The mechanism of action of mitochondrial dysfunction in the development of non-alcoholic fatty liver disease / 临床肝胆病杂志

Nonalcoholic fatty liver disease （NAFLD） has gradually become the main reason affecting human liver health， and many factors are involved in the development and progression of NAFLD. Mitochondria， as the “energy factory” of cells， plays an important role in maintaining normal physiological functions. Studies have shown that hepatic mitochondrial dysfunction promotes the development and progression of NAFLD. This article briefly introduces the latest research advances in the basic characteristics and physiological function of liver mitochondria and reviews new research findings in the association of mitochondrial dysfunction with obesity， simple fatty liver disease， and nonalcoholic steatohepatitis， in order to provide new ideas for the research on targeted mitochondrial therapy for NAFLD.

Traditional Chinese Medicine Regulating Mitochondrial Function in Prevention and Treatment of Liver Failure：A Review / 中国实验方剂学杂志

Liver failure （LF）， as a clinical syndrome of severe hepatocyte damage and liver dysfunction， has become a major obstacle to human health due to the triple superposition of high mortality， high morbidity， and high medical resource depletion. It is of great significance to further study the core factors of the disease and supplementary treatment methods to improve the survival rate of patients with LF. The pathogenesis of LF is complex， and mitochondrion is one of the sensitive organelles in hepatocytes and the central link of intracellular energy metabolism. A large number of studies have shown that the structure and function of mitochondria in hepatocytes are changed in LF， and the abnormal structure and function of mitochondria play an important role in the process of LF disease. Among them， multiple factors such as mitochondrial respiratory chain disorder， mitochondrial DNA damage， mitochondrial permeability transition pore opening， mitochondrial quality control imbalance， and mitochondrial oxidative stress are intertwined， forming a complex and unified whole network， which becomes the key node affecting the progression of LF. In recent years， researchers have begun to study drugs that can regulate the function of liver mitochondria to prevent and treat LF. With the deepening of research， traditional Chinese medicine has made breakthroughs in the prevention and treatment of LF. Many studies have confirmed that traditional Chinese medicine can play a role in the prevention and treatment of LF by protecting mitochondrial function， which can be summarized as reducing liver cell damage， inhibiting liver cell death， and promoting liver cell regeneration， so as to effectively compensate for liver function and promote the recovery of liver parenchyma quality and function. This article summarized the structure and function of mitochondria， the relationship between LF and mitochondria， and the research on the intervention of mitochondrial function in the field of traditional Chinese medicine to prevent and treat LF， so as to provide certain ideas and references for the clinical treatment of LF with traditional Chinese medicine.

Effect of Endometriosis on Cumulus ATP, Number of Mitochondria and Oocyte Maturity in Cumulus Oocyte Complex in Mice / Efeito da endometriose no cumulus ATP, número de mitocôndrias e maturidade oocitária no complexo oocitário cumulus em camundongos

Abstract Objective Endometriosis causes a decrease in oocyte quality. However, this mechanism is not fully understood. The present study aimed to analyze the effect of endometriosis on cumulus cell adenosine triphosphate ATP level, the number of mitochondria, and the oocyte maturity level. Methods A true experimental study with a post-test only control group design on experimental animals. Thirty-two mice were divided into control and endometriosis groups. Cumulus oocyte complex (COC) was obtained from all groups. Adenosine triphosphate level on cumulus cells was examined using the Elisa technique, the number of mitochondria was evaluated with a confocal laser scanning microscope and the oocyte maturity level was evaluated with an inverted microscope. Results The ATP level of cumulus cells and the number of mitochondria in the endometriosis group increased significantly (p < 0.05; p < 0.05) while the oocyte maturity level was significantly lower (p < 0.05). There was a significant relationship between ATP level of cumulus cells and the number of mitochondrial oocyte (p < 0.01). There was no significant relationship between cumulus cell ATP level and the number of mitochondrial oocytes with oocyte maturity level (p > 0.01; p > 0.01). The ROC curve showed that the number of mitochondrial oocytes (AUC = 0.672) tended to be more accurate than cumulus cell ATP level (AUC = 0.656) in determining the oocyte maturity level. Conclusion In endometriosis model mice, the ATP level of cumulus cells and the number of mitochondrial oocytes increased while the oocyte maturity level decreased. There was a correlation between the increase in ATP level of cumulus cells and an increase in the number of mitochondrial oocytes.

Over-expression of gastrin inhibits apoptosis of gastric cancer cells via reactive oxygen species and annexin A2-mediated mitochondrial dysfunction / La sobreexpresión de gastrina inhibe la apoptosis de las células de cáncer gástrico a través de especies reactivas de oxígeno y disfunción mitocondrial mediada por anexina A2

SUMMARY: Gastrin plays a vital role in the development and progression of gastric cancer (GC). Its expression is up-regulated in GC tissues and several GC cell lines. Yet, the underlying mechanism remains to be investigated. Here, we aim to investigate the role and mechanism of gastrin in GC proliferation. Gastrin-overexpressing GC cell model was constructed using SGC7901 cells. Then the differentially expressed proteins were identified by iTRAQ analysis. Next, we use flow cytometry and immunofluorescence to study the effect of gastrin on the mitochondrial potential and mitochondria-derived ROS production. Finally, we studied the underlying mechanism of gastrin regulating mitochondrial function using Co-IP, mass spectrometry and immunofluorescence. Overexpression of gastrin promoted GC cell proliferation in vitro and in vivo. A total of 173 proteins were expressed differently between the controls and gastrin- overexpression cells and most of these proteins were involved in tumorigenesis and cell proliferation. Among them, Cox17, Cox5B and ATP5J that were all localized to the mitochondrial respiratory chain were down-regulated in gastrin-overexpression cells. Furthermore, gastrin overexpression led to mitochondrial potential decrease and mitochondria-derived ROS increase. Additionally, gastrin-induced ROS generation resulted in the inhibition of cell apoptosis via activating NF-kB, inhibiting Bax expression and promoting Bcl-2 expression. Finally, we found gastrin interacted with mitochondrial membrane protein Annexin A2 using Co-IP and mass spectrometry. Overexpr ession of gastrin inhibits GC cell apoptosis by inducing mitochondrial dysfunction through interacting with mitochondrial protein Annexin A2, then up-regulating ROS production to activate NF-kB and further leading to Bax/Bcl-2 ratio decrease.

La gastrina juega un papel vital en el desarrollo y progresión del cáncer gástrico (CG). Su expresión está regulada al alza en tejidos de CG y en varias líneas celulares de CG. Sin embargo, el mecanismo subyacente aun no se ha investigado. El objetivo de este estudio fue investigar el papel y el mecanismo de la gastrina en la proliferación de CG. El modelo de células CG que sobre expresan gastrina se construyó usando células SGC7901. Luego, las proteínas expresadas diferencialmente se identificaron mediante análisis iTRAQ. A continuación, utilizamos la citometría de flujo y la inmunofluorescencia para estudiar el efecto de la gastrina en el potencial mitocondrial y la producción de ROS derivada de las mitocondrias. Finalmente, estudiamos el mecanismo subyacente de la gastrina que regula la función mitocondrial utilizando Co-IP, espectrometría de masas e inmunofluorescencia. La sobreexpresión de gastrina promovió la proliferación de células CG in vitro e in vivo. Un total de 173 proteínas se expresaron de manera diferente entre los controles y las células con sobreexpresión de gastrina y la mayoría de estas proteínas estaban implicadas en la tumorigenesis y la proliferación celular. Entre estas, Cox17, Cox5B y ATP5J, todas localizadas en la cadena respiratoria mitocondrial, estaban reguladas a la baja en las células con sobreexpresión de gastrina. Además, la sobreexpresión de gastrina provocó una disminución del potencial mitocondrial y un aumento de las ROS derivadas de las mitocondrias. Por otra parte, la generación de ROS inducida por gastrina resultó en la inhibición de la apoptosis celular mediante la activación de NF-kB, inhibiendo la expresión de Bax y promoviendo la expresión de Bcl-2. Finalmente, encontramos que la gastrina interactuaba con la proteína de membrana mitocondrial Anexina A2 usando Co-IP y espectrometría de masas. La sobreexpresión de gastrina inhibe la apoptosis de las células CG al inducir la disfunción mitocondrial a través de la interacción con la proteína mitocondrial Anexina A2, luego regula el aumento de la producción de ROS para activar NF-kB y conduce aún más a la disminución de la relación Bax/Bcl-2.

Remote ischemic preconditioning-induced late cardioprotection: possible role of melatonin-mitoKATP-H2S signaling pathway

Purpose: Remote ischemic preconditioning (RIPC) confers cardioprotection against ischemia reperfusion (IR) injury. However, the precise mechanisms involved in RIPC-induced cardioprotection are not fully explored. The present study was aimed to identify the role of melatonin in RIPC-induced late cardioprotective effects in rats and to explore the role of H2 S, TNF-α and mitoKATP in melatoninmediated effects in RIPC. Methods: Wistar rats were subjected to RIPC in which hind limb was subjected to four alternate cycles of ischemia and reperfusion of 5 min duration by using a neonatal blood pressure cuff. After 24 h of RIPC or ramelteon-induced pharmacological preconditioning, hearts were isolated and subjected to IR injury on the Langendorff apparatus. Results: RIPC and ramelteon preconditioning protected the hearts from IR injury and it was assessed by a decrease in LDH-1, cTnT and increase in left ventricular developed pressure (LVDP). RIPC increased the melatonin levels (in plasma), H2 S (in heart) and decreased TNF-α levels. The effects of RIPC were abolished in the presence of melatonin receptor blocker (luzindole), ganglionic blocker (hexamethonium) and mitochondrial KATP blocker (5-hydroxydecanoic acid). Conclusion: RIPC produce delayed cardioprotection against IR injury through the activation of neuronal pathway, which may increase the plasma melatonin levels to activate the cardioprotective signaling pathway involving the opening of mitochondrial KATP channels, decrease in TNF-α production and increase in H2 S levels. Ramelteon-induced pharmacological preconditioning may also activate the cardioprotective signaling pathway involving the opening of mitochondrial KATP channels, decrease in TNF-α production and increase in H2 S levels.

Characteristics and clinical significance of mitochondrial injury of T lymphocyte subsets in patients with autoimmune hepatitis / 中国医师进修杂志

Objective:To study the characteristics and clinical significance of mitochondrial injury of T lymphocyte subsets in patients with autoimmune hepatitis (AIH).Methods:The clinical data of 57 patients with AIH (AIH group) from June to December 2021 in Hangzhou Xixi Hospital were retrospectively analyzed, while 60 healthy physical examiners were included as healthy group. The peripheral blood T lymphocyte subsets (CD 8+ T lymphocyte count and CD 4+ T lymphocyte count) were detected by flow cytometry, and matched mitochondrial staining value according to certain algorithm was used to determine the mitochondrial damage of helper T lymphocyte (Th cell) and suppressor T lymphocyte (Ts cell). The levels of IgG, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured using a Roche E170 automatic electrochemiluminescence immunoassay. Anti-nuclear antibody (ANA) titer was measured by immunofluorescence. Multivariate Logistic regression was used to analyze the independent risk factors of mitochondrial damage of Th cell and Ts cell in patients with AIH. Results:The ALT, AST, IgG, positive rate of ANA titer, CD 4+ T lymphocyte count, CD 8+ T lymphocyte count, rate of Th cell mitochondrial injury and rate of Ts cell mitochondrial injury in AIH group were significantly higher than those in healthy group: (118.90 ± 37.61) U/L vs. (30.96 ± 14.37) U/L, (102.40 ± 36.51) U/L vs. (31.12 ± 14.06) U/L, (18.40 ± 3.71) g/L vs. (13.89 ± 1.98) g/L, 96.49% (55/57) vs. 16.67% (10/60), 438 (323, 637) × 10 6/L vs. 398 (272, 469) × 10 6/L, 296 (211, 296) × 10 6/L vs. 270 (193, 322) × 10 6/L, 61.40% (35/57) vs. 8.33% (5/60) and 82.46% (47/57) vs. 11.67% (7/60), and there were statistical differences ( P<0.01 or <0.05). Multivariate Logistic regression analysis result showed that the AST elevated and CD 8+ T lymphocyte count reduced were the independent risk factors of Ts cell mitochondrial injury in patients with AIH ( OR = 1.06 and 0.99, 95% CI 1.01 to 1.10 and 0.99 to 1.00, P<0.05); the ALT elevated and IgG elevated were the independent risk factors of Th cell mitochondrial injury in patients with AIH ( OR = 1.08 and 1.66, 95% CI 1.02 to 1.14 and 1.11 to 2.48, P<0.05). Conclusions:It is of positive clinical significance to measure the T lymphocyte subtype mitochondrial injury in patients with AIH. The probability of mitochondrial injury of T lymphocyte subtype can be predicted by biochemical indexes such as ALT, AST and IgG, so as to indirectly evaluate the liver cell necrosis.

Research progress of mitochondrial genetics in age-related macular degeneration / 中华实验眼科杂志

Mitochondria are the center of cellular energy metabolism, and their functions are tightly regulated by the nuclear and mitochondria genomes.Potential mechanisms responsible for age-related mitochondrial dysfunction include the accumulation of mitochondrial DNA (mtDNA) damage caused by replication errors or oxidative damage, and the epigenetic changes in mtDNA (mitoepigenetics). These mechanisms are essential for the development and progression of age-related macular degeneration (AMD). Age-related mtDNA damage disrupts energy metabolism and cellular function in the retinal pigment epithelium (RPE) and neuroretinal cells, which further mediates oxidative stress, lysosomal dysfunction and pyroptosis, resulting in RPE degeneration, drusen deposition and retinal inflammation.Mitochondrial genome protection, such as humanin administration, may be a promising preventive or therapeutic target in the early stages of AMD.This review focused on the research progress of the mitochondrial genetic mechanism in AMD pathogenesis and provided new ideas for exploring the prevention and treatment strategies of AMD.

Investigation of endothelial cell pathological characteristics in murine choroidal neovascularization model based on single-cell RNA sequencing / 中华实验眼科杂志

Objective:To investigate the molecular expression and pathological features of endothelial cell (EC) in a murine model of choroidal neovascularization (CNV) based on single-cell RNA sequencing (scRNA-seq).Methods:Six C57BL/6 mice aged 6-8 weeks were randomly divided into two groups, with 3 mice in each group.Bilateral eyeballs were enucleated.The choroidal tissues from the two groups were isolated by shearing the complex and scraping the choroid, respectively.Single-cell suspension was prepared by continuous digestion with trypsin/type Ⅰ collagenase at 37 ℃, and the cell viability and EC ratio were detected by flow cytometry to determine the preparation method of single-cell suspension.Another 6 mice were randomly assigned into the control group and the CNV group, with 3 mice in each group.The CNV model was induced by laser photocoagulation and single-cell suspensions were prepared 7 days after modeling.Gene expression library construction was performed using the Chromi-um (10x Genomics) instrument.High throughput sequencing was performed using the Illumina Novaseq6000 to obtain the expression matrix.The EC subpopulations were classified according to previous researches and the Cellmarker database.Pseudo-time analysis was performed in EC, revealing the gene expression matrix of different states.CNV-EC were further selected with preliminary analysis of the expression characteristics.Another 6 mice were selected to establish the CNV model and eyeball frozen sections were prepared 7 days after modeling.Expression and distribution as well as the area percentage of EC marker Pecam1, mitochondrial outer membrane proteins Tomm20 and mt-Co1, and capillary markers Kdr and Plvap were observed by immunofluorescence staining, and the vascular diameter was calculated.The use and care of animals followed the ARVO statement.This study protocol was approved by the Experimental Animal Welfare and Ethics Committee of Air Force Military Medical University (No.20200181).Results:The cell viability of the single-cell suspension prepared from choroidal-scleral fragments and choroidal scrapings was 99.4% and 99.1%, respectively, both of which met the sequencing requirements.The percentage of EC detected by flow cytometry was approximately 1.58%.The scRNA-seq result revealed that both the normal control and CNV groups contained 13 choroidal cell clusters.Compared with the normal control group, the proportions of rod/cone photoreceptor cells, EC and hematopoietic cells all increased, while the retinal pigment epithelium (RPE) and Schwan cells reduced in the CNV group.Among all clusters, EC constituted 18.4%.The pseudo-time analysis demonstrated that EC could be further divided into 4 states.The percentage of state 2 EC was 29.1% in the CNV group, which was significantly higher than 9.5% in the normal control group.Differentially expressed gene analysis showed that the expression of mitochondrion-related genes, including mt-Nd4 and mt-Atp6, were upregulated in state 2 EC, while capillary-related genes, including Kdr and Esm1, were downregulated.Immunofluorescent staining revealed that the area of Tomm20 and mt-Co1 in Pecam1-positive EC in the CNV area was (19.50±4.68)% and (4.64±2.82)%, respectively, which were both higher than (3.00±2.09)% and (0.18±0.34)% in normal area ( t=7.88, 3.84; both at P<0.01). The area of Kdr and Plvap in Pecam1-positive EC in the CNV area was (1.50±0.29)% and (0.79±0.97)%, respectively, which were both lower than (31.30±5.44)% and (10.43±2.28)% in the normal area ( t=13.40, 9.48; both at P<0.01). The vascular diameter in the CNV area was (5.52±1.85)μm, which was larger than (4.21±1.84)μm in the normal area ( t=9.57, P<0.001). Conclusions:When CNV occurs, the proportion of EC in choroid increases, and CNV-EC shows pathologic features of mitochondrial metabolic activation and loss of capillary properties, suggesting the mitochondrial activation of EC may play a role in the formation of CNV.

Protective effect and mechanism of zonisamide on oxygen-glucose deprivation cell model of traumatic brain injury / 中华急诊医学杂志

Objective:To explore the protective effect of zonisamide (ZNS) on oxygen-glucose deprivation (OGD) cell model of traumatic brain injury (TBI), and its underlying mechanism.Methods:Human neuroblastoma cells (SH-SY5Y) were cultured in vitro and divided into the control group, OGD group, and drug administration group (OGD+ZNS group) according to the random number table method. The OGD method was used to establish a TBI cell model. After modeling, the cell activity, the release of lactate dehydrogenase (LDH), and β-galactosidase staining were detected to evaluate cell function and senescence. Additionally, mitochondrial morphology and potential membrane changes were observed using Mito Tracker Red and JC-1 mitochondrial membrane potential staining. ATP concentration was measured, and protein was extracted from SH-SY5Y cells and then subjected to Western blot analysis to detect endoplasmic reticulum stress-related markers, including glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), protein disulfide isomerase (PDI), and β-actin.Results:The OGD group had a significantly lower cell survival rate compared to the control group ( P<0.01), while the OGD+ZNS group had a significant higher cell survival rate than the OGD group ( P<0.01). The LDH release rate was significantly higher in the OGD group than in the control group ( P<0.01), while the OGD+ZNS group had a significant lower LDH release rate compared to the OGD group ( P<0.01). Moreover, the cell staining results indicated that compared to the control and OGD+ZNS groups, the cells in the OGD group exhibited significant damage and senescence with darker staining while the mitochondrial staining results demonstrated a significant reduction in mitochondrial linear junctions and decreased mitochondrial activity in the OGD group compared to the control and OGD+ZNS groups. Compared to the control and OGD+ZNS groups, the OGD group exhibited a significant reduction in mitochondrial staining red fluorescence, a significant increase in green fluorescence, and a significant decrease in mitochondrial membrane potential. The OGD group demonstrated a significant decrease in ATP concentration compared to the control group ( P<0.01), whereas the OGD+ZNS group exhibited a significant higher ATP concentration compared to the OGD group ( P<0.01). Western blot analysis revealed significant upregulation of GRP78, CHOP, and PDI in the OGD group compared to the control group (all P<0.05), while in the OGD+ZNS group, the expression levels of these proteins were significantly downregulated compared to the OGD group (all P<0.05). Conclusions:Zonisamide can protect OGD TBI cell model by preserving mitochondrial activity and inhibiting endoplasmic reticulum stress.

Protective effect and mechanism of hyperbaric oxygen on delayed encephalopathy after carbon monoxide poisoning via the mitochondrial pathway in mice / 中华急诊医学杂志

Objective:To explore the protective effect and underlying mechanism of hyperbaric oxygen (HBO) on delayed encephalopathy after carbon monoxide poisoning (DEACMP) in mice.Methods:Totally 225 adult male Kunming mice were selected to establish CO poisoning model via intraperitoneal injection carbon monoxide (CO), and were randomly divided into the air control group, CO poisoning group, and HBO group. Each group was further divided into five time points group, that was 1, 3, 7, 14 and 21 d. The mice in the air control group were injected intraperitoneally with the same amount of air, and the HBO group received HBO treatment at the same time every day. DEACMP mice model was screened by behaviors using the open field test, new object recognition test and nesting test, and the content of myelin basic protein (MBP) were assayed. The mouse brain tissue and mitochondrial were prepared and malonialdehyde (MDA) and adenosine triphosphate (ATP) content were measured with ultraviolet spectrophotometer. MBP content in brain tissue and cytochrome C (CytC) content in the mitochondrial were measured by ELISA. The mitochondria membrane potential (MMP) was measured by flow cytometry.Results:Compared with the air control group, the content of carboxyhemoglobin (COHB) in blood increased significantly and the content of MBP in brain tissue decreased significantly in CO poisoning mice. CO poisoning mice showed motor ability and cognitive dysfunction. Compared with the air control group, the contents of MMP, CytC and ATP were significantly decreased ( P<0.01) in the CO poisoning group; while the MDA content was significantly increased ( P<0.01). Compared with the CO poisoning group, mice behaviors were improved significantly ( P<0.05), the content of MBP, MMP, CytC and ATP were increased ( P<0.05), while the MDA content decreased significantly ( P<0.01) in the HBO group. Conclusions:The abnormal mitochondrial function might be closely related to the occurrence and development of DEACMP, and HBO therapy plays an effective role in preventing and treating the DEACMP mice model via the mitochondrial pathway.

Research progress on the role of mitochondrial dysfunction in the occurrence, progression and treatment of periodontitis / 口腔疾病防治

@#Periodontitis is a widespread disease worldwide, with the primary cause of tissue loss being an immune inflammatory response mediated by bacteria. Increasing evidence has revealed a significant correlation between mitochondrial dysfunction and the occurrence and progression of periodontitis. This paper provides a review of current research on the role of mitochondrial dysfunction in the occurrence and development of periodontitis and related therapies from the perspectives of oxidative stress, inflammatory responses, and the regulation of mitochondrial homeostasis. Mitochondria are the main source and target of cellular reactive oxygen species. Mitochondrial dysfunction can generate large amounts of reactive oxygen species, exacerbating local oxidative stress in periodontal tissues and causing cell toxicity and tissue damage. Mitochondria are also the center of cellular inflammatory responses, and the positive feedback loop of inflammation induced by mitochondrial dysfunction may explain the persistent and unresolved nature of periodontitis. Biomaterials loaded with pharmacological agents show potential in restoring mitochondrial function, controlling the development of periodontitis, and promoting periodontal tissue regeneration. However, the key sites of mitochondrial dysfunction in the occurrence and development of periodontitis are not yet fully understood, and the improvement of mitochondrial function in periodontal therapy is still in the experimental stage. Future research efforts should focus on the effect of mitochondrial dysfunction on periodontal cells and explore its specific mechanism in the occurrence and progression of periodontitis in order to provide new insights into the treatment of periodontitis.

Matrix Stiffness Affects Mitochondrial Heterogeneity of Tibial Plateau Chondrocytes in Knee Osteoarthritis / 医用生物力学

Objective To investigate the difference of matrix stiffness in different regions of tibial plateau in osteoarthritis (OA) and its effects on morphology of the cartilage and mitochondria. Methods The tibial plateau cartilage specimens of OA were obtained for nanoindentation test, transmission electron microscopy and histological analysis. The stiffness of cartilage matrix in different regions of OA tibial plateau was detected by nano-indentation. The morphology of cartilage mitochondria in different regions was observed by transmission electron microscopy, and the changes of mitochondrial plane area, shape and ridge volume density were quantitatively analyzed. Cartilage injury in different regions of OA tibial plateau was observed by histological staining. Results The cartilage of OA tibial plateau showed regional heterogeneity, and the cartilage and mitochondria on medial side of varus knee OA were more severe, and the matrix stiffness was higher. The OA scores were positively correlated with matrix stiffness. There was also a significant correlation between OA scores and mitochondrial morphology: the higher OA scores, the larger and rounder mitochondrial plane area, and the lower cristae volume density. Conclusions The differences of tibial plateau revealed the correlation between cartilage matrix stiffness, OA scores and mitochondrial morphological parameters. The increased cartilage matrix stiffness may be the main cause of chondrocyte mitochondrial injury, and further aggravate the progression of OA.

Advances in the study of the roles of mitochondrial dysfunction and neuroinflammation in the pathogenesis of schizophrenia / 四川精神卫生

This paper aims to present a review of the research progress on the roles of mitochondrial dysfunction and microglia-mediated inflammation in the pathophysiology of schizophrenia. Schizophrenia is a serious psychiatric disorder in which the immuno-inflammatory pathway is considered to be one of the main pathogenic mechanisms of disease， and manifested by microglia activation and elevated levels of inflammatory cytokines in the brain. However， the biological mechanism underlying immune disorder in schizophrenia has not been fully elucidated. In recent years， accumulating evidence has indicated that mitochondrial dysfunction may play a key role in the pathogenesis of schizophrenia. Therefore， this article reviews the research progress on the roles of mitochondrial days function and microglia-mediated inflammation in the pathophysiology of schizophrenia， so as to inform the study of the pathogenesis of schizophrenia.

Regulation and influence of mitochondria on macrophages during hepatitis B virus infection / 中华肝脏病杂志

Hepatitis B virus (HBV) infection is an important public health concern, as approximately 3.5% of the world's population is currently chronically infected. Chronic HBV infection is the primary cause of cirrhosis, hepatocellular carcinoma, and deaths related to liver disease globally. Studies have found that in HBV infection, viruses can directly or indirectly regulate mitochondrial energy metabolism, oxidative stress, respiratory chain metabolites, and autophagy, thereby altering macrophage activation status, differentiation types, and related cytokine secretion type and quantity regulations. Therefore, mitochondria have become an important signal source for macrophages to participate in the body's immune system during HBV infection, providing a basis for mitochondria to be considered as a potential therapeutic target for chronic hepatitis B.

Construction of folate receptors and mitochondria targeting celastrol-loaded PAMAM nano-drug delivery system and its in vitro anti-inflammatory effect / 药学学报

Pro-inflammatory macrophages play key regulatory role in the occurrence and development of rheumatoid arthritis (RA). In this study, we constructed a celastrol (Cel)-loaded polyamide-amine dendrimer (PAMAM) drug delivery system, which could target folate receptor and mitochondria. It could target inflammatory macrophages and realize chemo-photothermal synergistic therapy. Using PAMAM as the nano-carrier, folate receptor-targeting group folic acid (FA) and mitochondria-targeting group IR808 (also known as the photothermal agent) were conjugated with PAMAM through amide reaction, and then complexed with anti-inflammatory drug Cel to prepare the FA-PAMAM-IR808/Cel nanocomplex. In vitro characterization results showed that the drug loading efficiency of the nanocomplex was 50.90%, particle size was between 130 and 160 nm, average potential was between 1.0 and 3.5 mV, the drug release showed pH sensitivity, temperature reached to 42.5 ℃ after near-infrared (NIR) light irradiation for 10 min. In vitro cellular uptake experiments showed that the nanocomplex had obvious folate receptor-targeting and mitochondria-targeting ability. Following irradiation with NIR light, the cytotoxicity and cellular apoptosis enhanced. The secretion of pro-inflammatory factors tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6 and nitric oxide (NO) decreased in a concentration-dependent manner. This study provided insights for the development of novel anti-RA nanomedicines.

Role of organelle interaction in the development and progression of nonalcoholic fatty liver disease / 临床肝胆病杂志

In addition to its own specific functions, an organelle can also interact with other organelles to complete important physiological functions. The disorders of organelle interactions are closely associated the development and progression of various diseases. In recent years, the role of organelle interactions has attracted more attention in the progression of nonalcoholic fatty liver disease, especially the interactions between mitochondria, lipid droplets, and other organelles.

4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis

Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders, the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown. Here, we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem cells (hMSCs). Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration, increases mitochondrial reactive oxygen species (ROS) production, and accelerates cellular senescence. Mechanistically, the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes, especially several key subunits of complex III including UQCRC2. Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs. These f indings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis, particularly for the mitochondrial respiration complex III, thus providing a new potential target to counteract human stem cell senescence.

REEP1 Preserves Motor Function in SOD1G93A Mice by Improving Mitochondrial Function via Interaction with NDUFA4 / 神经科学通报·英文版

A decline in the activities of oxidative phosphorylation (OXPHOS) complexes has been consistently reported in amyotrophic lateral sclerosis (ALS) patients and animal models of ALS, although the underlying molecular mechanisms are still elusive. Here, we report that receptor expression enhancing protein 1 (REEP1) acts as an important regulator of complex IV assembly, which is pivotal to preserving motor neurons in SOD1G93A mice. We found the expression of REEP1 was greatly reduced in transgenic SOD1G93A mice with ALS. Moreover, forced expression of REEP1 in the spinal cord extended the lifespan, decelerated symptom progression, and improved the motor performance of SOD1G93A mice. The neuromuscular synaptic loss, gliosis, and even motor neuron loss in SOD1G93A mice were alleviated by increased REEP1 through augmentation of mitochondrial function. Mechanistically, REEP1 associates with NDUFA4, and plays an important role in preserving the integrity of mitochondrial complex IV. Our findings offer insights into the pathogenic mechanism of REEP1 deficiency in neurodegenerative diseases and suggest a new therapeutic target for ALS.

Mechanism of Liuwei Dihuang Pills in treatment of mice with diminished ovarian reserve based on proteomics / 中国中药杂志

This study aims to investigate the efficacy and possible mechanism of Liuwei Dihuang Pills in the treatment of diminished ovarian reserve(DOR) by using proteomic techniques. Firstly, cyclophosphamide(60 mg·kg~(-1)) combined with busulfan(6 mg·kg~(-1)) was injected intraperitoneally to establish the mouse model of DOR. After drug injection, the mice were continuously observed and the success of modeling was evaluated by the disturbance of the estrous cycle. After successful modeling, the mice were administrated with the suspension of Liuwei Dihuang Pills by gavage for 28 days. At the end of the gavage, four female mice were selected and caged together with males at a ratio of 2∶1 for the determination of the pregnancy rate. Blood and ovary samples were collected from the remaining mice on the next day after the end of gavage. Hematoxylin-eosin(HE) staining and transmission electron microscopy(TEM) were then employed to observe the morphological and ultrastructural changes in the ovaries. The serum levels of hormones and oxidation indicators were measured by enzyme-linked immunosorbent assay. Quantitative proteomics techniques were used to compare the ovarian protein expression before and after modeling and before and after the intervention with Liuwei Dihuang Pills. The results showed that Liuwei Dihuang Pills regulated the estrous cycle of DOR mice, elevated the serum levels of hormones and anti-oxidation indicators, promoted follicle development, protected the mitochondrial morphology of ovarian granulosa cells, and increased the litter size and survival of DOR mice. Furthermore, Liuwei Dihuang Pills negatively regulated the expression of 12 differentially expressed proteins associated with DOR, which were mainly involved in lipid catabolism, inflammatory response, immune regulation, and coenzyme biosynthesis. These differentially expressed proteins were significantly enriched in sphingolipid metabolism, arachidonic acid metabolism, ribosomes, ferroptosis, and cGMP-PKG signaling pathway. In summary, the occurrence of DOR and the treatment of DOR with Liuwei Dihuang Pills are associated with multiple biological pathways, mainly including oxidative stress response, inflammatory response, and immune regulation. "Mitochondria-oxidative stress-apoptosis" is the key to the treatment of DOR by Liuwei Dihuang Pills. YY1 and CYP4F3 may be the key upstream targets that trigger mitochondrial dysfunction and ROS accumulation, and the metabolism of arachidonic acid is the main signaling pathway of drug action.

Flavonoid-Rich Extract of Oldenlandia diffusa (Willd.) Roxb. Inhibits Gastric Cancer by Activation of Caspase-Dependent Mitochondrial Apoptosis / 中国结合医学杂志

OBJECTIVE@#To evaluate the apoptosis and cycle arrest effects of Oldenlandia diffusa flavonoids on human gastric cancer cells, determine the action mechanisms in association with the mitochondrial dependent signal transduction pathway that controls production of reactive oxygen species (ROS), and evaluate the pharmacodynamics of a mouse xenotransplantation model to provide a reference for the use of flavonoids in prevention and treatment of gastric cancer.@*METHODS@#Flavonoids were extracted by an enzymatic-ultrasonic assisted method and purified with D-101 resin. Bioactive components were characterized by high-performance liquid chromatography. Cell lines MKN-45, AGS, and GES-1 were treated with different concentrations of flavonoids (64, 96, 128, 160 µg/mL). The effect of flavonoids on cell viability was evaluated by MTT method, and cell nuclear morphology was observed by Hoechst staining. The apoptosis rate and cell cycle phases were measured by flow cytometry, the production of ROS was detected by laser confocal microscope, the mitochondrial membrane potential (MMP) were observed by fluorescence microscope, and the expression of apoptotic proteins related to activation of mitochondrial pathway were measured by immunoblotting. MKN-45 cells were transplanted into BALB/c nude mice to establish a xenograft tumor model. Hematoxylin and eosin staining was used to reveal the subcutaneous tumor tissue. The tumor volume and tumor weight were measured, the expression levels of proliferation markers proliferating cell nuclear antigen (PCNA) and Ki-67 were detected by immunohistochemistry, and the expression levels of CA72-4 were measured by enzyme linked immunosorbent assay.@*RESULTS@#Oldenlandia diffusa flavonoids inhibited proliferation of MKN-45 and AGS human gastric cancer cells, arrested the cell cycle in G1/S phase, induced accumulation of ROS in the process of apoptosis, and altered MMP. In addition, flavonoids increased Apaf-1, Cleaved-Caspase-3, and Bax, and decreased Cyclin A, Cdk2, Bcl-2, Pro-Caspase-9, and Mitochondrial Cytochrome C (P<0.05). The MKN-45 cell mouse xenotransplantation model further clarified the growth inhibitory effect of flavonoids towards tumors. The expression levels of PCNA and Ki-67 decreased in each flavonoid dose group, the expression level of CA72-4 decreased (P<0.05).@*CONCLUSION@#Flavonoids derived from Oldenlandia diffusa can inhibit proliferation and induce apoptosis of human gastric cancer cells by activating the mitochondrial controlled signal transduction pathway.