Ischemic stroke and diabetes: a TLR4-mediated neuroinflammatory perspective.

Ischemic stroke is the major contributor to morbidity and mortality in people with diabetes mellitus. In ischemic stroke patients, neuroinflammation is now understood to be one of the main underlying mechanisms for cerebral damage and recovery delay. It has been well-established that toll-like receptor 4 (TLR4) signaling pathway plays a key role in neuroinflammation. Emerging research over the last decade has revealed that, compared to ischemic stroke without diabetes mellitus, ischemic stroke with diabetes mellitus significantly upregulates TLR4-mediated neuroinflammation, increasing the risk of cerebral and neuronal damage as well as neurofunctional recovery delay. This review aims to discuss how ischemic stroke with diabetes mellitus amplifies TLR4-mediated neuroinflammation and its consequences. Additionally covered in this review is the potential application of TLR4 antagonists in the management of diabetic ischemic stroke.

Cyclosorus Terminans Extract Alleviates Neuroinflammation in Insulin Resistant Rats.

High-fat diet consumption for an extended period causes obesity, systemic metabolic disturbance, and brain insulin resistance, resulting in neuroinflammation. Although the beneficial effect of Cyclosorus terminans extract on obesity-related insulin resistance has been demonstrated, little is known about how it affects neuroinflammation and brain insulin resistance in obese rats. Male Wistar rats were given either a normal diet (ND, n = 6) or a high-fat diet (HFD, n = 24) for a total of 14 weeks. At the beginning of the week, 13 rats in the ND group were given vehicle orally for 2 weeks, while rats on HFD diets were randomized to one of four groups and given either vehicle, 100 mg/kg/day of Cyclosorus terminans extract, 200 mg/kg/day of Cyclosorus terminans extract, or 20 mg/kg/day of pioglitazone orally for 2 weeks. After the experimental period, blood and brain samples were taken to assess metabolic and brain parameters. HFD-fed rats had obesity, systemic and brain insulin resistance, brain inflammation, microglial and astrocyte hyperactivity, and brain necroptosis. Treatment with 200 mg/kg/day of Cyclosorus terminans extract and pioglitazone equally attenuated obesity, insulin resistance, brain insulin dysfunction, and neuroinflammation in insulin resistant rats. Our findings suggest that Cyclosorus terminans extract may hold promise as a therapeutic agent for insulin resistance and neuroinflammation in obese conditions.

Ferroptosis inhibitor improves cardiac function more effectively than inhibitors of apoptosis and necroptosis through cardiac mitochondrial protection in rats with iron-overloaded cardiomyopathy.

Iron overload cardiomyopathy (IOC) is the leading cause of death in cases of iron overload in patients. Previous studies demonstrated that iron overload led to cardiomyocyte dysfunction and death through multiple pathways including apoptosis, necroptosis and ferroptosis. However, the dominant cell death pathway in the iron-overloaded heart needs clarification. We tested the hypothesis that ferroptosis, an iron-dependent cell death, plays a dominant role in IOC, and ferroptosis inhibitor exerts greater efficacy than inhibitors of apoptosis and necroptosis on improving cardiac function in iron-overloaded rats. Iron dextran was injected intraperitoneally into male Wistar rats for four weeks to induce iron overload. Then, the rats were divided into 5 groups: treated with vehicle, apoptosis inhibitor (z-VAD-FMK), necroptosis inhibitor (Necrostatin-1), ferroptosis inhibitor (Ferrostatin-1) or iron chelator (deferoxamine) for 2 weeks. Cardiac function, mitochondrial function, apoptosis, necroptosis and ferroptosis were determined. The increased expression of apoptosis-, necroptosis- and ferroptosis-related proteins, were associated with impaired cardiac and mitochondrial function in iron-overloaded rats. All cell death inhibitors attenuated cardiac apoptosis, necroptosis and ferroptosis in iron-overloaded rats. Ferrostatin-1 was more effective than the other drugs in diminishing mitochondrial dysfunction and Bax/Bcl-2 ratio. Moreover, both Ferrostatin-1 and deferoxamine reversed iron overload-induced cardiac dysfunction as indicated by restored left ventricular ejection fraction and E/A ratio, whereas z-VAD-FMK and Necrostatin-1 only partially improved this parameter. These results indicated that ferroptosis could be the predominant form of cardiomyocyte death in IOC, and that inhibiting ferroptosis might be a potential novel treatment for IOC.

Toll-like Receptor 4 Inflammatory Perspective on Doxorubicin-Induced Cardiotoxicity.

Doxorubicin (Dox) is one of the most frequently used chemotherapeutic drugs in a variety of cancers, but Dox-induced cardiotoxicity diminishes its therapeutic efficacy. The underlying mechanisms of Dox-induced cardiotoxicity are still not fully understood. More significantly, there are no established therapeutic guidelines for Dox-induced cardiotoxicity. To date, Dox-induced cardiac inflammation is widely considered as one of the underlying mechanisms involved in Dox-induced cardiotoxicity. The Toll-like receptor 4 (TLR4) signaling pathway plays a key role in Dox-induced cardiac inflammation, and growing evidence reports that TLR4-induced cardiac inflammation is strongly linked to Dox-induced cardiotoxicity. In this review, we outline and address all the available evidence demonstrating the involvement of the TLR4 signaling pathway in different models of Dox-induced cardiotoxicity. This review also discusses the effect of the TLR4 signaling pathway on Dox-induced cardiotoxicity. Understanding the role of the TLR4 signaling pathway in Dox-induced cardiac inflammation might be beneficial for developing a potential therapeutic strategy for Dox-induced cardiotoxicity.

An Updated Review of Mitochondrial Transplantation as a Potential Therapeutic Strategy Against Cerebral Ischemia and Cerebral Ischemia/Reperfusion Injury.

Regardless of the progress made in the pathogenesis of ischemic stroke, it remains a leading cause of adult disability and death. To date, the most effective treatment for ischemic stroke is the timely recanalization of the occluded artery. However, the short time window and reperfusion injury have greatly limited its application and efficacy. Mitochondrial dysfunction and ATP depletion have become regarded as being hallmarks of neuropathophysiology following ischemic stroke. Mitochondrial transplantation is a novel potential therapeutic intervention for ischemic stroke that has sparked widespread concern during the past few years. This review summarizes and discusses the effects of mitochondrial transplantation in in vitro and in vivo ischemic stroke models. In addition, pharmacological interventions promoting mitochondrial transplantation are reviewed and discussed. We also discuss the potential challenges to the clinical application of mitochondrial transplantation in the treatment of ischemic stroke.

Emerging roles of toll-like receptor 4 in chemotherapy-induced neurotoxicity.

Chemotherapy-induced neurotoxicity is one of the most prevalent side effects in cancer patients and survivors. Cognitive decline and peripheral neuropathy are the most common chemotherapy-induced neurotoxic symptoms. These symptoms lead not only to the limiting of the dose of chemotherapy given to cancer patients, but also have an impact on the quality of life of cancer survivors. Although the exact mechanisms involved in chemotherapy-induced neurotoxicity are still unclear, neuroinflammation is widely regarded as being one of the major causes involved in chemotherapy-induced neurotoxicity. It is known that Toll-like receptor 4 (TLR4) plays a critical role in the inflammatory process, and it has been recently reported that it is associated with chemotherapy-induced neurotoxicity. In this review, we summarize and discuss all available evidence regarding the activation of the TLR4 signaling pathway in various models of chemotherapy-induced neurotoxicity. This review also emphasizes the evidence pertinent to TLR4 inhibition on chemotherapy-induced neurotoxicity in rodent studies. Understanding the role of the TLR4 signaling pathway behind chemotherapy-induced neurotoxicity is crucial for improving treatments and ensuring the long-term survival of cancer patients.

The roles of HMGB1-produced DNA gaps in DNA protection and aging biomarker reversal.

The endogenous DNA damage triggering an aging progression in the elderly is prevented in the youth, probably by naturally occurring DNA gaps. Decreased DNA gaps are found during chronological aging in yeast. So we named the gaps "Youth-DNA-GAPs." The gaps are hidden by histone deacetylation to prevent DNA break response and were also reduced in cells lacking either the high-mobility group box (HMGB) or the NAD-dependent histone deacetylase, SIR2. A reduction in DNA gaps results in shearing DNA strands and decreasing cell viability. Here, we show the roles of DNA gaps in genomic stability and aging prevention in mammals. The number of Youth-DNA-GAPs were low in senescent cells, two aging rat models, and the elderly. Box A domain of HMGB1 acts as molecular scissors in producing DNA gaps. Increased gaps consolidated DNA durability, leading to DNA protection and improved aging features in senescent cells and two aging rat models similar to those of young organisms. Like the naturally occurring Youth-DNA-GAPs, Box A-produced DNA gaps avoided DNA double-strand break response by histone deacetylation and SIRT1, a Sir2 homolog. In conclusion, Youth-DNA-GAPs are a biomarker determining the DNA aging stage (young/old). Box A-produced DNA gaps ultimately reverse aging features. Therefore, DNA gap formation is a potential strategy to monitor and treat aging-associated diseases.

Inhibition of myeloid differentiation factor 2 attenuates cardiometabolic impairments via reducing cardiac mitochondrial dysfunction, inflammation, apoptosis and ferroptosis in prediabetic rats.

Systemic inflammation is a key mediator of left ventricular dysfunction (LV) in prediabetes via the activation of myeloid differentiation factor 2 (MD2)/toll-like receptor 4 complex. The MD2 inhibitor L6H21 effectively reduced systemic and cardiac inflammation in obese mice. However, its effects on cardiac function and regulated cell death pathways in the heart in prediabetes are still unknown. The prediabetic rats were divided into 3 subgroups to receive vehicle, L6H21 (10, 20, 40 mg/kg) or metformin (300 mg/kg) for 1, 2 and 4 weeks. Then, metabolic parameters, cardiac sympathovagal balance, LV function, cardiac mitochondrial function, oxidative stress, inflammation, apoptosis, necroptosis, and ferroptosis were determined. All prediabetic rats exhibited cardiac sympathovagal imbalance, LV dysfunction, and cardiac mitochondrial dysfunction. All doses of L6H21 treatment for 2- and 4-weeks attenuated insulin resistance. L6H21 at 40 mg/kg attenuated cardiac autonomic imbalance and LV dysfunction after 1 week of treatment. Both 10 and 20 mg/kg of L6H21 required longer treatment duration to show these benefits. Mechanistically, all doses of L6H21 reduced cardiac mitochondrial dysfunction after 1 week of treatment, resulting in alleviated oxidative stress and inflammation. L6H21 also effectively suppressed cardiac apoptosis and ferroptosis, but it did not affect necroptosis in prediabetic rats. L6H21 provided the cardioprotective efficacy in dose- and time-dependent manners in prediabetic rats via reduction in apoptosis and ferroptosis.

L6H21 protects against cognitive impairment and brain pathologies via toll-like receptor 4-myeloid differentiation factor 2 signalling in prediabetic rats.

BACKGROUND AND PURPOSE: Chronic high-fat diet (HFD) intake instigates prediabetes and brain pathologies, which include cognitive decline and neuroinflammation. The myeloid differentiation factor 2 (MD-2)/toll-like receptor 4 (TLR4) complex plays a pivotal role in neuroinflammation. The MD-2 inhibitor (L6H21) reduces systemic inflammation and metabolic disturbances in HFD-induced prediabetes. However, the potential role of L6H21, and its comparison with metformin, on brain pathologies in HFD-induced prediabetes has never been investigated. EXPERIMENTAL APPROACH: Male Wistar rats were given either a normal diet (ND) (n = 8) or a HFD (n = 104) for 16 weeks. At the 13th week, ND-fed rats were given a vehicle, whereas HFD-fed rats were randomly divided into 13 subgroups. Each subgroup was given vehicle, L6H21 (three doses) or metformin (300-mg·kg-1 ·day-1 ) for 1, 2 or 4 weeks. Metabolic parameters, cognitive function, brain mitochondrial function, brain TLR4-MD-2 signalling, microglial morphology, brain oxidative stress, brain cell death and dendritic spine density were investigated. KEY RESULTS: HFD-fed rats developed prediabetes, neuroinflammation, brain pathologies and cognitive impairment. All doses of L6H21 and metformin given to HFD-fed rats at 2 and 4 weeks attenuated metabolic disturbance. CONCLUSION AND IMPLICATIONS: In rats, L6H21 and metformin restored cognition and attenuated brain pathologies dose and time-dependently. These results indicate a neuroprotective role of MD-2 inhibitor in a model of prediabetes.

Potential Roles of Myeloid Differentiation Factor 2 on Neuroinflammation and Its Possible Interventions.

Neuroinflammation is the primary response by immune cells in the nervous system to protect against infection. Chronic and uncontrolled neuroinflammation triggers neuronal injury and neuronal death resulting in a variety of neurodegenerative disorders. Therefore, fine tuning of the immune response in the nervous system is now extensively considered as a potential therapeutic intervention for those diseases. The immune cells of the nervous system express Toll-like receptor 4 (TLR4) together with myeloid differentiation factor 2 (MD-2) to protect against the pathogens. Over the last 10 years, antagonists targeting the functional domains of MD-2 have become attractive pharmacological intervention strategies in pre-clinical studies into neuroinflammation and its associated brain pathologies. This review aims to summarize and discuss the roles of TLR4-MD-2 signaling pathway activation in various models of neuroinflammation. This review article also highlights the studies reporting the effect of MD-2 antagonists on neuroinflammation in in vitro and in vivo studies.