Rangjuan Cao

Effective nerve regeneration depends on the precise spatiotemporal coordination of immune responses and adaptive angiogenesis, often driven by injury‐induced hypoxia. However, how early hypoxic signals are sensed and translated into vascular niches remains poorly understood. Using peripheral nerve injury as a model, we show that hypoxia exerts stage‐specific functions dictating regenerative outcomes. Suppressing the early hypoxic response by premature oxygen supplementation lowers HIF‐1α, attenuates angiogenesis, and ultimately compromises long‐term regeneration, whereas prolonged hypoxia ex vivo causes axonal and myelin injury. Using spatiotemporal hypoxia mapping, genetic mouse models, and human nerve specimens, we identify Disabled‐1 (Dab1) as a previously unrecognized hypoxia‐responsive adaptor that is prominently induced in macrophages and links hypoxia to angiogenesis. Macrophage‐specific Dab1 deletion diminishes HIF‐1α/VEGF‐A signaling, impairs vascular remodeling, and delays nerve regeneration, whereas enhancing Dab1 signaling improves the regenerative microenvironment. Mechanistically, Dab1 sustains hypoxia‐associated HIF‐1α accumulation, partially through the Na ⁺ /H ⁺ exchanger NHE1, maintaining a pro‐angiogenic program in macrophages. Furthermore, the clinically approved drug valproic acid promotes angiogenesis and functional recovery by enhancing macrophage Dab1 signaling within an early therapeutic window. Together, these findings identify macrophage Dab1 as a crucial regulator of vascular‐immune crosstalk, highlighting therapies that balance early hypoxic signaling with timely vascular reconstruction.

Background: Ion homeostasis is disrupted following nerve injury, and elevated Ca²⁺ levels have been reported to induce Schwann cell (SC) death. Notably, clinical interventions such as electrical stimulation enhance Ca²⁺ influx and facilitate nerve regeneration. These findings highlight the need to clarify the precise role of Ca²⁺ signaling in nerve regeneration.

Neuropathic pain is a chronic condition with limited effective treatments, closely associated with astrocytes and their role in central sensitization. Apolipoprotein E (ApoE), predominantly expressed in astrocytes in central nervous system, exists in three ApoE isoforms (ApoE2, ApoE3, and ApoE4) in humans, with ApoE4 linked to increased susceptibility to neurological diseases. However, the relationship between ApoE4 and neuropathic pain, as well as underlying mechanisms, remains poorly understood. Here, we demonstrated that mice expressing human ApoE4 (ApoE4-TR) displayed increased pain sensitivity following spared nerve injury (SNI) compared to ApoE3-TR mice. This increased sensitivity was also observed in mice with astrocyte-specific expression of ApoE4, achieved through Cre-mediated recombination. Metabolomic profiling revealed reduced spermidine levels in the spinal dorsal horn of ApoE4-TR mice relative to ApoE3-TR mice. Daily gavage administration of spermidine alleviated mechanical pain to a comparable level in ApoE3-TR and ApoE4-TR mice, as assessed by von Frey test. However, lower dose of spermidine effectively alleviated neuropathic pain in ApoE3-TR mice but showed reduced efficacy in ApoE4-TR mice, likely due to limited spermidine retention in ApoE4 astrocytes, as demonstrated in vitro. Transcriptomic analysis identified Nos2 as a critical gene upregulated in ApoE4-TR mice. Mechanistically, spermidine suppressed Nos2 expression by inhibiting the NF-κB pathway in astrocytes, thereby alleviating neuropathic pain. These findings highlight an enhanced pain sensitivity associated with ApoE4 and suggest spermidine as a potential therapeutic strategy, emphasizing a tailored dosage approach for ApoE4 carriers.

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. Although studies have previously investigated metabolic disruptions in the peripheral nervous system (PNS), the exact metabolic mechanisms underlying DPN remain largely unknown. Herein, a specific form of metabolic remodeling involving aberrant ketogenesis within Schwann cells (SCs) in streptozotocin (STZ)‐induced type I diabetes mellitus is identified. The PNS adapts poorly to such aberrant ketogenesis, resulting in disrupted energy metabolism, mitochondrial damage, and homeostatic decompensation, ultimately contributing to DPN. Additionally, the maladaptive peripheral ketogenesis is highly dependent on the cannabinoid type‐1 receptor (CB₁R)‐Hmgcs2 axis. Silencing CB₁R reprogrammed the metabolism of SCs by blocking maladaptive ketogenesis, resulting in rebalanced energy metabolism, reduced histopathological changes, and improved neuropathic symptoms. Moreover, this metabolic reprogramming can be induced pharmacologically using JD5037, a peripheral CB₁R blocker. These findings revealed a new metabolic mechanism underlying DPN, and promoted CB₁R as a promising therapeutic target for DPN.

Neuropathic pain poses a significant clinical challenge, largely due to the incomplete understanding of its molecular mechanisms, particularly the role of mitochondrial dysfunction. Bioinformatics analysis revealed that pyroptosis and inflammatory responses induced by spared nerve injury (SNI) in the spinal dorsal horn play a critical role in the initiation and persistence of neuropathic pain. Among the factors involved, TSPO (translocator protein) emerged as a key regulator. Our experimental findings showed that TSPO expression was upregulated during neuropathic pain, accompanied by mitochondrial dysfunction, specifically manifested as impaired mitochondrial biogenesis, disrupted mitochondrial dynamics (including insufficient expression of mitochondrial biogenesis and fusion-related proteins, as well as significantly increased expression of fission-related proteins), and activation of pyroptosis. Pharmacological upregulation of TSPO, but not its downregulation, effectively alleviated SNI-induced pain hypersensitivity, improving mitochondrial function and reducing pyroptosis. Immunofluorescence staining confirmed that TSPO was primarily localized in astrocytes, and its expression mirrored the protective effects on mitochondrial health and pyroptosis prevention. PCR array analysis suggested a strong association between TSPO and the mitochondrial regulation pathway AMPK-PGC-1α. Notably, inhibition of AMPK-PGC-1α abolished TSPO effects on mitochondrial balance and pyroptosis suppression. Furthermore, Mendelian randomization analysis of GWAS data indicated that increased TSPO expression was linked to pain relief. Through drug screening, molecular docking, and behavioral assays, we identified zopiclone as a promising TSPO-targeting drug for pain treatment. In summary, this study enhances our understanding of the molecular interplay between TSPO, mitochondrial health, and neuropathic pain, highlighting TSPO as a potential therapeutic target for pain management.

Background: Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes and the main cause of non-traumatic amputation, with no ideal treatment. Multiple cell-derived exosomes have been reported to improve the progression of DPN. Blood therapy is thought to have a powerful repairing effect. However, whether it could also improve DPN remains unclear. Results: In this study, we found that microRNA (miRNA) expression in plasma-derived exosomes of healthy rats (hplasma-exos) was significantly different from that of age-matched DPN rats. By injection of hplasma-exos into DPN rats, the mechanical sensitivity of DPN rats was decreased, the thermal sensitivity and motor ability were increased, and the nerve conduction speed was accelerated. Histological analysis showed myelin regeneration of the sciatic nerve, increased intraepidermal nerve fibers, distal local blood perfusion, and enhanced neuromuscular junction and muscle spindle innervation after hplasma-exos administration. Compared with plasma exosomes in DPN, miR-20b-3p was specifically enriched in exosomes of healthy plasma and was found to be re-upregulated in the sciatic nerve of DPN rats after hplasma-exos treatment. Moreover, miR-20b-3p agomir improved DPN symptoms to a level similar to hplasma-exos, both of which also alleviated autophagy impairment induced by high glucose in Schwann cells. Mechanistic studies found that miR-20b-3p targeted Stat3 and consequently reduced the amount of p-Stat3, which then negatively regulated autophagy processes and contributed to DPN improvement. Conclusions: This study demonstrated that miRNA of plasma exosomes was different between DPN and age-matched healthy rats. MiR-20b-3p was enriched in hplasma-exos, and both of them could alleviated DPN symptoms. MiR-20b-3p regulated autophagy of Schwann cells in pathological states by targeting Stat3 and thereby inhibited the progression of DPN. Graphical

Background: Maintaining the repair phenotype of denervated Schwann cells in the injured distal nerve is crucial for promoting peripheral nerve regeneration. However, when chronically denervated, the capacity of Schwann cells to support repair and regeneration deteriorates, leading to peripheral nerve regeneration and poor functional recovery. Herein, we investigated whether neurotrophin-3 (NT-3) could sustain the reparative phenotype of Schwann cells and promote peripheral nerve regeneration after chronic denervation and aimed to uncover its potential molecular mechanisms. Methods: Western blot was employed to investigate the relationship between the expression of c-Jun and the reparative phenotype of Schwann cells. The inducible expression of c-Jun by NT-3 was examined both in vitro and in vivo with western blot and immunofluorescence staining. A chronic denervation model was established to study the role of NT-3 in peripheral nerve regeneration. The number of regenerated distal axons, myelination of regenerated axons, reinnervation of neuromuscular junctions, and muscle fiber diameters of target muscles were used to evaluate peripheral nerve regeneration by immunofluorescence staining, transmission electron microscopy (TEM), and hematoxylin and eosin (H&E) staining. Adeno-associated virus (AAV) 2/9 carrying shRNA, small molecule inhibitors, and siRNA were employed to investigate whether NT-3 could signal through the TrkC/ERK pathway to maintain c-Jun expression and promote peripheral nerve regeneration after chronic denervation. Results: After peripheral nerve injury, c-Jun expression progressively increased until week 5 and then began to decrease in the distal nerve following denervation. NT-3 upregulated the expression of c-Jun in denervated Schwann cells, both in vitro and in vivo. NT-3 promoted peripheral nerve regeneration after chronic denervation, mainly by upregulating or maintaining a high level of c-Jun rather than NT-3 itself. The TrkC receptor was consistently presented on denervated Schwann cells and served as NT-3 receptors following chronic denervation. NT-3 mainly upregulated c-Jun through the TrkC/ERK pathway. Conclusion: NT-3 promotes peripheral nerve regeneration by maintaining the repair phenotype of Schwann cells after chronic denervation via the TrkC/ERK/c-Jun pathway. It provides a potential target for the clinical treatment of peripheral nerve injury after chronic denervation.

Proprioception is sensed by muscle spindles for precise locomotion and body posture. Unlike the neuromuscular junction (NMJ) for muscle contraction which has been well studied, mechanisms of spindle formation are not well understood. Here we show that sensory nerve terminals are disrupted by the mutation ofLrp4, a gene required for NMJ formation; inducible knockout ofLrp4in adult mice impairs sensory synapses and movement coordination, suggesting that LRP4 is required for spindle formation and maintenance. LRP4 is critical to the expression of Egr3 during development; in adult mice, it interacts in trans with APP and APLP2 on sensory terminals. Finally, spindle sensory endings and function are impaired in aged mice, deficits that could be diminished by LRP4 expression. These observations uncovered LRP4 as an unexpected regulator of muscle spindle formation and maintenance in adult and aged animals and shed light on potential pathological mechanisms of abnormal muscle proprioception.

Background: Telemedicine based on wearable intelligent health devices becomes increasingly promissing for the elderly due to the accelerated aging population. Especially during COVID-19 pandemic, more elderly coronary heart disease patients with chronic comorbidities are in less secondary prevention management at home. Objective: To explore the prevention effect on main cardiovascular risk factors and repeated hospitalization in elderly comorbidities patients by telemedicine intervention based on multi-parameter wearable monitoring devices. Methods: Total of 337 patients with comorbidities of coronary heart disease, hypertension and diabetes, with age more than 65 years old were recruited in the study from October 2019 to January 2021. They were randomly divided into control group and telemedcine intervention group. The latter used remote multi-parameter wearable devices to measure blood pressure, glycemic and electrocardiograph at home every day. A real-time monitoring platform would alarm any abnormal data to the doctors. Both doctors and patients can read the measurement results on a real-time mobile phone APP and interact with each other remotely twice a week routinely. A medical team remotely indicated the medications, while offering guidance on lifestyle. In contrast, the control group adopted traditional outpatient medical strategy to manage diseases. Results: A total of 306 patients were enrolled in the follow-up experiment finally: 153 in the intervention group and 153 in the control group. Patient characteristics at baseline were balanced between two groups. After 12 months, compared with the control group, the intervention group saw the following metrics significantly reduced: systolic blood pressure (SBP) (131.66±9.43 vs 137.20±12.02 mmHg, P=0.000), total cholesterol (TC) (3.65±0.79 vs 4.08±0.82 mmol/L, P=0.001), low density lipoprotein cholesterol (LDL-C) (2.06±0.53 vs 2.38±0.61 mmol/L, P=0.002), and fasting blood glucose (FBG) (6.26±0.75 vs 6.81±0.97 mmol/L, P=0.000), while the following metrics went up significantly: blood pressure control rate (77.3% vs 59.1%, P=0.039), blood lipid control rate(39.4% vs 21.2%, P=0.037), glycemic control rate (71.2% vs 51.5%, P=0.031), and medication adherence score (7.10±0.77 vs 6.80±0.73, P=0.020). Linear regression model analysis indicates that when interaction frequency ≥1.53, 2.47 and 1.15 times/week, the SBP, LDL-C and FBG levels would be controlled, respectively. Cox survival analysis finds that the hospitalization rate of intervention group is significantly lower than that of the control group (24.18% vs 35.29%, P=0.031). Conclusion: The telemedicine interactive intervention based on multi-parameter wearable devices provides effectively improvement of cardiovascular risk controlling, medication adherence, while reducing the hospitalization rate of patients. A frequency of doctor-patient interactions more than 2 times/week is beneficial for disease management the elderly at home. Funding Acknowledgement: Type of funding sources: Foundation. Main funding source(s): Key scientific research project of Health Commission