The endoplasmic reticulum (ER) plays a fundamental role in maintaining cellular homeostasis by ensuring proper protein folding, lipid metabolism, and calcium regulation. However, disruptions to ER function, known as ER stress, activate the unfolded protein response (UPR) to restore balance. Chronic or unresolved ER stress contributes to metabolic dysfunctions, including insulin resistance, non-alcoholic fatty liver disease (NAFLD), and neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Recent studies have also highlighted the importance of mitochondria-ER contact sites (MERCs) and ER-associated inflammation in disease progression. This review explores the current pharmacological landscape targeting ER stress, focusing on therapeutic strategies for rare metabolic and neurodegenerative diseases. It examines small molecules such as tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA), repurposed drugs like 17-AAG (17-N-allylamino-17demethoxygeldanamycin (tanespimycin)) and berberine, and phytochemicals such as resveratrol and hesperidin. Additionally, it discusses emerging therapeutic areas, including soluble epoxide hydrolase (sEH) inhibitors for metabolic disorders and MERCs modulation for neurological diseases. The review emphasizes challenges in translating these therapies to clinical applications, such as toxicity, off-target effects, limited bioavailability, and the lack of large-scale randomized controlled trials (RCTs). It also highlights the potential of personalized medicine approaches and pharmacogenomics in optimizing ER stress-targeting therapies.

Elevated plasma levels of trimethylamine N-oxide (TMAO)-a compound derived from diet and the gut microbiome-have been widely studied for their association with diabetes risk and their potential role in disease pathophysiology and complications. However, clinical studies, both prospective and retrospective, have yielded conflicting results. For example, elevated levels of TMAO are frequently linked to an increased risk of cardiovascular and renal complications in individuals with diabetes. However, the robustness and independence of these associations differ across study populations and are influenced by the degree of adjustment for confounding risk factors. Considering insulin's regulatory effect on FMO3 activity in liver cells, TMAO may serve as a marker of hepatic insulin resistance, which could partially explain its association with diabetes risk. The role of TMAO in diabetes pathology remains controversial; while some studies emphasize its detrimental impact on insulin sensitivity and the progression of diabetes-related complications, others suggest potential protective effects. Investigating the largely unexplored role of TMAO's precursor, trimethylamine, may help elucidate these discrepancies. This review consolidates clinical and experimental findings to clarify TMAO's complex mechanistic contributions to diabetes pathology.

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes arising in part from glycemic damage to neurons and Schwann cells (SC). While the pathogenic mechanisms of DPN are complex, mitochondrial dysfunction and endoplasmic reticulum (ER) stress contribute to the development of DPN and serve as therapeutic targets for disease modification. Cemdomespib is an orally bioavailable small molecule which alleviates clinical indices of DPN that correlate with improvements in neuronal oxidative stress and mitochondrial bioenergetics. However, the contribution of SC ER stress in the onset of DPN and the therapeutic efficacy of cemdomespib remains unknown. To address this issue, mice expressing a conditional deletion of protein kinase RNA-like ER kinase (PERK) in myelinating SCs (SC-cPERK KO) and control SC-PERKf/f mice were rendered diabetic with streptozotocin. Diabetic SC-PERKf/f and SC-cPERK KO mice developed a similar magnitude of DPN as quantified by the onset of a thermal/mechanical hypoalgesia, decreases in nerve conduction velocity (NCV) and intraepidermal fiber density (iENFD). After 8 weeks of diabetes, daily treatment with 1 mg/kg cemdomespib for an additional 8 weeks significantly improved thermal/mechanical hypoalgesia, NCV, iENFD and decreased markers of ER stress in diabetic SC-PERKf/f mice, but the drug had no effect in diabetic SC-cPERK KO mice. Nrf2 is a PERK substrate and studies using rat SCs subjected to ER stress demonstrated that cemdomespib increased Nrf2 activity. Collectively, these data suggest that activation of SC PERK by diabetes is not necessary for the onset of DPN, but serves as a target in the action of cemdomespib, potentially by increasing Nrf2 activity.

Painful diabetes-related peripheral neuropathy (PDPN) is a common and debilitating complication of diabetes, contributing significantly to morbidity and healthcare costs. This systematic review and meta-analysis aim to determine the global prevalence of PDPN among individuals with diabetic peripheral neuropathy (DPN) and to identify associated risk factors. A comprehensive search of four English and three Chinese databases was conducted for observational studies on PDPN prevalence up to June 22, 2024. Of the 41 studies included, the pooled global prevalence of PDPN was 46.7 % (95 % CI, 41.8-51.7). In subgroup analysis, significant statistical differences were observed in prevalence estimates between different diagnostic methods for neuropathic pain, with neuropathic-specific pain scales indicating higher rates (P = 0.03). Studies with mean diabetes duration of less than 10 years or more than 15 years reported higher prevalence (P < 0.01). Significant risk factors for PDPN included older age (OR = 1.02, 95 % CI, 1.01-1.04), female gender (OR = 1.58, 95 % CI, 1.19-2.11), BMI ≥ 30 kg/m2 (OR = 1.62, 95 % CI, 1.43-1.83), longer diabetes duration (OR = 1.05, 95 % CI, 1.01-1.08), and nephropathy (OR = 1.32, 95 % CI, 1.24-1.40). Targeted screening and standardized diagnostic tools are urgently needed to enhance PDPN management and mitigate its burden globally.

Diabetic peripheral neuropathy (DPN) is a prevalent complication affecting over half of individuals with diabetes. This study investigates the role of mesencephalic Astrocyte-derived neurotrophic factor (MANF) in DPN progression and its potential as a therapeutic target. Using a streptozotocin (STZ)-induced diabetic mouse model, we analyzed MANF expression in the dorsal root ganglia (DRG) and sciatic nerve and assessed the effects of recombinant human MANF (rhMANF) administration on DPN symptoms. Our findings show significant upregulation of MANF protein levels in the DRG of diabetic mice, along with an increased presence of MANF-expressing macrophages in both the DRG and sciatic nerve. Intravenous administration of rhMANF from Day 7 to Day 21 post-STZ injection yielded multiple beneficial outcomes. Notably, rhMANF treatment alleviated mechanical hypoalgesia, as measured by the paw mechanical withdrawal threshold (PMWT), and enhanced sciatic nerve conduction, improving motor nerve conduction velocity (MNCV). Additionally, it increased intradermal nerve density, indicated by more PGP9.5-positive nerve fibers in the plantar skin of treated diabetic mice. These improvements were associated with reduced macrophage infiltration in the DRG and sciatic nerve, marked by fewer CD68 and Iba-1 positive cells, and inhibition of inflammatory signaling pathways. Specifically, rhMANF treatment decreased NF-κB p65 phosphorylation and suppressed p38 MAPK phosphorylation, indicating reduced inflammation. In summary, our research underscores MANF's potential as a novel therapeutic target for DPN, particularly due to its anti-inflammatory properties. Further exploration of MANF could lead to the development of more effective treatments for this debilitating aspect of diabetes.

Sephin1 was discovered as a protein phosphatase inhibitor, and its efficacy against neurodegenerative diseases has been confirmed. There are conflicting reports on whether inhibition of eIF2α dephosphorylation by PP1 holoenzyme with the protein phosphatase 1 regulatory subunit 15 A is the mechanism of action of Sephin1. In the present study, we found that Sephin1 significantly suppressed renal tubular cell death in an animal model of ER stress administered with tunicamycin. CHOP, which plays a central role in the ER stress-induced cell death pathway, requires nuclear translocation to act as a transcription factor to increase the expression of cell death-related genes. Sephin1 markedly suppressed this nuclear translocation of CHOP. To elucidate the molecular mechanism underlying the cell death suppressive effect of Sephin1, we used human renal tubular epithelial cells under ER stress with tunicamycin. Sephin1 reduced intracellular CHOP levels by promoting CHOP phosphorylation at Ser30, which led to protein degradation in UPS. Phosphorylated CHOP is generated by Thr172-phosphorylated activated AMPK, and Sephin1 increased phosphorylated AMPK. Phosphorylated AMPK is inactivated by PP2A through dephosphorylation of its Thr172, and Sephin1 inhibits the formation of the PP2A holoenzyme with the PP2A subunit B isoform delta. These results indicate that inhibition of PP2A holoenzyme formation is the molecular target of Sephin1 in this experimental system.

Aldose reductase (AR), a rate-limiting enzyme in the polyol pathway, mediates the conversion of several substrates, including glucose and galactose. In rodents, galactosemia induced by galactose feeding has been shown to develop peripheral nerve lesions resembling diabetic peripheral neuropathy. However, the mechanisms by which AR-mediated responses elicited Schwan cell lesions under galactosemic conditions remain unresolved. To investigate this, we examined the mechanism of high-galactose-induced damage mediated by AR using AR inhibitors such as ranirestat and epalrestat. The exposure of IMS32 Schwann cells under high-galactose conditions led to galactitol accumulation, the increased production of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, impaired mitochondrial morphology and membrane potential, decreased glycolysis, and aberrant glycosylation. Under these experimental conditions, ranirestat inhibited intracellular galactitol in a dose-dependent manner, whereas epalrestat failed to inhibit it. Interestingly, even at low concentrations where epalrestat did not inhibit AR activity, it prevented increased ROS production, ER stress, decreased glycolysis, and aberrant RCA120-binding glycosylation; however, no effect of ranirestat on the glycosylation was observed. Epalrestat and ranirestat did not recover mitochondrial morphology. These findings suggest that ER stress is induced by aberrant glycosylation under galactosemic conditions and that epalrestat may be effective in maintaining proper glycosylation in Schwann cells in these conditions.

Previous studies have reported a potential association between trimethylamine N-oxide (TMAO) and Parkinson's disease (PD). The objective of this study was to examine the potential relationship between the levels of circulating TMAO and its precursors and the risk of PD using a two-sample Mendelian randomization (MR) approach.

We aggregated data from three genome-wide association studies (International Parkinson's Disease Genomics Consortium, Parkinson's Research: The Organized Genetics Initiative and GenePD, and FinnGen) to extract single-nucleotide polymorphisms (SNPs) associated with circulating concentrations of TMAO, choline, carnitine, and betaine. These SNPs were employed as instrumental variables in a random-effects model to evaluate the causal relationship between circulating concentrations of TMAO and its precursors and the risk of Parkinson's disease, by estimating odds ratios with accompanying 95% confidence intervals. The primary analysis employed the inverse variance-weighted (IVW) method, which was complemented with MR-Egger regression analysis.

The analysis using the IVW method, which aggregated data from the three databases, did not show any causal relationship between circulating concentrations of TMAO and its precursors, and the risk of PD (p > 0.05). This finding was further confirmed by the results of the MR-Egger analysis. A sensitivity analysis demonstrated that the results were not influenced by any biases, and a heterogeneity test indicated no significant variation among the SNPs.

This study did not identify any conclusive evidence of a causal association between the circulating concentrations of TMAO or its precursors and the risk of PD. Further investigation is warranted to determine whether such an association indeed exists.

This study aims to examine the association between gut microbe-dependent trimethylamine N-oxide (TMAO) and its precursors (choline, betaine, and carnitine) levels and mild cognition impairment (MCI), alongside changes in the Chinese version of the Montreal Cognitive Assessment-Basic (ΔMoCA-BC) score in rural adults.

Drawing data from a large-scale epidemiological study conducted in rural areas of Fuxin County, Liaoning Province, China. 1,535 participants free from brain-related ailments were initially surveyed. MCI was assessed through the MoCA-BC score. Logistic regression models and restricted cubic spline were used to investigate the association between TMAO and its precursors levels and MCI. Additionally, the association between TMAO and its precursors levels and ΔMoCA-BC was analyzed using a generalized linear model in the longitudinal study.

The average age of the study participants was 58.6 ± 9.4 years and the prevalence rate of MCI was 34.5%. With the second quartile as the reference in the logistic regression model, the OR for risk of MCI in the highest quartile for TMAO, betaine, and carnitine was 1.685 (95% CI: 1.232-2.303, p = 0.001), 2.367 (95% CI: 1.722-3.255, p < 0.001), and 2.239 (95% CI: 1.742-3.295, p < 0.001), respectively. The OR of choline for the highest versus lowest quartile was 2.711 (95% CI: 2.012-3.817, p < 0.001) for the risk of MCI. We find a J-shaped association between betaine (P non-linear = 0.001) and carnitine (P non-linear = 0.003) levels and MCI. Furthermore, TMAO and its precursors levels were associated with ΔMoCA-BC in the third and fourth quartiles group (All p < 0.05).

The findings suggest the existence of an optimal concentration range for serum levels of TMAO, betaine, and carnitine that mitigates MCI risk, paving the way for enhanced dietary interventions aimed at preventing and treating MCI.

Chronic pain (CP) affects over 30 % of the global population, imposing significant financial burdens on individuals and society. However, existing treatments for CP offer limited efficacy and troublesome side effects, primarily owing to a lack of knowledge of its precise underlying mechanism. Pathological stimuli disrupt the intricate process of protein folding and endoplasmic reticulum (ER) homeostasis. This disruption leads to the accumulation of misfolded or unfolded proteins in the ER, generating a condition termed ER stress. Emerging data have indicated that ER stress, occurring in the peripheral and central nervous systems, contributes to the development and maintenance of CP. This review aimed to comprehensively explore the intersection of ER stress and CP within the lower and upper nervous systems and highlight the cell-specific contributions of the unfolded protein response in different CP types. We provide a comprehensive synthesis of evidence from animal models, examining neuronal and non-neuronal mechanisms and discuss the damaging ER stress-linked inflammation, autophagy, oxidative stress, and apoptosis, which collectively drive disease progression and contribute to a neurotoxic environment. However, the mechanisms through which ER stress influences the most advanced centre-of-pain projections in the brain remain unclear. Further investigation in this area is crucial to elucidate the relationship between ER stress and CP and facilitate the development of novel therapeutic drugs for this intractable dilemma.

Fu's subcutaneous needling (FSN) is a traditional Chinese acupuncture procedure used to treat pain-related neurological disorders. Moreover, the regulation of inflammatory cytokines may provide a favorable environment for peripheral nerve regeneration. In light of this, FSN may be an important novel therapeutic strategy to alleviate pain associated with peripheral neuropathy; however, the underlying molecular mechanisms remain unclear. This study revealed that patients who had osteoarthritis with peripheral neuropathic pain significantly recovered after 1 to 2 weeks of FSN treatment according to the visual analog scale, Western Ontario and McMaster Universities Osteoarthritis Index, Lequesne index, walking speed, and passive range of motion. Similarly, we demonstrated that FSN treatment in an animal model of chronic constriction injury (CCI) significantly improved sciatic nerve pain using paw withdrawal thresholds, sciatic functional index scores, and compound muscle action potential amplitude tests. In addition, transmission electron microscopy images of sciatic nerve tissue showed that FSN effectively reduced axonal swelling, abnormal myelin sheaths, and the number of organelle vacuoles in CCI-induced animals. Mechanistically, RNA sequencing and gene set enrichment analysis revealed significantly reduced inflammatory pathways, neurotransmitters, and endoplasmic reticulum stress pathways and increased nerve regeneration factors in the FSN+CCI group, compared with that in the CCI group. Finally, immunohistochemistry, immunoblotting and enzyme-linked immunosorbent assay showed similar results in the dorsal root ganglia and sciatic nerve. Our findings suggest that FSN can effectively ameliorate peripheral neuropathic pain by regulate inflammation and endoplasmic reticulum stress, thereby determine its beneficial application in patients with peripheral nerve injuries.

Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes which primarily affects the sensory nervous system. Pain is the most common complaint that prompts patients to seek medical advice. With various presentations and intricate pathological mechanisms, diabetic peripheral neuropathic pain is currently the most crucial and challenging aspect of managing diabetic complications. As a heterogeneous disorder, there is no medication or treatment modality that is effective for all types of DPN and its associated neuropathic pain. Peripheral nerve decompression provides a new option for treating patients with diabetic peripheral neuropathic pain in the lower extremities. However, the clinical applicability of nerve decompression has been debated since it was first proposed. This review discusses the theoretical basis of nerve decompression, the clinical indications, and the progress of basic research based on the pathological mechanisms and nerve impairment patterns of diabetic peripheral neuropathic pain. The heterogeneity of DPN patients is summarized in terms of three aspects: complex pathophysiological mechanisms, multilevel nervous system involvement, and various nerve impairment properties. Identifying the presence of nerve entrapment among complex pathophysiological mechanisms is the key to successful outcomes. Tinel signs, focal pain, mechanical allodynia, and two-point discrimination were reported to be prognostic factors for good surgical outcomes, and their predictive ability might stem from their association with the early stage of entrapment neuropathy.

Dysfunction of Schwann cells, including cell apoptosis, autophagy inhibition, dedifferentiation, and pyroptosis, is a pivotal pathogenic factor in induced diabetic peripheral neuropathy (DPN). Histone deacetylases (HDACs) are an important family of proteins that epigenetically regulate gene transcription by affecting chromatin dynamics. Here, we explored the effect of HDAC1 on high glucose-cultured Schwann cells. HDAC1 expression was increased in diabetic mice and high glucose-cultured RSC96 cells, accompanied by cell apoptosis. High glucose also increased the mitochondrial pathway apoptosis-related Bax/Bcl-2 and cleaved caspase-9/caspase-9 ratios and decreased endoplasmic reticulum response-related GRP78, CHOP, and ATF4 expression in RSC96 cells (P < 0.05). Furthermore, overexpression of HDAC1 increased the ratios of Bax/Bcl-2, cleaved caspase-9/caspase-9, and cleaved caspase-3 and reduced the levels of GRP78, CHOP, and ATF4 in RSC96 cells (P < 0.05). In contrast, knockdown of HDAC1 inhibited high glucose-promoted mitochondrial pathway apoptosis and suppressed the endoplasmic reticulum response. Moreover, RNA sequencing revealed that U4 spliceosomal RNA was significantly reduced in HDAC1-overexpressing RSC96 cells. Silencing of U4 spliceosomal RNA led to an increase in Bax/Bcl-2 and cleaved caspase-9 and a decrease in CHOP and ATF4. Conversely, overexpression of U4 spliceosomal RNA blocked HDAC1-promoted mitochondrial pathway apoptosis and inhibited the endoplasmic reticulum response. In addition, alternative splicing analysis of HDAC1-overexpressing RSC96 cells showed that significantly differential intron retention (IR) of Rpl21, Cdc34, and Mtmr11 might be dominant downstream targets that mediate U4 deficiency-induced Schwann cell dysfunction. Taken together, these findings indicate that HDAC1 promotes mitochondrial pathway-mediated apoptosis and inhibits the endoplasmic reticulum stress response in high glucose-cultured Schwann cells by decreasing the U4 spliceosomal RNA/IR of Rpl21, Cdc34, and Mtmr11.

Mitophagy, the cellular process of selectively eliminating damaged mitochondria, plays a crucial role in maintaining metabolic balance and preventing insulin resistance, both key factors in type 2 diabetes mellitus (T2DM) development. When mitophagy malfunctions in diabetic neuropathy, it triggers a cascade of metabolic disruptions, including reduced energy production, increased oxidative stress, and cell death, ultimately leading to various complications. Thus, targeting mitophagy to enhance the process may have emerged as a promising therapeutic strategy for T2DM and its complications. Notably, plant-derived compounds with β-cell protective and mitophagy-stimulating properties offer potential as novel therapeutic agents. This review highlights the intricate mechanisms linking mitophagy dysfunction to T2DM and its complications, particularly neuropathy, elucidating potential therapeutic interventions for this debilitating disease.

To improve exercise performance, the supplement of nutrients has become a common practice before prolonged exercise. Trimethylamine N-oxide (TMAO) has been shown to ameliorate oxidative stress damage, which may be beneficial in improving exercise capacity. Here, we assessed the effects of TMAO on mice with exhaustive swimming, analyzed the metabolic changes, and identified significantly altered metabolic pathways of skeletal muscle using a nuclear magnetic resonance-based (NMR-based) metabolomics approach to uncover the effects of TMAO improving exercise performance of mice. We found that TMAO pre-administration markedly prolonged the exhaustive time in mice. Further investigation showed that TMAO pre-administration increased levels of 3-hydroxybutyrate, isocitrate, anserine, TMA, taurine, glycine, and glutathione and disturbed the three metabolic pathways related to oxidative stress and protein synthesis in skeletal muscle. Our results provide a metabolic mechanistic understanding of the effects of TMAO supplements on the exercise performance of skeletal muscle in mice. This work may be beneficial in exploring the potential of TMAO to be applied in nutritional supplementation to improve exercise performance. This work will lay a scientific foundation and be beneficial to exploring the potential of TMAO to apply in nutritional supplementation.

Diabetic Peripheral Neuropathy (DPN) is a prevalent and debilitating complication of diabetes, affecting a significant proportion of the diabetic population. Neuromodulation, an emerging therapeutic approach, has shown promise in the management of DPN symptoms. This systematic review aims to synthesize and analyze the current advancements in neuromodulation techniques for the treatment of DPN utilizing studies with preclinical animal models. A comprehensive search was conducted across multiple databases, including PubMed, Scopus, and Web of Science. Inclusion criteria were focused on studies utilizing preclinical animal models for DPN that investigated the efficacy of various neuromodulation techniques, such as spinal cord stimulation, transcranial magnetic stimulation, and peripheral nerve stimulation. The findings suggest that neuromodulation significantly alleviated pain symptoms associated with DPN. Moreover, some studies reported improvements in nerve conduction velocity and reduction in nerve damage. The mechanisms underlying these effects appeared to involve modulation of pain pathways and enhancement of neurotrophic factors. However, the review also highlights the variability in methodology and stimulation parameters across studies, highlighting the need for standardization in future research. Additionally, while the results are promising, the translation of these findings from animal models to human clinical practice requires careful consideration. This review concludes that neuromodulation presents a potentially effective therapeutic strategy for DPN, but further research is necessary to optimize protocols and understand the underlying molecular mechanisms. It also emphasizes the importance of bridging the gap between preclinical findings and clinical applications to improve the management of DPN in diabetic patients.

We aimed to evaluate the neuroprotective effect of Indole-3-propionic acid (IPA) against streptozotocin (STZ) induced diabetic peripheral neuropathy (DPN) in rats and in high glucose (HG) induced neurotoxicity in neuro2a (N2A) cells.

Diabetes was induced in male SD rats STZ (55 mg/kg, i.p.) and IPA (10 and 20 mg/kg, p.o.) was administered for two weeks, starting from sixth week after diabetes induction. Neurobehavioral, functional assessments were made, and various molecular studies were performed to evaluate the effect of IPA on HG induced ER stress and mitochondrial dysfunction in sciatic nerves, DRGs and in N2A cells.

Diabetic rats and high glucose exposed N2A cells showed marked increase in oxidative damage accompanied by ER stress and mitochondrial dysfunction along with increased apoptotic markers. IPA treatment for two weeks markedly alleviated these changes and attenuated pain behaviour.

IPA exhibited neuroprotective activity against hyperglycaemic insults.

In chronic diabetic neuropathy (DN), the cellular mechanisms of neuropathic pain remain unclear. Protein kinase C epsilon (PKCε) is an intracellular signaling molecule that mediates chronic pain. This paper addresses the long-term upregulated PKCε in DN associated with endoplasmic reticulum (ER) stress and autophagic formation and correlates to chronic neuropathic pain. We found that thermal hyperalgesia and mechanical allodynia course development were associated with PKCε upregulation after DN but not skin denervation. Pathologically, PKCε upregulation was associated with the expression of inositol-requiring enzyme 1α (IRE1α; ER stress-related molecule) and ubiquitin D (UBD), which are involved in the ubiquitin-proteasome system (UPS)-mediated degradation of misfolded proteins under ER stress. Manders coefficient analyses revealed an approximately 50% colocalized ratio for IRE1α(+):PKCε(+) neurons (0.34-0.48 for M1 and 0.40-0.58 for M2 Manders coefficients). The colocalized coefficients of UBD/PKCε increased (M1: 0.33 ± 0.03 vs. 0.77 ± 0.04, p < 0.001; M2: 0.29 ± 0.05 vs. 0.78 ± 0.04; p < 0.001) in the acute DN stage. In addition, the regulatory subunit p85 of phosphoinositide 3-kinase, which is involved in regulating insulin signaling, exhibited similar expression patterns to those of IRE1α and UBD; for example, it had highly colocalized ratios to PKCε. The ultrastructural examination further confirmed that autophagic formation was associated with PKCε upregulation. Furthermore, PKCεv1-2, a PKCε specific inhibitor, reverses neuropathic pain, ER stress, and autophagic formation in DN. This finding suggests PKCε plays an upstream molecule in DN-associated neuropathic pain and neuropathology and could provide a potential therapeutic target.

Chronic pain is a severely debilitating condition with enormous socioeconomic costs. Current treatment regimens with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or opioids have been largely unsatisfactory with uncertain benefits or severe long-term side effects. This is mainly because chronic pain has a multifactorial aetiology. Although conventional pain medications can alleviate pain by keeping several dysfunctional pathways under control, they can mask other underlying pathological causes, ultimately worsening nerve pathologies and pain outcome. Recent preclinical studies have shown that endoplasmic reticulum (ER) stress could be a central hub for triggering multiple molecular cascades involved in the development of chronic pain. Several ER stress inhibitors and unfolded protein response modulators, which have been tested in randomised clinical trials or apprpoved by the US Food and Drug Administration for other chronic diseases, significantly alleviated hyperalgesia in multiple preclinical pain models. Although the role of ER stress in neurodegenerative disorders, metabolic disorders, and cancer has been well established, research on ER stress and chronic pain is still in its infancy. Here, we critically analyse preclinical studies and explore how ER stress can mechanistically act as a central node to drive development and progression of chronic pain. We also discuss therapeutic prospects, benefits, and pitfalls of using ER stress inhibitors and unfolded protein response modulators for managing intractable chronic pain. In the future, targeting ER stress to impact multiple molecular networks might be an attractive therapeutic strategy against chronic pain refractory to steroids, NSAIDs, or opioids. This novel therapeutic strategy could provide solutions for the opioid crisis and public health challenge.

Diabetic nephropathy and peripheral neuropathy are the two main complications of chronic diabetes that contribute to high morbidity and mortality. These conditions are characterized by the dysregulation of multiple molecular signaling pathways and the presence of specific biomarkers such as inflammatory cytokines, indicators of oxidative stress, and components of the renin-angiotensin system. In this review, we systematically collected and collated the relevant information from MEDLINE, EMBASE, ELSEVIER, PUBMED, GOOGLE, WEB OF SCIENCE, and SCOPUS databases. This review was conceived with primary objective of revealing the functions of these biomarkers and signaling pathways in the initiation and progression of diabetic nephropathy and peripheral neuropathy. We also highlighted the potential therapeutic effectiveness of rutin and quercetin, two plant-derived flavonoids known for their antioxidant and anti-inflammatory properties. The findings of our study demonstrated that both flavonoids can regulate important disease-promoting systems, such as inflammation, oxidative stress, and dysregulation of the renin-angiotensin system. Importantly, rutin and quercetin have shown protective benefits against nephropathy and neuropathy in diabetic animal models, suggesting them as potential therapeutic agents. These findings provide a solid foundation for further comprehensive investigations and clinical trials to evaluate the potential of rutin and quercetin in the management of diabetic nephropathy and peripheral neuropathy. This may contribute to the development of more efficient and comprehensive treatment approaches for diabetes-associated complications.

Both peripheral neuropathy and depression can be viewed as neurodegeneration's consequences of diabetes, at least in part coexisting with or resulting from sodium-calcium dysbalance. This study aims to assess the therapeutic potential of the orally applied reverse-mode inhibitor of the sodium-calcium exchanger (NCX) KB-R7943 in the streptozotocin (STZ) diabetes model in rats. A pilot pharmacokinetic (PK) study with high-performance liquid chromatography with high-resolution tandem mass spectrometric detection revealed higher drug exposure (AUC), lower volume of distribution (Vd) and clearance (Cl), and faster decline of the plasma concentration (ƛ) in rats with diabetes vs. controls. Brain and heart accumulation and urinary excretion of the unmetabolized KB-R7943 at least 24 h were also demonstrated in all rats. However, heart and hippocampus KB-R7943 penetration (AUCtissue/AUCplasma) was higher in controls vs. diabetic rats. The development of thermal, mechanical, and chemical-induced allodynia was assessed with the Cold plate test (CPT), Randall-Stiletto (R-S) test, and 0.5% formalin test (FT). Amitriptyline 10 mg/kg, KB-R7943 5 mg/kg, or 10 mg/kg p.o once daily was applied from the 28th to the 49th day. The body weight, coat status, CPT, R-S, and FT were evaluated on days (-5), 0, and 42. On day 41, a forced swim test and 24-h spontaneous physical activities were assessed. The chronic treatment effects were calculated as % of the maximum. A dose-depended amelioration of neuropathic and depression-like effects was demonstrated. The oral application of KB-R7943 for potentially treating neurodegenerative consequences of diabetes merits further studies. The brain, heart, and kidneys are essential contributors to the PKs of this drug, and their safety involvement needs to be further characterized.

Trimethylamine N-oxide (TMAO) has attracted interest because of its association with cardiovascular disease and diabetes, and evidence for the beneficial effects of TMAO is accumulating. This study investigates the role of TMAO in improving exercise performance and elucidates the underlying molecular mechanisms. Using C2C12 cells, we established an oxidative stress model and administered TMAO treatment. Our results indicate that TMAO significantly protects myoblasts from oxidative stress-induced damage by increasing the expression of Nrf2, heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase (NQO1), and catalase (CAT). In particular, suppression of Nrf2 resulted in a loss of the protective effects of TMAO and a significant decrease in the expression levels of Nrf2, HO-1, and NQO1. In addition, we evaluated the effects of TMAO in an exhaustive swimming test in mice. TMAO treatment significantly prolonged swimming endurance, increased glutathione and taurine levels, enhanced glutathione peroxidase activity, and increased the expression of Nrf2 and its downstream antioxidant genes, including HO-1, NQO1, and CAT, in skeletal muscle. These findings underscore the potential of TMAO to counteract exercise-induced oxidative stress. This research provides new insights into the ability of TMAO to alleviate exercise-induced oxidative stress via the Nrf2 signaling pathway, providing a valuable framework for the development of sports nutrition supplements aimed at mitigating oxidative stress.

Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes mellitus (DM). DPN is the primary risk factor for diabetic foot ulcers that can cause amputation. Although several observational studies have investigated the morphological and biomechanical characteristics of peripheral nerves in DPN, interventional studies regarding the effectiveness of neurodynamic techniques (NDT) in DPN patients are confined to a handful. The effects of NDT on neuropathy severity, nerve conduction parameters, quality of life (QoL), and mechanosensitivity have not been explored yet in this population.

Forty type 2 DPN (T2DPN) patients, diagnosed based on an electrodiagnosis study, will be recruited into two groups. The experimental group will receive the tibial nerve's real proximal and distal slider techniques in addition to DPN standard treatment as a basic treatment, and the control group will receive the tibial nerve's sham proximal and distal slider techniques along with the basic treatment for eight sessions twice a week. Baseline and post-intervention assessments will be based on the Michigan diabetic neuropathy score (MDNS) (primary outcome), tibial nerve conduction parameters, neuropathy-specific quality of life (Neuro QoL) questionnaire, and straight leg raising range of motion (SLR ROM) (secondary outcomes).

This study is expected to last approximately seven months, depending on recruitment. The results of the study will be published in a peer-reviewed journal.

The present study will evaluate the efficacy of NDT on the primary and secondary outcome measurements in DPN patients.

Chronic hyperglycemia-induced neuropathological changes include neuronal apoptosis, astrogliosis, decrease in neurotrophic support, impaired synaptic plasticity, and impaired protein quality control (PQC) system. Vitamin B12 is indispensable for neuronal development and brain function. Several studies reported the neuroprotective effect of B12 supplementation in diabetic patients. However, the underlying molecular basis for the neuroprotective effect of B12 supplementation in diabetes needs to be thoroughly investigated. Two-month-old Sprague-Dawley rats were randomly assigned into three groups: Control (CN), diabetes (D; induced with streptozotocin; STZ), and diabetic rats supplemented with vitamin B12 (DBS; vitamin B12; 50 μg/kg) for four months. At the end of 4 months of experimentation, the brain was dissected to collect the cerebral cortex (CC). The morphology of CC was investigated with H&E and Nissl body staining. Neuronal apoptosis was determined with TUNEL assay. The components of neurotrophic support, astrogliosis, synaptic plasticity, and PQC processes were investigated by immunoblotting and immunostaining methods. H& E, Nissl body, and TUNEL staining revealed that diabetes-induced neuronal apoptosis and degeneration. However, B12 supplementation ameliorated the diabetes-induced neuronal apoptosis. Further, B12 supplementation restored the markers of neurotrophic support (BDNF, NGF, and GDNF), and synaptic plasticity (SYP, and PSD-95) in diabetic rats. Interestingly, B12 supplementation also attenuated astrogliosis, ER stress, and ameliorated autophagy-related proteins in diabetic rats. Overall, these findings suggest that B12 acts as a neuroprotective agent by inhibiting the neuropathological changes in STZ-induced type 1 diabetes. Thus, B12 supplementation could produce beneficial outcomes including neuroprotective effects in diabetic patients.

Diabetes mellitus is a multifactorial metabolic disease, of which type 2 diabetes (T2D) is one of the most common. The complications of diabetes are far more harmful than diabetes itself. Type 2 diabetes complications include diabetic nephropathy (DN), diabetic heart disease, diabetic foot ulcers (DFU), diabetic peripheral neuropathy (DPN), and diabetic retinopathy (DR) et al. Many animal models have been developed to study the pathogenesis of T2D and discover an effective strategy to treat its consequences. In this sense, it is crucial to choose the right animal model for the corresponding diabetic complication. This paper summarizes and classifies the animal modeling approaches to T2D complications and provides a comprehensive review of their advantages and disadvantages. It is hopeful that this paper will provide theoretical support for animal trials of diabetic complications.

The gut microbiome interacts with the brain bidirectionally through the microbiome-gutbrain axis, which plays a key role in regulating various nervous system pathophysiological processes. Trimethylamine N-oxide (TMAO) is produced by choline metabolism through intestinal microorganisms, which can cross the blood-brain barrier to act on the central nervous system. Previous studies have shown that elevated plasma TMAO concentrations increase the risk of major adverse cardiovascular events, but there are few studies on TMAO in cerebrovascular disease and vascular cognitive impairment. This review summarized a decade of research on the impact of TMAO on stroke and related cognitive impairment, with particular attention to the effects on vascular cognitive disorders. We demonstrated that TMAO has a marked impact on the occurrence, development, and prognosis of stroke by regulating cholesterol metabolism, foam cell formation, platelet hyperresponsiveness and thrombosis, and promoting inflammation and oxidative stress. TMAO can also influence the cognitive impairment caused by Alzheimer's disease and Parkinson's disease via inducing abnormal aggregation of key proteins, affecting inflammation and thrombosis. However, although clinical studies have confirmed the association between the microbiome-gut-brain axis and vascular cognitive impairment (cerebral small vessel disease and post-stroke cognitive impairment), the molecular mechanism of TMAO has not been clarified, and TMAO precursors seem to play the opposite role in the process of poststroke cognitive impairment. In addition, several studies have also reported the possible neuroprotective effects of TMAO. Existing therapies for these diseases targeted to regulate intestinal flora and its metabolites have shown good efficacy. TMAO is probably a new target for early prediction and treatment of stroke and vascular cognitive impairment.

The sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal antinociceptive effect is approximately 24 h following dosing. We sought to understand this unique antineuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout mice for Tmem97, we find that a σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce antinociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain.

Diabetic neuropathic pain is associated with elevated plasma levels of methylglyoxal (MGO). MGO is a metabolite of glycolysis that causes mechanical hypersensitivity in mice by inducing the integrated stress response (ISR), which is characterized by phosphorylation of eukaryotic initiation factor 2α (p-eIF2α). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the expression of antioxidant proteins that neutralize MGO. We hypothesized that activating Nrf2 using diroximel fumarate (DRF) would alleviate MGO-induced pain hypersensitivity. We pretreated male and female C57BL/6 mice daily with oral DRF prior to intraplantar injection of MGO (20 ng). DRF (100 mg/kg) treated animals were protected from developing MGO-induced mechanical and cold hypersensitivity. Using Nrf2 knockout mice we demonstrate that Nrf2 is necessary for the anti-nociceptive effects of DRF. In cultured mouse and human dorsal root ganglion (DRG) sensory neurons, we found that MGO induced elevated levels of p-eIF2α. Co-treatment of MGO (1 μM) with monomethyl fumarate (MMF, 10, 20, 50 μM), the active metabolite of DRF, reduced p-eIF2α levels and prevented aberrant neurite outgrowth in human DRG neurons. Our data show that targeting the Nrf2 antioxidant system with DRF is a strategy to potentially alleviate pain associated with elevated MGO levels.

Diabetic nephropathy (DN) is a common complication affecting many diabetic patients, leading to end-stage renal disease. However, its pathogenesis still needs to be fully understood to enhance the effectiveness of treatment methods. Traditional theories are predominantly centered on glomerular injuries and need more explicit explanations of recent clinical observations suggesting that renal tubules equally contribute to renal function and that tubular lesions are early features of DN, even occurring before glomerular lesions. Although the conventional view is that DN is not an inflammatory disease, recent studies indicate that systemic and local inflammation, including tubulointerstitial inflammation, contributes to the development of DN. In patients with DN, intrinsic tubulointerstitial cells produce many proinflammatory factors, leading to medullary inflammatory cell infiltration and activation of inflammatory cells in the interstitial region. Therefore, understanding the molecular mechanism of renal tubulointerstitial inflammation contributing to DN injury is of great significance and will help further identify key factors regulating renal tubulointerstitial inflammation in the high glucose environment. This will aid in developing new targets for DN diagnosis and treatment and expanding new DN treatment methods.

The Sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal anti-nociceptive effect is approximately 24 hours following dosing. We sought to understand this unique anti-neuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout (KO) mice for Tmem97, we find that a new σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce anti-nociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion (DRG) neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain.

Emerging evidence have shown the importance of gut microbiota in regulating brain functions. The diverse molecular mechanisms involved in cross-talk between gut and brain provide insight into importance of this communication in maintenance of brain homeostasis. It has also been observed that disturbed gut microbiota contributes to neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and aging. Recently, gut microbiome-derived exosomes have also been reported to play an essential role in the development and progression of neurodegenerative diseases and could thereby act as a therapeutic target. Further, pharmacological interventions including antibiotics, prebiotics and probiotics can influence gut microbiome-mediated management of neurological diseases. However, extensive research is warranted to better comprehend this interconnection in maintenance of brain homeostasis and its implication in neurological diseases. Thus, the present review is aimed to provide a detailed understanding of gut-brain axis followed by possibilities to target the gut microbiome for improving neurological health.

Diabetes prevalence continues to climb with the aging population. Type 2 diabetes (T2D), which constitutes most cases, is metabolically acquired. Diabetic peripheral neuropathy (DPN), the most common microvascular complication, is length-dependent damage to peripheral nerves. DPN pathogenesis is complex, but, at its core, it can be viewed as a state of impaired metabolism and bioenergetics failure operating against the backdrop of long peripheral nerve axons supported by glia. This unique peripheral nerve anatomy and the injury consequent to T2D underpins the distal-to-proximal symptomatology of DPN. Earlier work focused on the impact of hyperglycemia on nerve damage and bioenergetics failure, but recent evidence additionally implicates contributions from obesity and dyslipidemia. This review will cover peripheral nerve anatomy, bioenergetics, and glia-axon interactions, building the framework for understanding how hyperglycemia and dyslipidemia induce bioenergetics failure in DPN. DPN and painful DPN still lack disease-modifying therapies, and research on novel mechanism-based approaches is also covered.

Damage to the central or peripheral nervous system causes neuropathic pain. Endoplasmic reticulum (ER) stress plays a role in peripheral neuropathy. Increase in ER stress is seen in diabetic neuropathy. Inducers of ER stress also give rise to peripheral neuropathy. ER stress leads to the formation of autophagosome but as their degradation is also stalled during ER stress accumulation of autophagosomes is seen. Accumulation of autophagosomes has deleterious effects on cells. In the present study, we show that treatment with tunicamycin (TM) (ER stress inducer) in mice leads to peripheral neuropathy as assessed by Von Frey and Hot plate method. Administration of a promoter of autophagy viz. 6-bromoindirubin-3'-oxime (6-BIO) subsequent to ER stress induced by TM exhibits a decrease in peripheral neuropathy. 6-BIO was also effective in reducing diabetic peripheral neuropathy. To understand the type of autophagy activated, SH-SY5Y cells were treated with 6-BIO after TM treatment. Levels of cathepsin D (CTSD), a marker for degradative autophagy was higher in cells treated with 6-BIO after TM treatment compared to only TM-treated SH-SY5Y cells while levels of Rab8A,-a marker for secretory autophagy was reduced. Furthermore, in parallel during ER stress secretory, we noted increased levels of lysozyme in autophagosomes destined for secretion. Cells treated with 6-BIO showed reduction of lysozyme in secretory autophagosomes. This shows that 6-BIO increased degradative autophagy and reduced the secretory autophagy. 6-BIO also reduced the caspase-3 activity in 6-BIO-treated cells. Thus, 6-BIO reduced neuropathy in animals by activating degradative autophagy and reducing the secretory autophagy.

Endoplasmic stress response, the unfolded protein response (UPR), is a homeostatic signaling pathway comprising transmembrane sensors that get activated upon alterations in ER luminal environment. Studies suggest a relation between activated UPR pathways and several disease states such as Parkinson, Alzheimer, inflammatory bowel disease, tumor growth, and metabolic syndrome. Diabetic peripheral neuropathy (DPN), a common microvascular complication of diabetes-related chronic hyperglycemia, causes chronic pain, loss of sensation, foot ulcers, amputations, allodynia, hyperalgesia, paresthesia, and spontaneous pain. Factors like disrupted calcium signaling, dyslipidemia, hyperglycemia, inflammation, insulin signaling, and oxidative stress disturb the UPR sensor levels manifesting as DPN. We discuss new effective therapeutic alternatives for DPN that can be developed by targeting UPR pathways like synthetic ER stress inhibitors like 4-PhenylButyric acid (4-PBA), Sephin 1, Salubrinal and natural ER stress inhibitors like Tauroursodeoxycholic acid (TUDCA), Cordycepin, Proanthocyanidins, Crocin, Purple Rice extract and cyanidin and Caffeic Acid Phenethyl Ester (CAPE).

Diabetic peripheral neuropathy (DPN) is a major complication of diabetes. This study aimed to investigate the therapeutic effects and molecular mechanisms of Compound Qiying Granules (CQYG) for DPN.

Rats and RSC96 cells of DPN models were established to evaluate the therapeutic effects of CQYG. Then the morphology and apoptotic changes of sciatic nerves were detected. Further, tandem mass tag based quantitative proteomics technology was used to identify differentially expressed proteins (DEPs) and the underlying molecular mechanisms. Protein expression of key signaling pathways was also detected.

CQYG treatment significantly improved blood glucose and oxidative stress levels, and further reduced nerve fiber myelination lesions, denervation, and apoptosis in DPN rats. Further, 2176 DEPs were found in CQYG treated DPN rats. Enrichment analysis showed that protein processing in the endoplasmic reticulum (ER), and apoptosis were all inhibited after CQYG treatment. Next, CQYG treatment reduced inflammatory factor expression, mitochondrial damage, and apoptosis in RSC96 cells which induced by high glucose. Transmission electron microscopy results found that CQYG treatment improved the morphology of nerve myelin, mitochondria, and ER. CQYG treatment decreased ER stress and apoptosis pathway proteins that were highly expressed in DPN models. In addition, we also predicted the potential targets of CQYG in DEPs.

CQYG exerts neuroprotective effects in experimental diabetic neuropathy through anti-ER stress and anti-apoptosis.

Diffusion tensor imaging (DTI) has found clinical applications in the evaluation of the central nervous system and has been extensively used to image peripheral neuropathy. However, few studies have focused on lumbosacral nerve root fiber damage in diabetic peripheral neuropathy (DPN). The aim of the study was to evaluate whether DTI of the lumbosacral nerve roots can be used to detect DPN.

Thirty-two type 2 diabetic patients with DPN and thirty healthy controls (HCs) were investigated with a 3T MRI scanner. DTI with tractography of the L4, L5, and S1 nerve roots was performed. Anatomical fusion with the axial T2 sequences was used to provide correlating anatomical information. Mean fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were measured from tractography images and compared between groups. Diagnostic value was assessed using receiver operating characteristic (ROC) analysis. The Pearson correlation coefficient was used to explore the correlation between DTI parameters and clinical data and the nerve conduction study (NCS) in the DPN group.

In the DPN group, FA was decreased (p < 0.001) and ADC was increased (p < 0.001) compared with the values of the HC group. FA displayed the best diagnostic accuracy, with an area under the ROC curve of 0.716. ADC was positively correlated with HbA1c level (r = 0.379, p = 0.024) in the DPN group.

DTI of lumbosacral nerve roots demonstrates appreciable diagnostic accuracy in patients with DPN.

Diabetic neuropathy (DN) is a type of nerve damage and the most common complication of diabetes. Regarding the association between endoplasmic reticulum (ER) stress with the pathogenesis of neuropathy, this study aims to examine binding immunoglobulin protein (BiP) gene expression and long noncoding RNA nuclear enriched abundant transcript 1 (NEAT1), miR-199a-5 as its regulator in the peripheral blood of DN patients compared to diabetic patients without neuropathy.

Peripheral blood samples were obtained from DN (n = 20) patients and diabetic patients without neuropathy (non-DN) (n = 20). After RNA extraction from peripheral blood mononuclear cells, reverse transcription-quantitative polymerase chain reaction was performed to evaluate RNA expression.

The results showed that the expression level of NEAT1 and BiP genes in the DN group increased significantly compared to the non-DN group. Also, the expression level of miR-199a-5p in the DN group was significantly downregulated.

As a result, the axis of NEAT1, miR-199a-5p, and BiP may have a role in the DN pathogenesis.

C-peptide therapy exerts several positive actions on nerves, vasculature, smooth muscle relaxation, kidney function and bone. To date, the role of C-peptide in preventing type 1 diabetes-related muscle atrophy has not been investigated. Our aim was to evaluate if C-peptide infusion prevents muscle wasting in diabetic rats.

Twenty-three male Wistar rats were randomly divided into three groups: normal control group, diabetic group and diabetic group plus C-peptide. Diabetes was induced by streptozotocin injection, and C-peptide was administered subcutaneously for 6 weeks. The blood samples were obtained at baseline, before streptozotocin injection and at the end of the study to assess C-peptide, ubiquitin and other laboratory parameters. We also tested the ability of C-peptide to regulate the skeletal muscle mass, the ubiquitin-proteasome system, the autophagy pathway as well as to improve muscle quality.

C-peptide administration reversed hyperglycaemia (P = 0.02) and hypertriglyceridaemia (P = 0.01) in diabetic plus C-peptide rats compared with diabetic control rats. The diabetic-control animals displayed a lower weight of the muscles in the lower limb considered individually than the control rats and the diabetic plus C-peptide rats (P = 0.03; P = 0.03; P = 0.04; P = 0.004, respectively). The diabetic-control rats presented a significantly higher serum concentration of ubiquitin compared with the diabetic plus C-peptide and the control animals (P = 0.02 and P = 0.01). In muscles of the lower limb, the pAmpk expression was higher in the diabetic plus C-peptide than the diabetic-control rats (in the gastrocnemius, P = 0.002; in the tibialis anterior P = 0.005). The protein expression of Atrogin-1 in gastrocnemius and tibialis was lower in the diabetic plus C-peptide than in diabetic-control rats (P = 0.02, P = 0.03). After 42 days, the cross-sectional area in the gastrocnemius of the diabetic plus C-peptide group had been reduced by 6.6% while the diabetic-control rats had a 39.5% reduction compared with the control animals (P = 0.02). The cross-sectional area of the tibialis and the extensor digitorum longus muscles was reduced, in the diabetic plus C-peptide rats, by 10% and 11%, respectively, while the diabetic-control group had a reduction of 65% and 45% compared with the control animals (both P < 0.0001). Similar results were obtained for the minimum Feret's diameter and perimeter.

C-peptide administration in rats could protect skeletal muscle mass from atrophy induced by type 1 diabetes mellitus. Our findings could suggest that targeting the ubiquitin-proteasome system, Ampk and muscle-specific E3 ubiquitin ligases such as Atrogin-1 and Traf6 may be an effective strategy for molecular and clinical intervention in the muscle wasting pathological process in T1DM.

Morbidity and mortality of cardiovascular diseases (CVDs) are exceedingly high worldwide. Researchers have found that the occurrence and development of CVDs are closely related to intestinal microecology. Imbalances in intestinal microecology caused by changes in the composition of the intestinal microbiota will eventually alter intestinal metabolites, thus transforming the host physiological state from healthy mode to pathological mode. Trimethylamine N-oxide (TMAO) is produced from the metabolism of dietary choline and L-carnitine by intestinal microbiota, and many studies have shown that this important product inhibits cholesterol metabolism, induces platelet aggregation and thrombosis, and promotes atherosclerosis. TMAO is directly or indirectly involved in the pathogenesis of CVDs and is an important risk factor affecting the occurrence and even prognosis of CVDs. This review presents the biological and chemical characteristics of TMAO, and the process of TMAO produced by gut microbiota. In particular, the review focuses on summarizing how the increase of gut microbial metabolite TMAO affects CVDs including atherosclerosis, heart failure, hypertension, arrhythmia, coronary artery disease, and other CVD-related diseases. Understanding the mechanism of how increases in TMAO promotes CVDs will potentially facilitate the identification and development of targeted therapy for CVDs.