals compared to control animals. We report that early in SS disease, dysregulated Ca2+ signals lead to decreased fluid secretion and disrupted mitochondrial function contributing to salivary gland hypofunction and likely the progression of SS disease.

Chlorantraniliprole induces mitophagy, ferroptosis, and cytokine homeostasis imbalance in grass carp (Ctenopharyngodon idella) hepatocytes via the mtROS-mitochondrial fission/fusion axis.

Chlorantraniliprole (CAP) is a bis-amide pesticide used for pest control mainly in agricultural production activities and rice-fish co-culture systems. CAP residues cause liver damage in non-target organism freshwater fish. However, it is unclear whether CAP-exposure-induced liver injury in fish is associated with mitochondrial dysfunction-mediated mitophagy, ferroptosis, and cytokines. Therefore, we established grass carp hepatocyte models exposed to different concentrations of CAP (20, 40, and 80 µM) in vitro. MitoSOX probe, JC-1 staining, immunofluorescence double staining, Fe2+ staining, lipid peroxidation staining, qRT-PCR, and Western blot were used to verify the physiological regulatory mechanism of CAP induced liver injury. In the present study, the CAP-treated groups exhibited down-regulation of antioxidant-related enzyme activities and accumulation of peroxides. CAP treatment induced an increase in mitochondrial reactive oxygen species (mtROS) levels and altered expression of mitochondrial fission/fusion (Drp1, Fis1, Mfn1, Mfn2, and Opa1) genes in grass carp hepatocytes. In addition, mitophagy (Parkin, Pink1, p62, LC3II/I, and Beclin-1), ferroptosis (GPX4, COX2, ACSL4, FTH, and NCOA4), and cytokine (IFN-γ, IL-18, IL-17, IL-6, IL-10, IL-1ß, IL-2, and TNF-α)-related gene expression was significantly altered. Collectively, these findings suggest that CAP exposure drives mitophagy activation, ferroptosis occurrence, and cytokine homeostasis imbalance in grass carp hepatocytes by triggering mitochondrial dysfunction mediated by the mtROS-mitochondrial fission/fusion axis. This study partly explained the physiological regulation mechanism of grass carp hepatocyte injury induced by insecticide CAP from the physiological and biochemical point of view and provided a basis for evaluating the safety of CAP environmental residues to non-target organisms.

Exploring the Gut-Mitochondrial Axis: p66Shc Adapter Protein and Its Implications for Metabolic Disorders.

This review investigates the multifaceted role of the p66Shc adaptor protein and the gut microbiota in regulating mitochondrial function and oxidative stress, and their collective impact on the pathogenesis of chronic diseases. The study delves into the molecular mechanisms by which p66Shc influences cellular stress responses through Rac1 activation, Forkhead-type transcription factors inactivation, and mitochondria-mediated apoptosis, alongside modulatory effects of gut microbiota-derived metabolites and endotoxins. Employing an integrative approach, the review synthesizes findings from a broad array of studies, including molecular biology techniques and analyses of microbial metabolites' impacts on host cellular pathways. The results underscore a complex interplay between microbial metabolites, p66Shc activation, and mitochondrial dysfunction, highlighting the significance of the gut microbiome in influencing disease outcomes through oxidative stress pathways. Conclusively, the review posits that targeting the gut microbiota-p66Shc-mitochondrial axis could offer novel therapeutic strategies for mitigating the development and progression of metabolic diseases. This underscores the potential of dietary interventions and microbiota modulation in managing oxidative stress and inflammation, pivotal factors in chronic disease etiology.

Circumlimbal suture and laser burns: Comparison between two different chronic glaucoma models. / çŽ¯è§’è†œç¼˜ç¼åˆä¸Žæ¿€å ‰å ‰å‡æ¨¡åž‹ï¼šä¸¤ç§æ ¢æ€§é«˜çœ¼åŽ‹æ¨¡åž‹çš„æ¯”è¾ƒï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Glaucoma is a multifactorial optic neuropathy with a high rate of irreversible visual loss, and its pathogenesis is complex and still unclear. Elevated intraocular pressure (IOP) is well recognized as the sole modifiable risk factor for the development of glaucoma in the majority of cases. This study aims to compare 2 different methods of inducing chronic ocular hypertension by circumlimbal suture or by laser burns in degree and lasting time of the IOP, different status of the retina and retinal ganglion cells (RGCs), and changes of the microstructure of neurons. METHODS: The chronic ocular hypertension models were induced by 2 different ways. One kind of the models was built by unilateral circumlimbal suture (10/0) implantation (suture group), another kind of model was built by laser burns at trabecular meshwork and episcleral veins (laser group). The untreated contralateral eye served as the control group. Changes in IOP were observed and regularly monitored in the 2 groups of rats. HE staining was applied to observe the retinal and optic nerve pathology. Transmission electron microscope (TEM) was used to observe the mitochondrial morphology. RGCs were specifically labeled with Brn3b antibody and counted. The expression of caspase-3 was detected by Western blotting to clarify the apoptosis of RGCs. RESULTS: Compared with the control group, IOP were significantly increased in the suture group and the laser group (both P<0.05). The suture group induced a 1.5-fold elevation of IOP, and sustained for 8 weeks. The laser group induced a 2-fold elevation of IOP for 12 weeks. Both methods could cause RGCs loss (both P<0.05), which were verified by pathology and immune staining of Brn3b. The expressions of caspase-3 were also increased (both P<0.05). The mitochondrial morphology became more fragment, which changed from long shape to round and small one under TEM in 2 models. For comparison, the pathology changes of retinal structure in suture group were not obviously than those in the laser group. CONCLUSIONS: Circumlimbal suture can build an effective model of chronic elevated IOP and induce glaucomatous pathologic changes similar to those in the laser photocoagulation, but the pathologic changes are milder than those in laser photocoagulation. Compare with translimbal laser photocoagulation, equipment and skill demand for circumlimbal suture is less.

Research progress in mitochondrial quality control in schizophrenia. / çº¿ç²’ä½“è´¨é‡æŽ§åˆ¶åœ¨ç²¾ç¥žåˆ†è£‚ç—‡ä¸­çš„ç ”ç©¶è¿›å±•.

Mitochondria are the main site of energy metabolism within cells, generating a substantial amount of ATP to supply energy to the human body. Research has shown that alterations in mitochondrial structure and function exist in individuals with schizophrenia, suggesting their potential impact on the onset of psychiatric disorders and clinical treatment efficacy. Therefore, understanding the research progress on the genetic mechanisms, pathological processes, image manifestations of schizophrenia and mitochondrial quality control, and summarizing the relevant evidence of mitochondrial-related targets as potential therapeutic targets for schizophrenia, can provide references for further research.

Mitochondrial dysfunction induced by HIF-1α under hypoxia contributes to the development of gastric mucosal lesions.

INTRODUCTION: Hypoxia is an important characteristic of gastric mucosal diseases, and hypoxia-inducible factor-1α (HIF-1α) contributes to microenvironment disturbance and metabolic spectrum abnormalities. However, the underlying mechanism of HIF-1α and its association with mitochondrial dysfunction in gastric mucosal lesions under hypoxia have not been fully clarified. OBJECTIVES: To evaluate the effects of hypoxia-induced HIF-1α on the development of gastric mucosal lesions. METHODS: Portal hypertensive gastropathy (PHG) and gastric cancer (GC) were selected as representative diseases of benign and malignant gastric lesions, respectively. Gastric tissues from patients diagnosed with the above diseases were collected. Portal hypertension (PHT)-induced mouse models in METTL3 mutant or NLRP3-deficient littermates were established, and nude mouse gastric graft tumour models with relevant inhibitors were generated. The mechanisms underlying hypoxic condition, mitochondrial dysfunction and metabolic alterations in gastric mucosal lesions were further analysed. RESULTS: HIF-1α, which can mediate mitochondrial dysfunction via upregulation of METTL3/IGF2BP3-dependent dynamin-related protein 1 (Drp1) N6-methyladenosine modification to increase mitochondrial reactive oxygen species (mtROS) production, was elevated under hypoxic conditions in human and mouse portal hypertensive gastric mucosa and GC tissues. While blocking HIF-1α with PX-478, inhibiting Drp1-dependent mitochondrial fission via mitochondrial division inhibitor 1 (Mdivi-1) treatment or METTL3 mutation alleviated this process. Furthermore, HIF-1α influenced energy metabolism by enhancing glycolysis via lactate dehydrogenase A. In addition, HIF-1α-induced Drp1-dependent mitochondrial fission also enhanced glycolysis. Drp1-dependent mitochondrial fission and enhanced glycolysis were associated with alterations in antioxidant enzyme activity and dysfunction of the mitochondrial electron transport chain, resulting in massive mtROS production, which was needed for activation of NLRP3 inflammasome to aggravate the development of the PHG and GC. CONCLUSIONS: Under hypoxic conditions, HIF-1α enhances mitochondrial dysfunction via Drp1-dependent mitochondrial fission and influences the metabolic profile by altering glycolysis to increase mtROS production, which can trigger NLRP3 inflammasome activation and mucosal microenvironment alterations to contribute to the development of benign and malignant gastric mucosal lesions.