Compound XiongShao Capsule ameliorates streptozotocin-induced diabetic peripheral neuropathy in rats via inhibiting apoptosis, oxidative - nitrosative stress and advanced glycation end products.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound XiongShao Capsule (CXSC), a traditional herb formula, has been approved for using to treat diabetic peripheral neuropathy (DPN) by the Shanghai Food and Drug Administration, with significant efficacy in clinic. AIM OF THE STUDY: This study aimed to investigate the multidimensional pharmacological mechanisms and synergism of CXSC against DPN in rats. METHODS: The quality analysis of CXSC was performed by high-performance liquid chromatography (HPLC) and thin-layer chromatography. Rats with DPNinduced by streptozotocin/high-fat diet for 4 weeks were treated with CXSC at three doses (1.2 g/kg, 0.36 g/kg, and 0.12 g/kg), or epalrestat (15 mg/kg) daily for 8 weeks continuously. During the treatment period, body weight, serum glucose levels, and nerve function, including nerve conduction velocity (NCV), and mechanical and thermal hyperalgesia were tested and assessed every 4 weeks. In the 13th week, the histopathological examination in the sciatic nerve was performed using a transmission electron microscope. The expression of apoptosis-related proteins of BAX, BCL2, and caspase-3 in the sciatic nerve was examined using hematoxylin and eosin staining. The serum levels of advanced glycation end products (AGEs), oxidative-nitrosative stress biomarkers of superoxide dismutase (SOD), and nitric oxide synthase (NOS) were measured using a rat-specific ELISA kit. RESULTS: CXSC had no significant effect on body weight or serum glucose levels (P > 0.05), but it significantly improved mechanical hyperalgesia (F5,36 = 18.24, P < 0.0001), thermal hyperalgesia (F5,36 = 8.45, P < 0.0001), and NCV (motor NCV: F5,36 = 7.644, P < 0.0001, sensory NCV: F5,36 = 12.83, P < 0.0001). Besides, it maintained myelin and axonal structure integrity, downregulated the expression of apoptosis-related proteins in the sciatic nerve tissue, reduced AGEs and NOS levels, and enhanced antioxidant enzyme SOD activities in the serum. CONCLUSION: CXSC exerted neuroprotective effects against rats with DPN through multidimensional pharmacological mechanisms including antiapoptotic activity in the sciatic nerve and downregulation of the level of serum NOS, SOD and AGEs.

Coriandrum sativum improve neuronal function via inhibition of oxidative/nitrosative stress and TNF-α in diabetic neuropathic rats.

ETHNOPHRAMACOLOGICAL RELEVANCE: Coriandrum sativum L. is traditionally acknowledged for its use in inflammatory disorders, altered blood lipid levels, respiratory and digestive problems. AIM OF THE STUDY: The present study investigates possible role of hydro-alcoholic extract of C. sativum (CHA) seeds in the attenuation of indices of diabetic peripheral neuropathy (DPN). MATERIALS AND METHODS: Phytochemical analysis was carried out by employing chromatographic, spectroscopic as well as spectrometric techniques. Diabetes was induced by a single i.p. injection of freshly prepared STZ (65 mg/kg). The indexed markers of DPN, i.e., thermal and mechanical hyperalgesia were found to be prominent on the 60th day of STZ administration. Administration of CHA (100, 200, and 400 mg/kg, p.o.) for 30 days was started on the substantiation of DPN onset. Molecular docking study was performed by targeting TNF-α. RESULTS: Phytochemical analysis revealed the presence of flavonoids, terpenoids, and phenolic acids. Oral administration of CHA considerably attenuated hyperglycemia and decreased pain threshold in diabetic rats as well as modulated oxidative-nitrosative stress. Docking study suggested good affinity of flavonoids when docked into the binding site of TNF-α. CONCLUSION: In conclusion, using STZ model, it was successfully predicted that CHA might be beneficial in diabetes-induced neuropathic pain by inhibiting oxidative/nitrosative stress and inflammatory cytokine.

Therapeutic targets of oxidative/nitrosative stress and neuroinflammation in ischemic stroke: Applications for natural product efficacy with omics and systemic biology.

Oxidative/nitrosative stress and neuroinflammation are critical pathological processes in cerebral ischemia-reperfusion injury, and their intimate interactions mediate neuronal damage, blood-brain barrier (BBB) damage and hemorrhagic transformation (HT) during ischemic stroke. We review current progress towards understanding the interactions of oxidative/nitrosative stress and inflammatory responses in ischemic brain injury. The interactions between reactive oxygen species (ROS)/reactive nitrogen species (RNS) and innate immune receptors such as TLR2/4, NOD-like receptor, RAGE, and scavenger receptors are crucial pathological mechanisms that amplify brain damage during cerebral ischemic injury. Furthermore, we review the current progress of omics and systematic biology approaches for studying complex network regulations related to oxidative/nitrosative stress and inflammation in the pathology of ischemic stroke. Targeting oxidative/nitrosative stress and neuroinflammation could be a promising therapeutic strategy for ischemic stroke treatment. We then review recent advances in discovering compounds from medicinal herbs with the bioactivities of simultaneously regulating oxidative/nitrosative stress and pro-inflammatory molecules for minimizing ischemic brain injury. These compounds include sesamin, baicalin, salvianolic acid A, 6-paradol, silymarin, apocynin, 3H-1,2-Dithiole-3-thione, (-)-epicatechin, rutin, Dl-3-N-butylphthalide, and naringin. We finally summarize recent developments of the omics and systematic biology approaches for exploring the molecular mechanisms and active compounds of Traditional Chinese Medicine (TCM) formulae with the properties of antioxidant and anti-inflammation for neuroprotection. The comprehensive omics and systematic biology approaches provide powerful tools for exploring therapeutic principles of TCM formulae and developing precision medicine for stroke treatment.

A novel pyrazole-containing selenium compound modulates the oxidative and nitrergic pathways to reverse the depression-pain syndrome in mice.

Bearing in mind that pain and major depressive disorder (MDD) often share biological pathways, this condition is classified as depression-pain syndrome. Mounting evidence suggests that oxidative stress is implicated in the pathophysiology of this syndrome. The development of effective pharmacological interventions for the depression-pain syndrome is of particular importance as clinical treatments for this comorbidity have shown limited efficacy. Therefore, the present study aimed to evaluate whether the 3,5-dimethyl-1-phenyl-4-(phenylselanyl)-1H-pyrazole (SePy) was able to reverse the depression-pain syndrome induced by intracerebroventricular (i.c.v) streptozotocin (STZ) in mice and the possible modulation of oxidative and nitrergic pathways in its effect. The treatment with SePy (1 and 10 mg/kg) administered intragastrically (i.g.) reversed the increased immobility time in the tail suspension test, decreased grooming time in the splash test, latency time to nociceptive response in the hot plate test, and the response frequency of Von Frey hair (VFH) stimulation induced by STZ (0.2 mg/4 µl/per mouse). Additionally, SePy (10 mg/kg, i.g.) reversed STZ-induced alterations in the levels of reactive oxygen species, nitric oxide, and lipid peroxidation and the superoxide dismutase and catalase activities in the prefrontal cortices (PFC) and hippocampi (HC) of mice. Treatment with SePy (10 mg/kg, i.g.) also reversed the STZ-induced increased expression of inducible nitric oxide synthase (iNOS) and glycogen synthase kinase 3 beta (GSK3ß) in the PFC and HC. An additional molecular docking investigation found that SePy binds to the active site of iNOS and GSK3ß. Altogether, these results indicate that the antidepressant-like effect of SePy is accompanied by decreased hyperalgesia and mechanical allodynia, which were associated with its antioxidant effect.

Antioxidant effects of curcumin in models of neurodegeneration, aging, oxidative and nitrosative stress: A review.

The global burden of neurodegenerative disorders has increased substantially over the past 2 decades due to rising rates of population aging. Although neurodegenerative disorders differ in their clinical presentation, the underlying pathobiological processes are largely shared. Oxidative stress, among other mechanisms, is strongly implicated in neurodegenerative disorders and aging, and can potentially be targeted by antioxidative agents. Curcumin, a component of turmeric, is a compound that has received considerable attention for its therapeutic properties, and it is considered to be a powerful antioxidant. In this review, we analyzed the evidence for curcumin as an antioxidant in models of neurodegenerative disorders as well as oxido-nitrosative stress. A total of 1451 articles were found from 3 scientific literature databases (PubMed, Scopus, and Web of Science). After all exclusions, a final total of 64 articles were included in this review. The majority of the studies showed that curcumin, or derivatives thereof, were protective against oxidative and/or nitrosative stress in various cellular and animal models. Overall, curcumin protected against lipid and protein oxidation with a reduction in levels of malondialdehyde, and protein carbonyls, thiols and nitrotyrosines. Furthermore, it stimulated the activities of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. In conclusion, curcumin appears to be a promising compound for phytomedicine. However, due to some concerns about its efficacy, further targeted experiments are needed to identify its exact molecular targets and pathways responsible for its antioxidant effects.

Repeated Restraint Stress Decreases Na,K-ATPase Activity via Oxidative and Nitrosative Damage in the Frontal Cortex of Rats.

Chronic psychogenic stress can increase neuronal calcium influx and generate the intracellular accumulation of oxidative (ROS) and nitrosative (RNS) reactive species, disrupting synaptic transmission in the brain. These molecules impair the Na,K-ATPase (NKA) activity, whose malfunction has been related to neuropsychiatric disorders, including anxiety, depression, schizophrenia, and neurodegenerative diseases. In this study, we assessed how 14 days of restraint stress in rats affect NKA activity via oxidative/nitrosative damage in the frontal cortex (FCx), a crucial region for emotional and cognitive control. One day after the last stress session (S14 + 1d), but not immediately after the last stress session (S14), α2,3-NKA activity was significantly reduced in the FCx, without changes in the protein levels. The S14 + 1d animals also showed increased lipid peroxidation, iNOS, and AP-1 activities, as well as TNF-α protein levels, evidencing oxidative stress and neuroinflammation. No cellular death or neurodegeneration was observed in the FCx of S14 + 1d animals. Pharmacological inhibition of iNOS or COX-2 before each stress session prevented lipid peroxidation and the α2,3-NKA activity loss. Our results show that repeated restraint exposure for 14 days decreases the activity of α2,3-NKA in FCx 24 h after the last stress, an effect associated with augmented inflammatory response and oxidative and nitrosative damage and suggest new pathophysiological roles to neuroinflammation in neuropsychiatric diseases.

The Deleterious Effects of Oxidative and Nitrosative Stress on Palmitoylation, Membrane Lipid Rafts and Lipid-Based Cellular Signalling: New Drug Targets in Neuroimmune Disorders.

Oxidative and nitrosative stress (O&NS) is causatively implicated in the pathogenesis of Alzheimer's and Parkinson's disease, multiple sclerosis, chronic fatigue syndrome, schizophrenia and depression. Many of the consequences stemming from O&NS, including damage to proteins, lipids and DNA, are well known, whereas the effects of O&NS on lipoprotein-based cellular signalling involving palmitoylation and plasma membrane lipid rafts are less well documented. The aim of this narrative review is to discuss the mechanisms involved in lipid-based signalling, including palmitoylation, membrane/lipid raft (MLR) and n-3 polyunsaturated fatty acid (PUFA) functions, the effects of O&NS processes on these processes and their role in the abovementioned diseases. S-palmitoylation is a post-translational modification, which regulates protein trafficking and association with the plasma membrane, protein subcellular location and functions. Palmitoylation and MRLs play a key role in neuronal functions, including glutamatergic neurotransmission, and immune-inflammatory responses. Palmitoylation, MLRs and n-3 PUFAs are vulnerable to the corruptive effects of O&NS. Chronic O&NS inhibits palmitoylation and causes profound changes in lipid membrane composition, e.g. n-3 PUFA depletion, increased membrane permeability and reduced fluidity, which together lead to disorders in intracellular signal transduction, receptor dysfunction and increased neurotoxicity. Disruption of lipid-based signalling is a source of the neuroimmune disorders involved in the pathophysiology of the abovementioned diseases. n-3 PUFA supplementation is a rational therapeutic approach targeting disruptions in lipid-based signalling.