[Regulatory mechanisms of mitochondrial dynamics and its emerging role in renal pathophysiology].

Mitochondria are dynamically changing organelles that maintain stable mitochondrial morphology, number, and function through constant fusion and division, a process known as mitochondrial dynamics, which is an important mechanism for mitochondrial quality control. Excessive fusion and division of mitochondria can lead to a homeostatic imbalance in mitochondrial dynamics, causing mitochondrial dysfunction, leading to cellular damage, and even death. The physiological functions of the kidney are mainly powered by mitochondria, and homeostatic imbalance in mitochondrial dynamics affects mitochondrial function and is closely related to renal diseases such as acute kidney injury and diabetic nephropathy. This article reviews the regulation of mitochondrial kinetics, how imbalances in mitochondrial kinetic homeostasis affect mitochondrial injury, and the impact of mitochondrial injury on renal pathophysiology, in order to improve understanding and knowledge of the role of mitochondria in renal disease.

Transcutaneous Electrical Nerve Stimulation (TENS) Alleviates Brain Ischemic Injury by Regulating Neuronal Oxidative Stress, Pyroptosis, and Mitophagy.

Background: As a noninvasive treatment, transcutaneous electrical nerve stimulation (TENS) has been utilized to treat various diseases in clinic. However, whether TENS can be an effective intervention in the acute stage of ischemic stroke still remains unclear. In the present study, we aimed to explore whether TENS could alleviate brain infarct volume, reduce oxidative stress and neuronal pyroptosis, and activate mitophagy following ischemic stroke. Methods: TENS was performed at 24 h after middle cerebral artery occlusion/reperfusion (MCAO/R) in rats for 3 consecutive days. Neurological scores, the volume of infarction, and the activity of SOD, MDA, GSH, and GSH-px were measured. Moreover, western blot was performed to detect the related protein expression, including Bcl-2, Bax, TXNIP, GSDMD, caspase-1, NLRP3, BRCC3, HIF-1α, BNIP3, LC3, and P62. Real-time PCR was performed to detect NLRP3 expression. Immunofluorescence was performed to detect the levels of LC3. Results: There was no significant difference of neurological deficit scores between the MCAO group and the TENS group at 2 h after MCAO/R operation (P > 0.05), while the neurological deficit scores of TENS group significantly decreased in comparison with MCAO group at 72 h following MACO/R injury (P < 0.05). Similarly, TENS treatment significantly reduced the brain infarct volume compared with the MCAO group (P < 0.05). Moreover, TENS decreased the expression of Bax, TXNIP, GSDMD, caspase-1, BRCC3, NLRP3, and P62 and the activity of MDA as well as increasing the level of Bcl-2, HIF-1α, BNIP3, and LC3 and the activity of SOD, GSH, and GSH-px (P < 0.05). Conclusions: In conclusion, our results indicated that TENS alleviated brain damage following ischemic stroke via inhibiting neuronal oxidative stress and pyroptosis and activating mitophagy, possibly via the regulation of TXNIP, BRCC3/NLRP3, and HIF-1α/BNIP3 pathways.

Toll-Like Receptor 4: A Promising Therapeutic Target for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that primarily manifests as memory deficits and cognitive impairment and has created health challenges for patients and society. In AD, amyloid ß-protein (Aß) induces Toll-like receptor 4 (TLR4) activation in microglia. Activation of TLR4 induces downstream signaling pathways and promotes the generation of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß), which also trigger the activation of astrocytes and influence amyloid-dependent neuronal death. Therefore, TLR4 may be an important molecular target for treating AD by regulating neuroinflammation. Moreover, TLR4 regulates apoptosis, autophagy, and gut microbiota and is closely related to AD. This article reviews the role of TLR4 in the pathogenesis of AD and a range of potential therapies targeting TLR4 for AD. Elucidating the regulatory mechanism of TLR4 in AD may provide valuable clues for developing new therapeutic strategies for AD.

The role of exosomes in stroke.

Stroke is induced by a partial disruption of cerebral blood flow to the brain and is related to high morbidity and mortality. In the central nervous system, exosomes have been proven to exert neuroprotective effects, reducing brain damage following a stroke. This review was performed by searching the relevant articles in the SCIENCEDIRECT, PUBMED, and Web of Science databases from respective inception to November 2018. We review the relationship between exosomes and angiogenesis, neurogenesis, antiapoptosis, autophagy, and the blood-brain barrier in stroke. Moreover, exosomes are found to be a promising tool for the diagnosis and treatment of stroke. In summary, exosomes provide a novel way to alleviate brain damage following a stroke.

Transcutaneous electrical acupoint stimulation attenuated neuroinflammation and oxidative stress by activating SIRT1-induced signaling pathway in MCAO/R rat models.

BACKGROUND: Silent information regulator 1 (SIRT1) plays a beneficial role in cerebral ischemic injury. Previous reports have demonstrated that transcutaneous electrical acupoint stimulation (TEAS) exerts a beneficial effect on ischemic stroke; however, whether SIRT1 participates in the underlying mechanism for the neuroprotective effects of TEAS against ischemic brain damage has not been confirmed. METHODS: The rat models of middle cerebral artery occlusion/reperfusion (MCAO/R) were utilized in the current experiment. After MCAO/R surgery, rats in TEAS, EC and EX group received TEAS intervention with or without the injection of EX527, the SIRT1 inhibitor. Neurological deficit scores, infarct volume, hematoxylin eosin (HE) staining and apoptotic cell number were measured. The results of RNA sequencing were analyzed to determine the differential expression changes of genes among sham, MCAO and TEAS groups, in order to investigate the possible pathological processes involved in cerebral ischemia and explore the protective mechanisms of TEAS. Moreover, oxidative stress markers including MDA, SOD, GSH and GSH-Px were measured with assay kits. The levels of the proinflammatory cytokines, such as IL-6, IL-1ß and TNF-α, were detected by ELISA assay, and Iba-1 (the microglia marker protein) positive cells was measured by immunofluorescence (IF). Western blot and IF were utilized to examine the levels of key molecules in SIRT1/FOXO3a and SIRT1/BRCC3/NLRP3 signaling pathways. RESULTS: TEAS significantly decreased brain infarcted size and apoptotic neuronal number, and alleviated neurological deficit scores and morphological injury by activating SIRT1. The results of RNA-seq and bioinformatic analysis revealed that oxidative stress and inflammation were the key pathological mechanisms, and TEAS alleviated oxidative injury and inflammatory reactions following ischemic stroke. Then, further investigation indicated that TEAS notably attenuated neuronal apoptosis, neuroinflammation and oxidative stress damage in the hippocampus of rats with MCAO/R surgery. Moreover, TEAS intervention in the MCAO/R model significantly elevated the expressions of SIRT1, FOXO3a, CAT, BRCC3, NLRP3 in the hippocampus. Furthermore, EX527, as the inhibitor of SIRT1, obviously abolished the anti-oxidative stress and anti-neuroinflammatory roles of TEAS, as well as reversed the TEAS-mediated elevation of SIRT1, FOXO3a, CAT and reduction of BRCC3 and NLRP3 mediated by following MCAO/R surgery. CONCLUSIONS: In summary, these findings clearly suggested that TEAS attenuated brain damage by suppressing apoptosis, oxidative stress and neuroinflammation through modulating SIRT1/FOXO3a and SIRT1/BRCC3/NLRP3 signaling pathways following ischemic stroke, which can be a promising treatment for stroke patients.

The role and therapeutic potential of nuclear factor κB (NF-κB) in ischemic stroke.

Stroke is a prevalent cerebrovascular condition with a global impact, causing significant rates of illness and death. Despite extensive research, the available treatment options for stroke remain restricted. Hence, it is crucial to gain a deeper understanding of the molecular mechanisms associated with the onset and advancement of stroke in order to establish a theoretical foundation for novel preventive and therapeutic approaches. NF-κB, also known as nuclear factor κB, is a transcription factor responsible for controlling the expression of numerous genes and plays a crucial role in diverse physiological processes. NF-κB is triggered and regulates neuroinflammation and other processes after stroke, promoting the generation of cytokine storms and contributing to the advancement of ischemic stroke (IS). Therefore, NF-κB could potentially play a vital role in stroke by regulating diverse pathophysiological processes. This review provides an overview of the functions of NF-κB in stroke and its governing mechanisms. In addition, our attention is directed towards various potential therapies that aim to inhibit the NF-κB signaling pathway in order to offer valuable insights for the advancement of innovative treatment approaches for stroke.

Impact of climate change on SARS-CoV-2 epidemic in China.

The outbreak and prevalence of SARS-CoV-2 have severely affected social security. Physical isolation is an effective control that affects the short-term human-to-human transmission of the epidemic, although weather presents a long-term effect. Understanding the effect of weather on the outbreak allow it to be contained at the earliest possible. China is selected as the study area, and six weather factors that receive the most attention from January 20, 2020 to April 30, 2020 are selected to investigate the correlation between weather and SARS-CoV-2 to provide a theoretical basis for long-term epidemic prevention and control. The results show that (1) the average growth rate (GR) of SARS-CoV-2 in each province is logarithmically distributed with a mean value of 5.15%. The GR of the southeastern region is higher than that of the northwestern region, which is consistent with the Hu Line. (2) The specific humidity, 2-m temperature (T), ultraviolet (UV) radiation, and wind speed (WS) adversely affect the GR. By contrast, the total precipitation (TP) and surface pressure (SP) promote the GR. (3) For every 1 unit increase in UV radiation, the GR decreases by 0.30% in 11 days, and the UV radiation in China is higher than that worldwide (0.92% higher per day). Higher population aggregation and urbanization directly affect the epidemic, and weather is an indirect factor.

Transcutaneous electrical acupoint stimulation alleviates cerebral ischemic injury through the TLR4/MyD88/NF-κ B pathway.

This study was to explore whether transcutaneous electrical acupoint stimulation (TEAS) treatment could mediate inflammation, apoptosis, and pyroptosis of neuronal cells and microglia activation through the TLR4/MyD88/NF-κB pathway in the early stage of ischemic stroke. TEAS treatment at Baihui (GV20) and Hegu (LI4) acupoints of the affected limb was administered at 24, 48, and 72 h following middle cerebral artery occlusion/reperfusion (MCAO/R), with lasting for 30 min each time. Neurological impairment scores were assessed 2 h and 72 h after ischemia/reperfusion (I/R). TTC staining was used to evaluate the volume of brain infarction. The histopathologic changes of hippocampus were detected by H&E staining. WB analysis was performed to assess the levels of TLR4, MyD88, p-NF-κB p65/NF-κB p65, and inflammation, apoptosis, pyroptosis-related proteins. TLR4 expression was measured using immunohistochemistry. The expression of inflammation-related proteins was also measured using ELISA. Immunofluorescence was used to detect the expression level of Iba1. Our findings demonstrated that TEAS intervention after I/R improved neurological function, reduced the volume of brain infarction, and mitigated pathological damage. Moreover, TEAS reduced the levels of TLR4, MyD88, p-NF-κB p65/NF-κB p65, TNF-α, IL-6, Bax, NLRP3, cleaved caspase-1/pro caspase-1, IL-1ß, IL-18, GSDMD, and Iba1 while enhancing Bcl-2 expression. Moreover, the protective effects of TEAS could be counteracted by lipopolysaccharide (LPS, a TLR4 agonist). In conclusion, TEAS can reduce cerebral damage and suppress inflammation, cell death, and microglia activation after ischemic stroke via inhibiting the TLR4/MyD88/NF-κB pathway.

The Role of Iron Metabolism, Lipid Metabolism, and Redox Homeostasis in Alzheimer's Disease: from the Perspective of Ferroptosis.

In the development of Alzheimer's disease (AD), cell death is common. Novel cell death form-ferroptosis is discovered in recent years. Ferroptosis is an iron-regulated programmed cell death mechanism and has been identified in AD clinical samples. Typical characteristics of ferroptosis involve the specific changes in cell morphology, iron-dependent aggregation of reactive oxygen species (ROS) and lipid peroxides, loss of glutathione (GSH), inactivation of glutathione peroxidase 4 (GPX4), and a unique group of regulatory genes. Increasing evidence demonstrates that ferroptosis may be associated with neurological dysfunction in AD. However, the underlying mechanisms have not been fully elucidated. This article reviews the potential role of ferroptosis in AD, the involvement of ferroptosis in the pathological progression of AD through the mechanisms of iron metabolism, lipid metabolism, and redox homeostasis, as well as a range of potential therapies targeting ferroptosis for AD. Intervention strategies based on ferroptosis are promising for Alzheimer's disease treatment at present, but further researches are still needed.

Brain Microstructural Changes in Patients with Amnestic mild Cognitive Impairment : Detected by Neurite Orientation Dispersion and Density Imaging (NODDI) Combined with Machine Learning.

PURPOSE: This study investigated brain microstructural changes in patients with amnestic mild cognitive impairment (aMCI) by retrospectively analyzing neurite orientation dispersion and density imaging (NODDI) data with machine learning algorithms. METHODS: A total of 26 aMCI patients and 24 healthy controls (HC) underwent NODDI magnetic resonance imaging (MRI) examinations. The NODDI parameters including neurite density index (NDI), orientation dispersion index (ODI), and volume fraction of isotropic water molecules (Viso) were estimated. Machine learning algorithms such as K­nearest neighbor (KNN), logistic regression (LR), random forest (RF), and support vector machine (SVM) were used to evaluate the diagnostic efficacy of NODDI parameters in predicting aMCI. The differences in the NODDI parameter values between the aMCI and HC groups were analyzed using the independent sample t­test, False discovery rate (FDR) correction was used for multiple testing. After adjusting for age, sex, and educational years, partial correlation analysis was used to evaluate the relationship between NODDI parameters and clinical cognitive status of aMCI patients. RESULTS: The NDI, ODI, and Viso values of white matter (WM) and gray matter (GM) structure templates combined with the KNN, LR, RF and SVM machine learning algorithms accomplished the discrimination between aMCI and HC groups. The NDI and ODI values decreased (p value range, < 0.001-0.042) and Viso values increased (p value range, < 0.001-0.043) in the aMCI group compared to the HCs. The NDI, ODI, and Viso values of the WM and GM structure templates with significant differences were significantly correlated with mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) scores. CONCLUSION: NODDI combined with machine learning algorithms is a promising strategy for early diagnosis of aMCI. Moreover, NODDI parameters correlated with the clinical cognitive status of aMCI patients.

The Role of Oxidative Stress in Intervertebral Disc Degeneration.

Intervertebral disc degeneration is a very common type of degenerative disease causing severe socioeconomic impact, as well as a major cause of discogenic low back pain and herniated discs, placing a heavy burden on patients and the clinicians who treat them. IDD is known to be associating with a complex process involving in extracellular matrix and cellular damage, and in recent years, there is increasing evidence that oxidative stress is an important activation mechanism of IDD and that reactive oxygen and reactive nitrogen species regulate matrix metabolism, proinflammatory phenotype, autophagy and senescence in intervertebral disc cells, apoptosis, autophagy, and senescence. Despite the tremendous efforts of researchers within the field of IDD pathogenesis, the proven strategies to prevent and treat this disease are still very limited. Up to now, several antioxidants have been proved to be effective for alleviating IDD. In this article, we discussed that oxidative stress accelerates disc degeneration by influencing aging, inflammation, autophagy, and DNA methylation, and summarize some antioxidant therapeutic measures for IDD, indicating that antioxidant therapy for disc degeneration holds excellent promise.

The Beneficial Role of Exercise on Treating Alzheimer's Disease by Inhibiting ß-Amyloid Peptide.

Alzheimer's disease (AD) is associated with a very large burden on global healthcare systems. Thus, it is imperative to find effective treatments of the disease. One feature of AD is the accumulation of neurotoxic ß-amyloid peptide (Aß). Aß induces multiple pathological processes that are deleterious to nerve cells. Despite the development of medications that target the reduction of Aß to treat AD, none has proven to be effective to date. Non-pharmacological interventions, such as physical exercise, are also being studied. The benefits of exercise on AD are widely recognized. Experimental and clinical studies have been performed to verify the role that exercise plays in reducing Aß deposition to alleviate AD. This paper reviewed the various mechanisms involved in the exercise-induced reduction of Aß, including the regulation of amyloid precursor protein cleaved proteases, the glymphatic system, brain-blood transport proteins, degrading enzymes and autophagy, which is beneficial to promote exercise therapy as a means of prevention and treatment of AD and indicates that exercise may provide new therapeutic targets for the treatment of AD.

The involvement of NLRP3 inflammasome in the treatment of neurodegenerative diseases.

In an ageing society, neurodegenerative diseases have attracted attention because of their high incidence worldwide. Despite extensive research, there is a lack of conclusive insights into the pathogenesis of neurodegenerative diseases, which limit the strategies for symptomatic treatment. Therefore, better elucidation of the molecular mechanisms involved in neurodegenerative diseases can provide an important theoretical basis for the discovery of new and effective prevention and treatment methods. The innate immune system is activated during the ageing process and in response to neurodegenerative diseases. Inflammasomes are multiprotein complexes that play an important role in the activation of the innate immune system. They mediate inflammatory reactions and pyroptosis, which are closely involved in neurodegeneration. There are different types of inflammasomes, although the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is the most common inflammasome; NLRP3 plays an important role in the pathogenesis of neurodegenerative diseases. In this review, we will discuss the mechanisms that are involved in the activation of the NLRP3 inflammasome and its crucial role in the pathology of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. We will also review various treatments that target the NLRP3 inflammasome pathway and alleviate neuroinflammation. Finally, we will summarize the novel treatment strategies for neurodegenerative disorders.

The involvement of NLRP3 inflammasome in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and it is characterised by progressive deterioration in cognitive and memory abilities, which can severely influence the elderly population's daily living abilities. Although researchers have made great efforts in the field of AD, there are still no well-established strategies to prevent and treat this disease. Therefore, better clarification of the molecular mechanisms associated with the onset and progression of AD is critical to provide a theoretical basis for the establishment of novel preventive and therapeutic strategies. Currently, it is generally believed that neuroinflammation plays a key role in the pathogenesis of AD. Inflammasome, a multiprotein complex, is involved in the innate immune system, and it can mediate inflammatory responses and pyroptosis, which lead to neurodegeneration. Among the various types of inflammasomes, the NLRP3 inflammasome is the most characterised in neurodegenerative diseases, especially in AD. The activation of the NLRP3 inflammasome causes the generation of caspase-1-mediated interleukin (IL)-1ß and IL-18 in microglia cells, where neuroinflammation is involved in the development and progression of AD. Thus, the NLRP3 inflammasome is likely to be a crucial therapeutic molecular target for AD via regulating neuroinflammation. In this review, we summarise the current knowledge on the role and regulatory mechanisms of the NLRP3 inflammasome in the pathogenic mechanisms of AD. We also focus on a series of potential therapeutic treatments targeting NLRP3 inflammasome for AD. Further clarification of the regulatory mechanisms of the NLRP3 inflammasome in AD may provide more useful clues to develop novel AD treatment strategies.

The benefits and mechanisms of exercise training for Parkinson's disease.

Parkinson's disease (PD) is a significantly progressive neurodegenerative disease characterised by both motor and nonmotor disorders. The main pathological characteristics of PD consist of the loss of dopaminergic neurons and the formation of alpha-synuclein-containing Lewy bodies in the substantia nigra. Currently, the main therapeutic method for PD is anti-Parkinson medications, including levodopa, madopar, sirelin, and so on. However, the effect of pharmacological treatment has its own limitations, the most significant of which is that the therapeutic effect of dopaminergic treatments gradually diminishes with time. Exercise training, as an adjunctive treatment and complementary therapy, can improve the plasticity of cortical striatum and increase the release of dopamine. Exercise training has been proven to effectively improve motor disorders (including balance, gait, risk of falls and physical function) and nonmotor disorders (such as sleep impairments, cognitive function and quality of life) in PD patients. In recent years, various types of exercise training have been used to treat PD. In this review, we summarise the exercise therapy mechanisms and the protective effects of different types of exercise training on PD patients.

Electroacupuncture Inhibits Neuronal Autophagy and Apoptosis via the PI3K/AKT Pathway Following Ischemic Stroke.

Electroacupuncture (EA) is a safe and effective therapy for ischemic stroke in both clinical and laboratory settings. However, the underlying mechanism behind EA treatment for stroke remains unclear. Here, we aimed to evaluate whether EA treatment at the acupoints of Zusanli (ST36) and Quchi (LI11) exerted a neuroprotective effect on ischemic stroke rats by modulating autophagy and apoptosis via the PI3K/AKT/mTOR signaling pathway. EA was performed at 24 h following brain ischemia/reperfusion (I/R) for 30 min per day for 3 days. Our results indicated that EA treatment significantly decreased neurological deficits and cerebral infarct volume in ischemic stroke rats. Also, EA intervention markedly reduced neuronal apoptosis by suppressing the activation of cleaved caspase-3 (CCAS3) at 72 h following I/R, as shown by a Western blot analysis. Furthermore, EA treatment after ischemic stroke suppressed the ischemia activated expression level of LC3II/I and Atg7 and increased the ischemia inhibited expression level of PI3K, phosphorylation of mTOR, phosphorylation of AKT, P62 and LAMP1, hence mediating the autophagy level of the neurocyte, which was reversed by the PI3K inhibitor Dactolisib. In summary, our results indicate that the protective effects of EA treatment at points of Quchi (LI11) and Zusanli (ST36) in rats following cerebral I/R injury was associated with the inhibition of neuronal apoptosis and autophagy via activating the PI3K/AKT/mTOR signaling pathway.

Inhibition of NLRP3 Inflammasome: A Prospective Target for the Treatment of Ischemic Stroke.

Stroke is one of the major devastating diseases with no effective medical therapeutics. Because of the high rate of disability and mortality among stroke patients, new treatments are urgently required to decrease brain damage following a stroke. In recent years, the inflammasome is a novel breakthrough point that plays an important role in the stroke, and the inhibition of inflammasome may be an effective method for stroke treatment. Briefly, inflammasome is a multi-protein complex that causes activation of caspase-1 and subsequent production of pro-inflammatory factors including interleukin (IL)-18 and IL-1ß. Among them, the NLRP3 inflammasome is the most typical inflammasome, which can detect cell damage and mediate inflammatory response to tissue damage in ischemic stroke. The NLRP3 inflammasome has become a key mediator of post-ischemic inflammation, leading to a cascade of inflammatory reactions and cell death eventually. Thus, NLRP3 inflammasome is an ideal therapeutic target due to its important role in the inflammatory response after ischemic stroke. In this mini review article, we will summarize the structure, assembly, and regulation of NLRP3 inflammasome, the role of NLRP3 inflammasome in ischemic stroke, and several treatments targeting NLRP3 inflammasome in ischemic stroke. The further understanding of the mechanism of NLRP3 inflammasome in patients with ischemic stroke will provide novel targets for the treatment of cerebral ischemic stroke patients.