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In this work, photophysical properties of the flavone-based dyes APG, BCN, CYS, LUT, and OX-A were investigated using TD-DFT calculations at PBE0/6-311++G (d,p) level in the gas phase and solvent media. The structural parameters, absorption and emission spectra, potential energy curves, natural charges, electron density properties, reduced density gradient, and protein–ligand docking properties were calculated. In the S1 state, the normal form of all dyes was directly converted to its tautomeric T form by no energy barrier. The results demonstrated that O1–H2···O6 H-bonding at S0 state is stronger than O1···H2–O6 one at S1 state. Upon photoexcitation to the S1 state, the flavones exhibit keto fluorescence emission in the near-infrared (NIR) wavelengths of 848.0 nm for APG to 1143.1 nm for OX-A, making the application of these molecules more attractive in the medical and physiological diagnostics. In addition, the anti-aging properties of the flavonoids were studied by docking process on the two aging targets brain-derived neurotrophic factor (BDNF) and nerve growth factors (NGF). Our study can provide insights into the design of a flavone-based ESIPT fluorescent probe and its anti-aging properties which might inspire future applications in the field of chemical sensing, imaging and drug design. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Results Conclusions and Implications Retinal ganglion cells (RGCs) are the output stage of retinal information processing, via their axons forming the optic nerve (ON). ON damage leads to axonal degeneration and death of RGCs, and results in vision impairment. Nerve growth factor (NGF) signalling is crucial for RGC operations and visual functions. Here, we investigate a new neuroprotective mechanism of a novel therapeutic candidate, a p75‐less, TrkA‐biased NGF agonist (hNGFp) in rat RGC degeneration, in comparison with wild type human NGF (hNGFwt).Both neonate and adult rats, whether subjected or not to ON lesion, were treated with intravitreal injections or eye drops containing either hNGFp or hNGFwt. Different doses of the drugs were administered at days 1, 4 or 7 after injury for a maximum of 10 days, when immunofluorescence, electrophysiology, cellular morphology, cytokine array and behaviour studies were carried out. Pharmacokinetic evaluation was performed on rabbits treated with hNGFp ocular drops.hNGFp exerted a potent RGC neuroprotection by acting on microglia cells, and outperformed hNGFwt in rescuing RGC degeneration and reducing inflammatory molecules. Delayed use of hNGFp after ON lesion resulted in better outcomes compared with treatment with hNGFwt. Moreover, hNGFp‐based ocular drops were less algogenic than hNGFwt. Pharmacokinetic measurements revealed that biologically relevant quantities of hNGFp were found in the rabbit retina.Our data point to microglia as a new cell target through which NGF‐induced TrkA signalling exerts neuroprotection of the RGC, emphasizing hNGFp as a powerful treatment to tackle retinal degeneration. [ABSTRACT FROM AUTHOR]

Sulforaphane is a natural compound with neuroprotective activity, but its effects on hypothalamus remain unknown. In line with this, astrocytes are critical cells to maintain brain homeostasis, and hypothalamic astrocytes are fundamental for sensing and responding to environmental changes involved in a variety of homeostatic functions. Changes in brain functionality, particularly associated with hypothalamic astrocytes, can contribute to age-related neurochemical alterations and, consequently, neurodegenerative diseases. Thus, here, we investigated the glioprotective effects of sulforaphane on hypothalamic astrocyte cultures and hypothalamic cell suspension obtained from aged Wistar rats (24 months old). Sulforaphane showed anti-inflammatory and antioxidant properties, as well as modulated the mRNA expression of astroglial markers, such as aldehyde dehydrogenase 1 family member L1, aquaporin 4, and vascular endothelial growth factor. In addition, it increased the expression and extracellular levels of trophic factors, such as glia-derived neurotrophic factor and nerve growth factor, as well as the release of brain-derived neurotrophic factor and the mRNA of TrkA, which is a receptor associated with trophic factors. Sulforaphane also modulated the expression of classical pathways associated with glioprotection, including nuclear factor erythroid-derived 2-like 2, heme oxygenase-1, nuclear factor kappa B p65 subunit, and AMP-activated protein kinase. Finally, a cell suspension with neurons and glial cells was used to confirm the predominant effect of sulforaphane in glial cells. In summary, this study indicated the anti-aging and glioprotective activities of sulforaphane in aged astrocytes. [ABSTRACT FROM AUTHOR]

Summary: Objective: Children with overweight/obesity (OW/OB) exhibit poor cardiometabolic health, yet mechanisms influencing brain health remain unclear. We examined the differences in neurological‐related circulating proteins in plasma among children with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) and the association with metabolic syndrome markers. Methods: In this cross‐sectional study, we included 84 Caucasian children (39% girls), aged 10.1 ± 1.1 years, from the ActiveBrains project (NCT02295072). A ninety‐two‐protein targeted approach using Olink's® technology was used. Results: We identified distinct concentrations of CD38, LAIR2, MANF and NRP2 proteins in MHO compared with MUO. Moreover, individual metabolic syndrome (MS) markers were linked to nine proteins (CD38, CPM, EDA2R, IL12, JAMB, KYNU, LAYN, MSR1 and SMOC2) in children with OW/OB. These proteins play crucial roles in diverse biological processes (e.g., angiogenesis, cholesterol transport, nicotinamide adenine dinucleotide (NAD+) catalysis and maintenance of blood–brain barrier) related to brain health. Conclusion: Our proteomics study suggests that cardiometabolic health (represented by MHO/MUO or individual MS markers) is associated with the concentration in plasma of several proteins involved in brain health. Larger‐scale studies are needed to contrast/confirm these findings, with CD38 standing out as a particularly noteworthy and robust discovery. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM), an important public health problem, aggravates the global economic burden. Diabetic encephalopathy (DE) is a serious complication of DM in the central nervous system. Metformin has been proven to improve DE. However, the mechanism is still unclear. In this study, the db/db mice, a common model used for DE, were employed to explore and study the neuroprotective effect of metformin and related mechanisms. Behavioral tests indicated that metformin (100 or 200 mg/kg/day) could significantly improve the learning and memory abilities of db/db mice. The outcomes from the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) demonstrate that metformin effectively modulates glucose and insulin signaling pathways in db/db mice. The results of body weight and blood lipid panel (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) show that metformin promotes the level of lipid metabolism in db/db mice. Furthermore, data from oxidative stress assays, which measured levels of malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase, suggest that metformin suppresses oxidative stress–induced brain damage in db/db mice. In addition, western blot, Nissl staining, and immunofluorescence results showed that metformin increased the expressions of nerve growth factor and postsynaptic density 95 and repaired neuronal structural damage. For the mechanism study, metformin activated SIRT1 and inhibited the expression of NLRP3 inflammasome (NLRP3, ASC, caspase-1, IL-1β, and IL-18) and inflammatory cytokines (TNFα and IL-6). In conclusion, metformin could ameliorate cognitive dysfunction through the SIRT1/NLRP3 pathway, which might be a promising mechanism for DE treatment. [ABSTRACT FROM AUTHOR]

The regeneration of peripheral nerves after injury is often slow and impaired, which may be associated with weakened and denervated muscles subsequently leading to atrophy. Adipose-derived stem cells (ADSCs) are often regarded as cell-based therapeutic candidate due to their regenerative potential. The study aims to assess the therapeutic efficacy of gene-modified ADSCs on sciatic nerve injury. We lentivirally transduced ADSCs with shRNA-TWIST1 and transplanted modified cells to rats undergoing sciatic nerve transection and repair. Results showed that TWIST1 knockdown accelerated functional recovery of rats with sciatic nerve injury as faster nerve conduction velocity and higher wire hang scores obtained by rats transplanted with TWIST1-silenced ADSCs than scramble ADSCs. Although the rats experienced degenerated axons and decreased myelin sheath thickness after sciatic nerve injury 8 weeks after operation, those transplanted with TWIST1-silenced ADSCs exhibited more signs of regenerated nerve fibers surrounded by newly formed myelin sheaths than those with scramble ADSCs. The rats transplanted with TWIST1-silenced ADSCs presented increased expressions of neurotrophic factors including neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) in the sciatic nerves than those with scramble ADSCs. These results suggest that genetically modifying TWIST1 in ADSCs could facilitate peripheral nerve repair after injury in a more efficient way than that with ADSCs alone. [ABSTRACT FROM AUTHOR]

Low back pain (LBP) has become a leading cause of disability worldwide. Astrocyte activation in the spinal cord plays an important role in the maintenance of latent sensitization of dorsal horn neurons in LBP. However, the role of spinal c-Jun N-terminal kinase (JNK) in astrocytes in modulating pain behavior of LBP model rats and its neurobiological mechanism have not been elucidated. Here, we investigate the role of the JNK signaling pathway on hypersensitivity and anxiety-like behavior caused by repetitive nerve growth factor (NGF) injections in male non-specific LBP model rats. LBP was produced by two injections (day 0, day 5) of NGF into multifidus muscle of the low backs of rats. We observed prolonged mechanical and thermal hypersensitivity in the low backs or hindpaws. Persistent anxiety-like behavior was observed, together with astrocyte, p-JNK, and neuronal activation and upregulated expression of monocyte chemoattractant protein-1 (MCP-1), and chemokine (C-X-C motif) ligand 1 (CXCL1) proteins in the spinal L2 segment. Second, the JNK inhibitor SP600125 was intrathecally administrated in rats from day 10 to day 12. It attenuated mechanical and thermal hypersensitivity of the low back or hindpaws and anxiety-like behavior. Meanwhile, SP600125 decreased astrocyte and neuronal activation and the expression of MCP-1 and CXCL1 proteins. These results showed that hypersensitivity and anxiety-like behavior induced by NGF in LBP rats could be attenuated by the JNK inhibitor, together with downregulation of spinal astrocyte activation, neuron activation, and inflammatory cytokines. Our results indicate that intervening with the spinal JNK signaling pathway presents an effective therapeutic approach to alleviating LBP. [ABSTRACT FROM AUTHOR]

Acetylcholine regulates various cognitive functions through broad cholinergic innervation. However, specific cholinergic subpopulations, circuits and molecular mechanisms underlying recognition memory remain largely unknown. Here we show that Ngfr+ cholinergic neurons in the substantia innominate (SI)/nucleus basalis of Meynert (nBM)-medial prefrontal cortex (mPFC) circuit selectively underlies recency judgements. Loss of nerve growth factor receptor (Ngfr−/− mice) reduced the excitability of cholinergic neurons in the SI/nBM-mPFC circuit but not in the medial septum (MS)-hippocampus pathway, and impaired temporal order memory but not novel object and object location recognition. Expression of Ngfr in Ngfr−/− SI/nBM restored defected temporal order memory. Fiber photometry revealed that acetylcholine release in mPFC not only predicted object encounters but also mediated recency judgments of objects, and such acetylcholine release was absent in Ngfr−/− mPFC. Chemogenetic and optogenetic inhibition of SI/nBM projection to mPFC in ChAT-Cre mice diminished mPFC acetylcholine release and deteriorated temporal order recognition. Impaired cholinergic activity led to a depolarizing shift of GABAergic inputs to mPFC pyramidal neurons, due to disturbed KCC2-mediated chloride gradients. Finally, potentiation of acetylcholine signaling upregulated KCC2 levels, restored GABAergic driving force and rescued temporal order recognition deficits in Ngfr−/− mice. Thus, NGFR-dependent SI/nBM-mPFC cholinergic circuit underlies temporal order recognition memory. Functional roles of the diverse cholinergic subpopulations such as those in the substantia innominate (SI) and the nucleus basalis of Meynert (nBM) are not fully understood. Here the authors show that Ngfr+ cholinergic neurons in the SI/nBM-mPFC circuit selectively regulates recency judgement in recognition memory. [ABSTRACT FROM AUTHOR]

Lower back pain (LBP) is a common condition closely associated with intervertebral disc degeneration (IDD), causing a significant socioeconomic burden. Inflammatory activation in degenerated discs involves pro-inflammatory cytokines, dysregulated regulatory cytokines, and increased levels of nerve growth factor (NGF), leading to further intervertebral disc destruction and pain sensitization. Macrophage polarization is closely related to autophagy. Based on these pathological features, a structured biomimetic nanoparticle coated with TrkA-overexpressing macrophage membranes (TMNP@SR) with a rapamycin-loaded mesoporous silica core is developed. TMNP@SR acted like sponges to adsorbe inflammatory cytokines and NGF and delivers the autophagy regulator rapamycin (RAPA) into macrophages through homologous targeting effects of the outer engineered cell membrane. By regulating autophagy activation, TMNP@SR promoted the M1-to-M2 switch of macrophages to avoid continuous activation of inflammation within the degenerated disc, which prevented the apoptosis of nucleus pulposus cells. In addition, TMNP@SR relieved mechanical and thermal hyperalgesia, reduced calcitonin gene-related peptide (CGRP) and substance P (SP) expression in the dorsal root ganglion, and downregulated GFAP and c-FOS signaling in the spinal cord in the rat IDD model. In summary, TMNP@SR spontaneously inhibits the aggravation of disc inflammation to alleviate disc degeneration and reduce the ingress of sensory nerves, presenting a promising treatment strategy for LBP induced by disc degeneration. [ABSTRACT FROM AUTHOR]

Simple Summary: In this work, we documented the presence of two neurotrophins NGF (Nerve Growth Factor) and BDNF (Brain-Derived Neurotrophic Factor) in the pancreas of two species of marine mammals, Tursiops truncatus (common bottlenose dolphin) and Otaria flavescens (South American sea lion). Pancreas samples were provided by the Mediterranean Marine Mammal Tissue Bank of the Department of Comparative Biomedicine and Food Science of the University of Padua (Italy). These two growth factors are well-known mediators for maintaining the survival of neurons but also exert a metabotrophic effect. The localization in the pancreas of bottlenose dolphins and sea lions of these neurotrophins could help to better understand how these marine animals handle metabolic challenges in their adaptation to ocean life. In this study, we have investigated the immunolocalization of NGF (Nerve Growth Factor) and BDNF (Brain-Derived Neurotrophic Factor) in the pancreas of two species of marine mammals: Tursiops truncatus (common bottlenose dolphin), belonging to the order of the Artiodactyla, and Otaria flavescens (South American sea lion), belonging to the order of the Carnivora. Our results demonstrated a significant presence of NGF and BDNF in the pancreas of both species with a wide distribution pattern observed in the exocrine and endocrine components. We identified some differences that can be attributed to the different feeding habits of the two species, which possess a different morphological organization of the digestive system. Altogether, these preliminary observations open new perspectives on the function of neurotrophins and the adaptive mechanisms of marine mammals in the aquatic environment, suggesting potential parallels between the physiology of marine and terrestrial mammals. [ABSTRACT FROM AUTHOR]

Background: Sepsis is a life-threatening condition that is characterized by multiorgan dysfunction and caused by dysregulated cytokine networks, which are closely associated with sepsis progression and outcomes. However, currently available treatment strategies that target cytokines have failed. Thus, this study aimed to investigate the interplay between genetically predicted circulating concentrations of cytokines and the outcomes of sepsis and to identify potential targets for sepsis treatment. Methods: Data related to 35 circulating cytokines in 31,112 individuals (including 11,643 patients with sepsis) were included in genome-wide association studies (GWASs) from the UK Biobank and FinnGen consortia. A bidirectional two-sample Mendelian randomization (MR) analysis was performed using single nucleotide polymorphisms (SNPs) to evaluate the causal effects of circulating cytokines on sepsis outcomes and other cytokines. Results: A total of 35 inflammatory cytokine genes were identified in the GWASs, and 11 cytokines, including Interleukin-1 receptor antagonist (IL-1ra), macrophage inflammatory protein 1 (MIP1α), IL-16, et al., were associated with sepsis outcome pairs according to the selection criteria of the cis-pQTL instrument. Multiple MR methods verified that genetically predicted high circulating levels of IL-1ra or MIP1α were negatively correlated with genetic susceptibility to risk of sepsis, including sepsis (28-day mortality), septicaemia, streptococcal and pneumonia-derived septicaemia (P ≤ 0.01). Furthermore, genetic susceptibility of sepsis outcomes except sepsis (28-day mortality) markedly associated with the circulating levels of five cytokines, including active plasminogen activator inhibitor (PAI), interleukin 7 (IL-7), tumour necrosis factor alpha (TNF-α), beta nerve growth factor (NGF-β), hepatic growth factor (HGF) (P < 0.05). Finally, we observed that the causal interaction network between MIP1α or IL-1ra and other cytokines (P < 0.05). Conclusions: This comprehensive MR analysis provides insights into the potential causal mechanisms that link key cytokines, particularly MIP1α, with risk of sepsis, and the findings suggest that targeting MIP1α may be a potential strategy for preventing sepsis. [ABSTRACT FROM AUTHOR]

Observational studies suggest dyslipidemia as an atopic dermatitis (AD) risk factor and posit that lipid-lowering drugs may influence AD risk, but the causal link remains elusive. Mendelian randomization was applied to elucidate the causal role of serum lipids in AD and assess the therapeutic potential of lipid-lowering drug targets. Genetic variants related to serum lipid traits and lipid-lowering drug targets were sourced from the Global Lipid Genetics Consortium GWAS data. Comprehensive AD data were collated from the UK Biobank, FinnGen, and Biobank Japan. Colocalization, Summary-data-based Mendelian Randomization (SMR), and mediation analyses were utilized to validate the results and pinpoint potential mediators. Among assessed targets, only Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) was significantly linked to a reduced AD risk, corroborated across three separate AD cohorts. No association between serum lipid concentrations or other lipid-lowering drug targets and diminished AD risk was observed. Mediation analysis revealed that beta nerve growth factor (b-NGF) might mediate approximately 12.8% of PCSK9's influence on AD susceptibility. Our findings refute dyslipidemia's role in AD pathogenesis. Among explored lipid-lowering drug targets, PCSK9 stands out as a promising therapeutic agent for AD. [ABSTRACT FROM AUTHOR]

Functional genetics has identified drug targets for metabolic disorders. Opioid use impacts metabolic homeostasis, although mechanisms remain elusive. Here, we explore the OPRD1 gene (encoding delta opioid receptor, DOP) to understand its impact on type 2 diabetes. Large-scale sequencing of OPRD1 and in vitro analysis reveal that loss-of-function variants are associated with higher adiposity and lower hyperglycemia risk, whereas gain-of-function variants are associated with lower adiposity and higher type 2 diabetes risk. These findings align with studies of opium addicts. OPRD1 is expressed in human islets and beta cells, with decreased expression under type 2 diabetes conditions. DOP inhibition by an antagonist enhances insulin secretion from human beta cells and islets. RNA-sequencing identifies pathways regulated by DOP antagonism, including nerve growth factor, circadian clock, and nuclear receptor pathways. Our study highlights DOP as a key player between opioids and metabolic homeostasis, suggesting its potential as a therapeutic target for type 2 diabetes. Opioid use impacts metabolic homeostasis, although the mechanisms remain elusive. Here, the authors explore the OPRD1 gene (encoding the delta opioid receptor, DOP) to understand its impact on type 2 diabetes and highlight DOP as a key player between opioids and metabolic homeostasis. [ABSTRACT FROM AUTHOR]

Neurotrophins are important regulators of neuronal and non-neuronal functions. As such, the neurotrophins and their receptors, the tropomyosin receptor kinase (Trk) family of receptor tyrosine kinases, has attracted intense research interest and their role in multiple diseases including Alzheimer's disease has been described. Attempts to administer neurotrophins to patients have been reported, but the clinical trials have so far have been hampered by side effects or a lack of clear efficacy. Thus, much of the focus during recent years has been on identifying small molecules acting as agonists or positive allosteric modulators (PAMs) of Trk receptors. Two examples of successful discovery and development of PAMs are the TrkA-PAM E2511 and the pan-Trk PAM ACD856. E2511 has been reported to have disease-modifying effects in preclinical models, whereas ACD856 demonstrates both a symptomatic and a disease-modifying effect in preclinical models. Both molecules have reached the stage of clinical development and were reported to be safe and well tolerated in clinical phase 1 studies, albeit with different pharmacokinetic profiles. These two emerging small molecules are interesting examples of possible novel symptomatic and disease-modifying treatments that could complement the existing anti-amyloid monoclonal antibodies for the treatment of Alzheimer's disease. This review aims to present the concept of positive allosteric modulators of the Trk receptors as a novel future treatment option for Alzheimer's disease and other neurodegenerative and cognitive disorders, and the current preclinical and clinical data supporting this new concept. Preclinical data indicate dual mechanisms, not only as cognitive enhancers, but also a tentative neurorestorative function. [ABSTRACT FROM AUTHOR]

A 22-month-old girl of consanguineous parents was admitted with a high-grade fever. She was found to have insensitivity to painful stimuli and an absence of perspiration. She also displayed self-mutilating behaviour and was insensitive to cold/hot water on her body. On examination, there was loss of the tip of the tongue, missing teeth, generalised xerosis, and several ulcers at sites of minor trauma. She also had dysplastic nails and digital ulcers. Sensory examination demonstrated a complete lack of awareness of pain and temperature, vibration and fine touch were intact and lacrimation was normal. Differential diagnoses of hereditary sensory and autonomic neuropathy (HSAN), Lesch—Nyhan syndrome, hypohidrotic ectodermal dysplasia and leprosy were considered. Results of routine blood investigations including serum uric acid were normal. On performing clinical exome sequencing, the diagnosis of congenital insensitivity to pain with anhidrosis (CIPA) of autosomal recessive inheritance was confirmed. A novel, predicted to be pathogenic variant detected at exon 16 of the NTRK1 gene resulting in congenital insensitivity to pain with anhidrosis is reported. Abbreviations: CIPA: congenital Insensitivity to pain with anhidrosis; HSAN: hereditary sensory and autonomic neuropathy; NGF: nerve growth factor; NTRK1: neurotrophic tyrosine kinase receptor 1 gene; TrKA: tropomyosin receptor kinase A. [ABSTRACT FROM AUTHOR]

Dry eye disease (DED) is caused by inflammation and damage to the corneal surface due to tear film instability and hyperosmolarity. Various eye drops are used to treat this condition. Each eye drop has different properties and mechanisms of action, so the appropriate drug should be used according to clinical phenotypes. This study aims to compare the therapeutic mechanisms of cyclosporine A (CsA) and diquafosol tetrasodium (DQS). An experimental in vivo/in vitro model of DED using hyperosmolarity showed decreased cell viability, inhibited wound healing, and corneal damage compared to controls. Treatment with cyclosporine or diquafosol restored cell viability and wound healing and reduced corneal damage by hyperosmolarity. The expression of the inflammation-related genes il-1β, il-1α, and il-6 was reduced by cyclosporine and diquafosol, and the expression of Tnf-α, c1q, and il-17a was reduced by cyclosporine. Increased apoptosis in the DED model was confirmed by increased Bax and decreased Bcl-2 and Bcl-xl expression, but treatment with cyclosporine or diquafosol resulted in decreased apoptosis. Diquafosol increased NGF expression and translocation into the extracellular space. DED has different damage patterns depending on the progression of the lesion. Thus, depending on the type of lesion, eye drops should be selected according to the therapeutic target, focusing on repairing cellular damage when cellular repair is needed or reducing inflammation when inflammation is high and cellular damage is severe. [ABSTRACT FROM AUTHOR]

The neuroprotective effects of choline chloride, an essential nutrient, a precursor for the acetylcholine and synthesis of membrane phospholipids, have been associated with neurological and neurodegenerative diseases. Its contribution to autism spectrum disorder, a neurodevelopmental disorder, remains unknown. Thus, we aimed to evaluate the effects of choline chloride on social behaviours, and histopathological and biochemical changes in a rat autism model. The autism model was induced by administration of 100 μg/kg lipopolysaccharide (LPS) on the 10th day of gestation. Choline chloride treatment (100 mg/kg/day) was commenced on PN5 and maintained until PN50. Social deficits were assessed by three‐chamber sociability, open field, and passive avoidance learning tests. Tumour necrosis factor alpha (TNF‐α), interleukin‐2 (IL) and IL‐17, nerve growth factor (NGF), and glutamate decarboxylase 67 (GAD67) levels were measured to assess neuroinflammatory responses. In addition, the number of hippocampal and cerebellar neurons and glial fibrillary acidic protein (GFAP) expression were evaluated. Social novelty and passive avoidance learning tests revealed significant differences in choline chloride‐treated male rats compared with saline‐treated groups. TNF‐α, IL‐2, and IL‐17 were significantly decreased after choline chloride treatment in both males and females. NGF and GAD67 levels were unchanged in females, while there were significant differences in males. Histologically, significant changes in terms of gliosis were detected in hippocampal CA1 and CA3 regions and cerebellum in choline chloride‐treated groups. The presence of ameliorative effects of choline chloride treatment on social behaviour and neuroinflammation through neuroinflammatory, neurotrophic, and neurotransmission pathways in a sex‐dependent rat model of LPS‐induced autism was demonstrated. [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration is common and may play an important role in low back pain, but it is not well-understood. Previous studies have shown that the outer layer of the annulus fibrosus of a healthy disc is innervated by nociceptive nerve fibers. In the process of disc degeneration, it can grow into the inner annulus fibrosus or nucleus pulposus and release neuropeptides. Disc degeneration is associated with inflammation that produces inflammatory factors and potentiates nociceptor sensitization. Subsequently neurogenic inflammation is induced by neuropeptide release from activated primary afferent terminals. Because the innervation of a lumbar disc comes from multisegmental dorsal root ganglion neurons, does neurogenic inflammation in a degenerative disc initiate neurogenic inflammation in neighboring healthy discs by antidromic activity? This study was based on animal experiments in Sprague-Dawley rats to investigate the role of neurogenic inflammation in adjacent healthy disc degeneration induced by disc injury. This was an experimental study. Seventy-five 12-week-old, male Sprague-Dawley rats were allocated to 3 groups (sham group, disc injury group and disc injury+TrkA antagonist group). The disc injury group was punctured in the tail disc between the eighth and ninth coccygeal vertebrae (Co8–9) to establish an animal model of tail intervertebral disc degeneration. The sham group underwent only skin puncture and the disc injury+TrkA antagonist group was intraperitoneally injected with GW441756 two days before disc puncture. The outcome measure included quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Disc injury induced an increase in aggrecan, NGF, TrkA, CGRP, SP, IL-1β, and IL-6 mRNA levels in the injured (Co8–9) and adjacent discs (Co7–8), which reached a peak on day 1, then gradually decreased, and returned to normal on day 14. After intraperitoneal injection of GW441756 prior to puncture, the mRNA levels of the above indicators were down-regulated in Co7–8 and Co8–9 intervertebral discs on the 1st and 7th days. The protein content of the above indicators in Co7–8 and Co8–9 intervertebral discs showed roughly the same trend as mRNA levels. Degeneration of one disc can induce neurogenic inflammation of adjacent healthy discs in a rat model. This model supports a key role of neurogenic inflammation in disc degeneration, and may play a role in the experience of low back pain. [ABSTRACT FROM AUTHOR]

The hippocampus is one of the most commonly studied brain regions in the context of depression. The volume of the hippocampus is significantly reduced in patients with depression, which severely disrupts hippocampal neuroplasticity. However, antidepressant therapies that target hippocampal neuroplasticity have not been identified as yet. Chinese medicine (CM) can slow the progression of depression, potentially by modulating hippocampal neuroplasticity. Xiaoyaosan (XYS) is a CM formula that has been clinically used for the treatment of depression. It is known to protect Gan (Liver) and Pi (Spleen) function, and may exert its antidepressant effects by regulating hippocampal neuroplasticity. In this review, we have summarized the association between depression and aberrant hippocampal neuroplasticity. Furthermore, we have discussed the researches published in the last 30 years on the effects of XYS on hippocampal neuroplasticity in order to elucidate the possible mechanisms underlying its therapeutic action against depression. The results of this review can aid future research on XYS for the treatment of depression. [ABSTRACT FROM AUTHOR]

Altered serum Netrin-1 levels have been widely reported in cancer and other clinical diseases and they are often measured by commercial ELISA kits. However, we found the questionable results using these kits and therefore performed this simple study to evaluate their accuracy in detection of serum Netrin-1. Four commonly used commercial kits were collected. The kit standards were serially diluted or spiked into serum samples. The cells with confirmed expression of Netrin-1 and their culture medium, as well as the Netrin-1 controls of each kit were used for the kits to detect. The cell lysate samples and the kit controls were also blotted on a nitrocellulose membrane for detection antibodies of each kit to probe. Detection of the Netrin-1 standards in serum by each kit were all affected. Only one kit was able to detect Netrin-1 in the cell lysate or medium. No ELISA kits could detect all Netrin-1 controls of the four kits. None of the detection antibodies correctly probed Netrin-1 in the dot blot. The accuracy of these four Netrin-1 ELISA kits is under question. Reported serum Netrin-1 levels based on measurements by these kits need be carefully interpreted. [ABSTRACT FROM AUTHOR]

Background: Salidroside is the major bioactive and pharmacological active substance in Rhodiola rosea L. It has been reported to have neuroprotective effects on cerebral ischemia/reperfusion (I/R). However, whether salidroside can enhance neural regeneration after cerebral I/R is still unknown. This study investigated the effects of salidroside on the endogenous neural regeneration after cerebral I/R and the related mechanism. Methods: Focal cerebral I/R was induced in rats by transient middle cerebral artery occlusion/reperfusion (MCAO/R). The rats were intraperitoneally treated salidroside once daily for 7 consecutive days. Neurobehavioral assessments were performed at 3 days and 7 days after the injury. TTC staining was performed to assess cerebral infarct volume. To evaluate the survival of neurons, immunohistochemical staining of Neuronal Nuclei (NeuN) in the ischemic hemisphere were conducted. Also, immunofluorescence double or triple staining of the biomarkers of proliferating neural progenitor cells in Subventricular Zone (SVZ) and striatum of the ischemia hemisphere were performed to investigate the neurogenesis. Furthermore, reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect the expression of neurotrophic factors (NTFs) brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Expression of Notch1 and its target molecular Hes1 were also analyzed by western-blotting and RT-PCR. Results: Salidroside treatment ameliorated I/R induced neurobehavioral impairment, and reduced infarct volume. Salidroside also restored NeuN positive cells loss after I/R injury. Cerebral I/R injury significantly increased the expression of 5-Bromo-2'-Deoxyuridine (BrdU) and doublecotin (DCX), elevated the number of BrdU/Nestin/DCX triple-labeled cells in SVZ, and BrdU/Nestin/glial fibrillary acidic protein (GFAP) triple-labeled cells in striatum. Salidroside treatment further promoted the proliferation of BrdU/DCX labeled neuroblasts and BrdU/Nestin/GFAP labeled reactive astrocytes. Furthermore, salidroside elevated the mRNA expression and protein concentration of BDNF and NGF in ischemia periphery area, as well. Mechanistically, salidroside elevated Notch1/Hes1 mRNA expression in SVZ. The protein levels of them were also increased after salidroside administration. Conclusions: Salidroside enhances the endogenous neural regeneration after cerebral I/R. The mechanism of the effect may involve the regulation of BDNF/NGF and Notch signaling pathway. [ABSTRACT FROM AUTHOR]

Background: With the rapid growth of the ageing population, chronic diseases such as osteoarthritis have become one of the major diseases affecting the quality of life of elderly people. The main pathological manifestation of osteoarthritis is articular cartilage damage. Alleviating and repairing damaged cartilage has always been a challenge. The application of cartilage tissue engineering methods has shown promise for articular cartilage repair. Many studies have used cartilage tissue engineering methods to repair damaged cartilage and obtained good results, but these methods still cannot be used clinically. Therefore, this study aimed to investigate the effect of incorporating nerve growth factor (NGF) into a silk fibroin (SF)/chitosan (CS) scaffold containing bone marrow-derived mesenchymal stem cells (BMSCs) on the repair of articular cartilage defects in the knees of rabbits and to explore the possible underlying mechanism involved. Materials and methods: Nerve growth factor-loaded sustained-release microspheres were prepared by a double emulsion solvent evaporation method. SF/CS scaffolds were prepared by vacuum drying and chemical crosslinking. BMSCs were isolated and cultured by density gradient centrifugation and adherent culture. NGF-SF/CS-BMSC composites were prepared and implanted into articular cartilage defects in the knees of rabbits. The repair of articular cartilage was assessed by gross observation, imaging and histological staining at different time points after surgery. The repair effect was evaluated by the International Cartilage Repair Society (ICRS) score and a modified Wakitani score. In vitro experiments were also performed to observe the effect of different concentrations of NGF on the proliferation and directional differentiation of BMSCs on the SF/CS scaffold. Results: In the repair of cartilage defects in rabbit knees, NGF-SF/CS-BMSCs resulted in higher ICRS scores and lower modified Wakitani scores. The in vitro results showed that there was no significant correlation between the proliferation of BMSCs and the addition of different concentrations of NGF. Additionally, there was no significant difference in the protein and mRNA expression of COL2a1 and ACAN between the groups after the addition of different concentrations of NGF. Conclusion: NGF-SF/CS-BMSCs improved the repair of articular cartilage defects in the knees of rabbits. This repair effect may be related to the early promotion of subchondral bone repair. [ABSTRACT FROM AUTHOR]

Reproductive aging not only affects the fertility and physical and mental health of women but also accelerates the aging process of other organs. There is an urgent need newfor novel mechanisms, targets, and drugs to break the vicious cycle of mitochondrial dysfunction, redox imbalance, and germ cell apoptosis associated with ovarian aging. Autophagy, recognized as a longevity mechanism, has recently become a focal point in anti-aging research. Although mitophagy is a type of autophagy, its role and regulatory mechanisms in ovarian aging, particularly in age-related ovarian function decline, remain unclear. Nerve growth factor inducible gene B (Nur77) is an early response gene that can be stimulated by oxidative stress, DNA damage, metabolism, and inflammation. Recent evidence recommends that decreased expression of Nur77 is associated with age-related myocardial fibrosis, renal dysfunction, and Parkinson's disease; however, its association with ovarian aging has not been studied yet. We herein identified Nur77 as a regulator of germ cell senescence, apoptosis, and mitophagy and found that overexpression of Nur77 can activate mitophagy, improve oxidative stress, reduce apoptosis, and ultimately enhance ovarian reserve in aged mice ovaries. Furthermore, we discovered an association between Nur77 and the AKT pathway through String and molecular docking analyses. Experimental confirmation revealed that the AKT/mTOR signaling pathway is involved in the regulation of Nur77 in ovarian function. In conclusion, our results suggest Nur77 as a promising target for preventing and treating ovarian function decline related to reproductive aging. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a significant global cause of death and disability. Currently, treatment options for acute ischemic stroke are limited to intravenous thrombolysis and mechanical recanalization. Therefore, novel neuroprotective strategies are imperative. Stem cell transplantation possesses the capabilities of differentiation, proliferation, neuronal replacement, nerve pathway reconstruction, secretion of nerve growth factors, and enhancement of the microenvironment; thus, it is a potential therapeutic approach for ischemic stroke. In addition, the immunomodulatory function of stem cells and the combined treatment of stem cells and exosomes exhibit a favorable protective effect on brain injury and neurological dysfunction following stroke. Meanwhile, the theory of microbiota-gut-brain axis provides us with a novel perspective for comprehending and managing neurological diseases. Lastly, stem cell transplantation has demonstrated promising outcomes not only in treating ischemic stroke but also in dealing with other neurological disorders, such as brain tumors. Furthermore, challenges related to the tissue source, delivery method, immune response, and timing of transplantation still need to be addressed to optimize the treatment. [ABSTRACT FROM AUTHOR]

Background: Dry eye disease (DED) includes neurosensory abnormalities as part of its multifactorial etiology. Nerve growth factor is important for maintaining corneal nerve integrity and wound healing. Cenegermin (recombinant human nerve growth factor) is a topical biologic that promotes corneal healing in patients with neurotrophic keratitis. The purpose of this study was to evaluate efficacy and safety of cenegermin in moderate-to-severe DED and identify an optimal dosing strategy. Methods: This was a phase II, multicenter, randomized, double-masked, vehicle-controlled, dose-ranging clinical trial in patients with moderate-to-severe DED, including Sjögren's DED (NCT03982368). Patients received 1 drop of cenegermin 3 times daily (t.i.d.; 20 mcg/mL), cenegermin 2 times daily (b.i.d.; 20 mcg/mL) and vehicle once daily, or vehicle t.i.d. for 4 weeks. Follow-up continued for 12 additional weeks. The primary endpoint was change in Schirmer I score from baseline to week 4. Other key endpoints included rate of responders (Schirmer I test > 10 mm/5 min) after treatment and change in Symptoms Assessment iN Dry Eye (SANDE) scores from baseline to end of follow-up. A 1-sided test (α = 0.025) was used to evaluate statistical significance. Results: At week 4, mean changes in Schirmer I scores were not statistically significantly different in either cenegermin group versus vehicle (cenegermin vs vehicle [treatment difference; 95% CI]: t.i.d., 2.60 mm and b.i.d., 3.99 mm vs 1.68 mm [t.i.d.: 0.93; −1.47 to 3.32, P = 0.078; b.i.d.: 2.31; −0.08 to 4.70, P = 0.066]). More patients responded to treatment with cenegermin t.i.d. and b.i.d. versus vehicle (t.i.d.: 25.9% [21/81, P = 0.028]; b.i.d.: 29.3% [24/82, P = 0.007] vs 11.9% [10/84]), with statistical significance (set at P < 0.025) observed in the b.i.d. group. Only cenegermin t.i.d. yielded statistically significant (P < 0.025) reductions in SANDE scores versus vehicle, which were sustained up to the end of follow-up (P value range, 0.002–0.008). Eye pain, primarily mild and transient, was the most frequently observed treatment-emergent adverse event with cenegermin. Similar results were observed in patients with Sjögren's DED. Conclusions: Cenegermin was well tolerated and although this study did not meet its primary endpoint, significant improvement in patient-reported symptoms of dry eye was observed through follow-up. Larger studies evaluating cenegermin in patients with DED are warranted. Trial registration: NCT03982368; registered May 23, 2019. [ABSTRACT FROM AUTHOR]

The Apple polysaccharides (AP), extracted from the fruit of apple, has been used to treat multiple pathological diseases. In this study, we evaluated the effects of AP on cognitive impairment and intestinal aging in naturally aging mice. As a result, it was found that AP could improve spatial learning and memory impairment in aging mice through the Morris water maze experiment. Additionally, AP intervention can upregulate the expression of nerve growth factor (BDNF), postsynaptic marker (PSD95), and presynaptic marker (SYP) proteins. Moreover, AP can enhance total antioxidant capacity, reduce the level of pro-inflammatory cytokine, and inhibit the activation of the NF-κB signaling pathway, exerting anti-inflammatory and antioxidant functions. And the administration of AP restored intestinal mucosal barrier function, reduced the expression of aging and apoptosis related proteins. The administration of AP also altered the gut microbiota of mice. At the genus level, AP decreased the abundance of Helicobacter and Bilophila, while increased the abundance of Lactobacillus and Bacteroides. In summary, these data demonstrate that AP treatment can alleviate cognitive impairment, oxidative stress, and inflammatory reactions, repair the intestinal mucosal barrier, reduce intestinal aging, and alter specific microbial characteristics, ultimately improving the health of the elderly. [ABSTRACT FROM AUTHOR]

The abuse of nitrous oxide (N2O) poses a substantial public health challenge. In many countries, including China, regulations governing the utilization and accessibility to N2O remain ambiguous, particularly within the food industry. Here, we report a case of a 21-year-old female who presented with symptoms of subacute combined degeneration (SCD) of the spinal cord due to N2O abuse. The patient exhibited bilateral lower limb numbness and weakness, low serum vitamin B12 levels with elevated homocysteine levels, and lumbar spine magnetic resonance imaging (MRI) revealed abnormal signals of the spinal cord. Following cessation of N2O and comprehensive therapy including methylcobalamin and nerve growth factor, the symptoms significantly improved. A follow-up examination 3 months later showed good progress in gait stability. At a 5-year follow-up, the patient’s previous clinical symptoms had completely disappeared, and her quality of life had returned to normal. This case underscores the urgency of raising awareness and prevention of N2O abuse, emphasizing the importance of timely diagnosis and comprehensive treatment for patient recovery. Clear formulation and enforcement of relevant regulatory measures are equally crucial in reducing instances of abuse. [ABSTRACT FROM AUTHOR]

Paired related homeobox 1 (PRRX1) is an inducer of epithelial‐to‐mesenchymal transition (EMT) in different types of cancer cells. We detected low PRRX1 expression in nevus but increased levels in primary human melanoma and cell lines carrying the BRAFV600E mutation. High expression of PRRX1 correlates with invasiveness and enrichment of genes belonging to the EMT programme. Conversely, we found that loss of PRRX1 in metastatic samples is an independent prognostic predictor of poor survival for melanoma patients. Here, we show that stable depletion of PRRX1 improves the growth of melanoma xenografts and increases the number of distant spontaneous metastases, compared to controls. We provide evidence that loss of PRRX1 counteracts the EMT phenotype, impairing the expression of other EMT‐related transcription factors, causing dysregulation of the ERK and signal transducer and activator of transcription 3 (STAT3) signaling pathways, and abrogating the invasive and migratory properties of melanoma cells while triggering the up‐regulation of proliferative/melanocytic genes and the expression of the neural‐crest‐like markers nerve growth factor receptor (NGFR; also known as neurotrophin receptor p75NTR) and neural cell adhesion molecule L1 (L1CAM). Overall, our results indicate that loss of PRRX1 triggers a switch in the invasive programme, and cells de‐differentiate towards a neural crest stem cell (NCSC)‐like phenotype that accounts for the metastatic aggressiveness. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationships between the serum 5-hydroxytryptamine (5-HT) and nerve growth factor (NGF) levels and recurrence after selective resection of the dorsal nerve of the penis in patients with primary premature ejaculation. Methods Totally 200 patients who underwent selective resection of the dorsal nerve of the penis were selected as the study subjects. Six months after surgery, they were divided into the recurrent group (n=23) and nonrecurrent group (n=177) based on whether the patients had recurrence or not. The clinical data, serum levels of 5-HT and NGF were compared between two groups. The correlations between 5-HT and NGF with the Chinese Index of Premature Ejaculation-5 questionnaire (CIPE-5), International Index of Erectile Function-5（IIEF-5) score, and ejaculation latency time (IELT) were analyzed. Factors affecting postoperative recurrence were analyzed, and we constructed a nomogram model to evaluate the consistency between the postoperative recurrence predicted by model containing serum indicators and the actual observation, and used the decision curve to evaluate the clinical benefit of the model. Results The serum 5- HT level, IELT, and CIPE-5 score in the recurrent group were lower than those in the non-recurrent group at 3 months after surgery, while the NGF level was higher than that in the non-recurrent group (all P<0. 05) . The serum 5-HT level was positively correlated with CIPE-5 score and IELT in patients with primary premature ejaculation before surgery, 1 months after surgery, and 3 months after surgery (all P<0. 05), but was not related to IIEF-5 score (P>0. 05) ； the serum NGF level was negatively correlated with CIPE-5 score and IELT (all P<0. 05), but was not related to IIEF-5 score (P>0. 05) .IELT, CIPE-5 score, serum 5-HT, and NGF levels at 3 months after surgery were independent influencing factors for postoperative recurrence in patients with primary premature ejaculation (all P<0. 05) . The consistency index of the nomogram model in predicting postoperative recurrence related factors in patients with primary premature ejaculation was 0. 775 (95% CI=0. 674-0. 802) . The decision curve showed that when the model containing serum indicators predicted postoperative recurrence in patients with primary premature ejaculation in the range of 0. 2-0. 85, it could provide additional clinical benefits. Conclusion The serum 5-HT level decreases and NGF level increases 3 months after selective resection of the dorsal penile nerve, which has certain reference value for predicting postoperative recurrence in patients with primary premature ejaculation [ABSTRACT FROM AUTHOR]

Bilingual language process is a key factor in left side of the brain. The cognition of the learning modalities is very crucial for assimilation, organization, and interpretation of knowledge. The neurochemical events like estrogen, testosterone, dopamine 5HT, Oxytocin, nerve growth factor (NGF) play as neuro-endocrine brain axis for learning to cognition. The human cognition recognises the language in five stages that is input, status of language, getting access over the literature of that language, interaction with family, and finally social network communication. The factors influence the bilingual aspects include language exposure, genes, perception and receiving, neurochemical pathways, social communication, and environmental conditions. Apart from these elements the other external influencing factors like health humanities and technological advances and make a lot of impact on cognition processes and mental health. [ABSTRACT FROM AUTHOR]

BACKGROUND: The traditional method of post-hospital intervention and guidance of stroke patients has some limitations. OBJECTIVE: To investigate the effects of Internet + wearable device training on limb function recovery and the levels of serum neurocytokines (BDNF, NT-3, and NGF) in stroke patients. METHODS: 80 stroke patients with hemiplegia were randomly selected from the Department of Neurorehabilitation, Affiliated Rehabilitation Hospital of Chongqing Medical University. They were divided into a control group and an observation group, with 40 patients in each group. The control group received routine post-hospital follow-up guidance, while the observation group received Internet remote home rehabilitation guidance combined with wearable device training. The interventions were compared between the two groups. RESULTS: At 4 weeks and 12 weeks after discharge, the observation group showed higher scores on the Fugl-Meyer scale (FMA), Berg Balance Scale (BBS), modified Barthel Index (MBI), stride length, gait speed, gait frequency, and higher levels of BDNF, NT-3, and NGF. Additionally, the observation group had lower scores on the Hamilton Anxiety and Depression Scale (HADS) (P < 0.05). CONCLUSIONS: The application of Internet remote home rehabilitation guidance combined with wearable device training in stroke patients with hemiplegia can improve limb function recovery. It effectively increases the levels of BDNF, NT-3, and NGF, promoting the nutritional repair of damaged nerves. These findings hold clinical significance. [ABSTRACT FROM AUTHOR]

Leucine-rich repeat kinase-2 (LRRK2), a gene mutated in familial and sporadic Parkinson's disease (PD), controls multiple cellular processes important for GLIA physiology. Interestingly, emerging studies report that LRRK2 is highly expressed in oligodendrocyte precursor cells (OPCs) compared to the pathophysiology of other brain cells and oligodendrocytes (OLs) in PD. Altogether, these observations suggest crucial function(s) of LRRK2 in OPCs/Ols, which would be interesting to explore. In this study, we investigated the role of LRRK2 in OLs. We showed that LRRK2 knock-out (KO) OPC cultures displayed defects in the transition of OPCs into OLs, suggesting a role of LRRK2 in OL differentiation. Consistently, we found an alteration of myelin basic protein (MBP) striosomes in LRRK2 KO mouse brains and reduced levels of oligodendrocyte transcription factor 2 (Olig2) and Mbp in olig2:EGFP and mbp:RFP transgenic zebrafish embryos injected with lrrk2 morpholino (MO). Moreover, lrrk2 knock-down zebrafish exhibited a lower amount of nerve growth factor (Ngf) compared to control embryos, which represents a potent regulator of oligodendrogenesis and myelination. Overall, our findings indicate that LRRK2 controls OL differentiation, affecting the number of mature OLs. [ABSTRACT FROM AUTHOR]

Simple Summary: Nerve growth factor (NGF) is a crucial protein for the growth and survival of neurons involved in various neuroprotective and regenerative processes. In neurological disorders, NGF plays a key role in maintaining neuronal health and function. In the context of traumatic brain injury (TBI), NGF levels increase in response to the damage, facilitating neuronal regeneration and reducing the extent of brain injury. These effects make NGF a promising candidate for therapies targeting both neurological diseases and traumatic brain injuries, offering hope for improving neurological function in affected patients. Nerve growth factor (NGF) is a neurotrophic peptide largely revealed for its ability to regulate the growth and survival of peripheral sensory, sympathetic, and central cholinergic neurons. The pro-survival and regenerative properties of neurotrophic factors propose a therapeutic potential in a wide range of brain diseases, and NGF, in particular, has appeared as an encouraging potential treatment. In this review, a summary of clinical studies regarding NGF and its therapeutic effects published to date, with a specific interest in the pediatric context, will be attempted. NGF has been studied in neurological disorders such as hypoxic–ischemic encephalopathy, traumatic brain injury, neurobehavioral and neurodevelopmental diseases, congenital malformations, cerebral infections, and in oncological and ocular diseases. The potential of NGF to support neuronal survival, repair, and plasticity in these contexts is highlighted. Emerging therapeutic strategies for NGF delivery, including intranasal administration as well as advanced nanotechnology-based methods, are discussed. These techniques aim to enhance NGF bioavailability and target specificity, optimizing therapeutic outcomes while minimizing systemic side effects. By synthesizing current research, this review underscores the promise and challenges of NGF-based therapies in pediatric neurology, advocating for continued innovation in delivery methods to fully harness NGF's therapeutic potential. [ABSTRACT FROM AUTHOR]

Background: Repairation of bone defects remains a major clinical problem. Constructing bone tissue engineering containing growth factors, stem cells, and material scaffolds to repair bone defects has recently become a hot research topic. Nerve growth factor (NGF) can promote osteogenesis of bone marrow mesenchymal stem cells (BMSCs), but the low survival rate of the BMSCs during transplantation remains an unresolved issue. In this study, we investigated the therapeutic effect of BMSCs overexpression of NGF on bone defect by inhibiting pyroptosis. Methods: The relationship between the low survival rate and pyroptosis of BMSCs overexpressing NGF in localized inflammation of fractures was explored by detecting pyroptosis protein levels. Then, the NGF+/BMSCs-NSA-Sca bone tissue engineering was constructed by seeding BMSCs overexpressing NGF on the allograft bone scaffold and adding the pyroptosis inhibitor necrosulfonamide(NSA). The femoral condylar defect model in the Sprague–Dawley (SD) rat was studied by micro-CT, histological, WB and PCR analyses in vitro and in vivo to evaluate the regenerative effect of bone repair. Results: The pyroptosis that occurs in BMSCs overexpressing NGF is associated with the nerve growth factor receptor (P75NTR) during osteogenic differentiation. Furthermore, NSA can block pyroptosis in BMSCs overexpression NGF. Notably, the analyses using the critical-size femoral condylar defect model indicated that the NGF+/BMSCs-NSA-Sca group inhibited pyroptosis significantly and had higher osteogenesis in defects. Conclusion: NGF+/BMSCs-NSA had strong osteogenic properties in repairing bone defects. Moreover, NGF+/BMSCs-NSA-Sca mixture developed in this study opens new horizons for developing novel tissue engineering constructs. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Impairment of mitochondrial pyruvate oxidation in dorsal root ganglia is sufficient to induce long-lasting allodynia and widespread transcriptomic alterations. Metabolism is inextricably linked to every aspect of cellular function. In addition to energy production and biosynthesis, metabolism plays a crucial role in regulating signal transduction and gene expression. Altered metabolic states have been shown to maintain aberrant signaling and transcription, contributing to diseases like cancer, cardiovascular disease, and neurodegeneration. Metabolic gene polymorphisms and defects are also associated with chronic pain conditions, as are increased levels of nerve growth factor (NGF). However, the mechanisms by which NGF may modulate sensory neuron metabolism remain unclear. This study demonstrated that intraplantar NGF injection reprograms sensory neuron metabolism. Nerve growth factor suppressed mitochondrial pyruvate oxidation and enhanced lactate extrusion, requiring 24 hours to increase lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 (PDHK1) expression. Inhibiting these metabolic enzymes reversed NGF-mediated effects. Remarkably, directly disrupting mitochondrial pyruvate oxidation induced severe, persistent allodynia, implicating this metabolic dysfunction in chronic pain. Nanopore long-read sequencing of poly(A) mRNA uncovered extensive transcriptomic changes upon metabolic disruption, including altered gene expression, splicing, and poly(A) tail lengths. By linking metabolic disturbance of dorsal root ganglia to transcriptome reprogramming, this study enhances our understanding of the mechanisms underlying persistent nociceptive sensitization. These findings imply that impaired mitochondrial pyruvate oxidation may drive chronic pain, possibly by impacting transcriptomic regulation. Exploring these metabolite-driven mechanisms further might reveal novel therapeutic targets for intractable pain. [ABSTRACT FROM AUTHOR]

Many routes may lead to the transition from a healthy to a diseased phenotype. However, there are not so many routes to travel in the opposite direction; that is, therapy for different diseases. The following pressing question thus remains: what are the pathogenic routes and how can be they counteracted for therapeutic purposes? Human cells contain >500 protein kinases and nearly 200 protein phosphatases, acting on thousands of proteins, including cell growth factors. We herein discuss neurotrophins with pathogenic or metabotrophic abilities, particularly brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), pro-NGF, neurotrophin-3 (NT-3), and their receptor Trk (tyrosine receptor kinase; pronounced "track"). Indeed, we introduced the word trackins, standing for Trk-targeting drugs, that play an agonistic or antagonistic role in the function of TrkBBDNF, TrkCNT−3, TrkANGF, and TrkApro-NGF receptors. Based on our own published results, supported by those of other authors, we aim to update and enlarge our trackins concept, focusing on (1) agonistic trackins as possible drugs for (1a) neurotrophin-deficiency cardiometabolic disorders (hypertension, atherosclerosis, type 2 diabetes mellitus, metabolic syndrome, obesity, diabetic erectile dysfunction and atrial fibrillation) and (1b) neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and multiple sclerosis), and (2) antagonistic trackins, particularly TrkANGF inhibitors for prostate and breast cancer, pain, and arrhythmogenic right-ventricular dysplasia. Altogether, the druggability of TrkANGF, TrkApro-NGF, TrkBBDNF, and TrkCNT−3 receptors via trackins requires a further translational pursuit. This could provide rewards for our patients. [ABSTRACT FROM AUTHOR]

Drinking coffee is a daily routine for many people. Supplement manufacturers have proposed adding powdered Cordyceps militaris, known for its ergogenic and immunostimulating properties, and Hericium erinaceus, known for its nerve growth factor (NGF)-stimulating properties, to coffee. The aim of this work was to compare the bioactive substances in three types of coffee: machine-brewed, instant, and traditionally brewed, prepared with the addition of H. erinaceus and C. militaris fruiting bodies. The analysis of bioactive substances was performed using AAS and RP-HPLC methods. Among the control samples of coffee, traditionally brewed coffee was the best source of bioelements. Considering the mushroom species tested, the best additional source of Mg, Zn, Cu, Na, K, and Ca was C. militaris. A slightly higher Fe content was determined for H. erinaceus. With the addition of C. militaris, the amounts of 4-feruloylquinic acid (18.6 mg/200 mL) and 3,5-di-caffeoylquinic acid (3.76 mg/200 mL) also increased. In conclusion, the C. militaris species has been proven to be a better source of bioactive substances as a coffee additive in the daily diet. The combination of brewed coffee and the tested mushrooms seems to be the most beneficial in terms of health-promoting effects. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effect of application of kangaroo-style intervention mode on neonatal cerebral palsy treated with mouse nerve growth factor. Methods: In this retrospective study, 153 newborns with cerebral palsy on admission to Wuhan Maternal and Child Healthcare Hospital, China between January 2016 and January 2020 were assigned to control group (n = 81) and study group (n = 72), based on differences in intervention schemes used. The control and study groups received mouse nerve growth factor and routine intervention, while study group received additional treatment with kangaroo-style intervention mode. After treatment, neonatal neurological function, intellectual development, intelligence development quotient, and growth and development indices were compared between the two groups. Results: Scores on neurological function, mental development index and psychomotor development index, as well as intelligence development quotient were significantly higher in the study group than in the control group (p < 0.05). There were no significant differences in growth and development indices between the two groups (p > 0.05). Conclusion: Kangaroo-style intervention mode effectively improves neurological function, and promotes intellectual development in cerebral palsy newborns treated with mouse nerve growth factor. However, it had no significant effect on neonatal physical development. [ABSTRACT FROM AUTHOR]

Neuronal differentiation is regulated by nerve growth factor (NGF) and other neurotrophins. We explored the impact of NGF on mitochondrial dynamics and metabolism through time‐lapse imaging, metabolomics profiling, and computer modeling studies. We show that NGF may direct differentiation by stimulating fission, thereby causing selective mitochondrial network fragmentation and mitophagy, ultimately leading to increased mitochondrial quality and respiration. Then, we reconstructed the dynamic fusion–fission–mitophagy cycling of mitochondria in a computer model, integrating these processes into a single network mechanism. Both the computational model and the simulations are able to reproduce the proposed mechanism in terms of mitochondrial dynamics, levels of reactive oxygen species (ROS), mitophagy, and mitochondrial quality, thus providing a computational tool for the interpretation of the experimental data and for future studies aiming to detail further the action of NGF on mitochondrial processes. We also show that changes in these mitochondrial processes are intertwined with a metabolic function of NGF in differentiation: NGF directs a profound metabolic rearrangement involving glycolysis, TCA cycle, and the pentose phosphate pathway, altering the redox balance. This metabolic rewiring may ensure: (a) supply of both energy and building blocks for the anabolic processes needed for morphological reorganization, as well as (b) redox homeostasis. [ABSTRACT FROM AUTHOR]

Background: Chronic pain can adversely affect cognitive functions such as learning, memory, and attention. However, the precise mechanisms underlying cognitive impairment in chronic pain remain elusive. Objectives: This study aims to investigate the impact of chronic pain induced by unilateral ureteral obstruction (UUO) on hippocampal neurons. Methods: In the current case-control study, 27 male Wistar rats (230 - 280 g) were randomly assigned to three groups: 1-sham, 2-UUO, and 3-UUO treated with naloxone (i.p.; 1 mg/kg for 5 days). Following transcardial perfusion, the rats' brains were removed, and histological studies were performed to count the number of neurons using an optical microscope. Concurrently, TNF-a and nerve growth factor (NGF) levels were measured in brain tissue homogenate. Results: The mean number of neurons in the CA1 region of the animals in the UUO group was 68.11 ± 1.34, which showed a significant decrease compared to the mean number of neurons in the sham-operated group (114.1 ± 1.77; P < 0.0001). In contrast, the mean number of neurons in the CA1 region of the UUO with naloxone group showed a significant increase compared to the animals in the UUO group (73.44 ± 1.37; P < 0.0001). TNF-a was 264.3 ± 2.6 pg/mL in the UUO animals and decreased significantly in the UUO animals treated with naloxone (P = 0.001). However, NGF was 115.2 ± 2.9 pg/mL in UUO animals and increased significantly in the UUO with naloxone group (P < 0.01). Conclusions: Unilateral ureteral obstruction, through inducing chronic pain and inflammation, resulted in neurodegeneration in the CA1 region of the hippocampus. The use of naloxone, an opioid antagonist, immediately after the surgery was able to provide neuronal protection and an anti-inflammatory effect. [ABSTRACT FROM AUTHOR]

Frequent itching and incessant scratching are commonly observed in various chronic inflammatory skin conditions, including atopic dermatitis and psoriasis. The persistent and prolonged nature of pruritus can worsen one's quality of life. Keratinocytes (KCs), the predominant cells of the epidermis, have been confirmed to interact with sensory neurons and immune cells and be involved in chronic skin inflammatory diseases associated with pruritus. Initially, KCs and sensory neurons form a unique synapse‐like connection within the epidermis, serving as the structural foundation for their interaction. Additionally, several receptors, including toll‐like receptors and protease‐activated receptor 2, expressed on KCs, become activated in an inflammatory milieu. On the one hand, activated KCs are sources of pro‐inflammatory cytokines and neurotrophic factors, such as adenosine triphosphate, thymic stromal lymphopoietin, and nerve growth factor, which directly or indirectly participate in stimulating sensory neurons, thereby contributing to the itch sensations. On the other hand, KCs also function as primary transducers alongside intraepidermal nerve endings, directly initiating pruritic responses. This review summarizes the current literature and highlights the critical role of KCs in the development and persistence of chronic itch in inflammatory skin disorders. [ABSTRACT FROM AUTHOR]

Lipoxins (LXs) are a class of endogenous bioactive lipid mediators that are involved in the regulation of inflammation. They exert immunomodulatory effects by regulating the behaviour of various immune cells, including neutrophils, macrophages, and T and B cells, by promoting the clearance of apoptotic neutrophils. This helps to dampen inflammation and promote tissue repair. LXs regulate the expression of many inflammatory genes by modulating the levels of transcription factors, such as nuclear factor κB (NF-κB), activator protein-1 (AP-1), nerve growth factor-regulated factor 1A binding protein 1 (NGF), and peroxisome proliferator activated receptor γ (PPAR-γ), which are elevated in various diseases, such as respiratory tract diseases, renal diseases, cancer, neurodegenerative diseases, and viral infections. Lipoxin-mediated signaling is involved in chronic inflammation, cancer, diabetes-associated kidney disease, lung injury, liver injury, endometriosis, respiratory tract diseases, neurodegenerative diseases, chronic cerebral hypoperfusion, and retinal degeneration. In this study, we systematically investigated the intricate network of lipoxin signaling by analyzing the relevant literature. The resulting map comprised 467 molecules categorized as activation/inhibition, enzyme catalysis, gene and protein expression, molecular associations, and translocation events. This map serves as a valuable resource for understanding the complexity of lipoxin signaling and its impact on various cellular functions. [ABSTRACT FROM AUTHOR]

In recent years, mouse nerve growth factor (mNGF) has emerged as an important biological regulator to repair peripheral nerve injury, but its systemic application is restricted by low efficiency and large dosage requirement. These limitations prompted us to search for biomaterials that can be locally loaded. Oxidized sodium alginate hydrogel (OSA) exhibits good biocompatibility and physicochemical properties, and can be loaded with drugs to construct a sustained-release system that can act locally on nerve injury. Here, we constructed a sustained-release system of OSA-mouse nerve growth factor (mNGF), and investigated the loading and release of the drug through Fourier transform infrared spectroscopy and drug release curves. In vitro and in vivo experiments showed that OSA-mNGF significantly promoted the biological activities of RSC-96 cells and facilitated the recovery from sciatic nerve crush injury in rats. This observation may be attributed to the additive effect of OSA on promoting Schwann cell biological activities or its synergistic effect of cross-activating phosphoinositide 3-kinase (PI3K) through extracellular signal regulated kinase (ERK) signaling. Although the specific mechanism of OSA action needs to be explored in the future, the current results provide a valuable preliminary research basis for the clinical application of the OSA-mNGF sustained-release system for nerve repair. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify key proteins of synaptic transmission in the cochlear nucleus (CN) that are involved in normal hearing, acoustic stimulation, and tinnitus. A gene list was compiled from the GeneCards database using the keywords "synaptic transmission" AND "tinnitus" AND "cochlear nucleus" (Tin). For comparison, two gene lists with the keywords "auditory perception" (AP) AND "acoustic stimulation" (AcouStim) were built. The STRING protein–protein interaction (PPI) network and the Cytoscape data analyzer were used to identify the top two high-degree proteins (HDPs) and their high-score interaction proteins (HSIPs), together referred to as key proteins. The top1 key proteins of the Tin-process were BDNF, NTRK1, NTRK3, and NTF3; the top2 key proteins are FOS, JUN, CREB1, EGR1, MAPK1, and MAPK3. Highly significant GO terms in CN in tinnitus were "RNA polymerase II transcription factor complex", "late endosome", cellular response to cadmium ion", "cellular response to reactive oxygen species", and "nerve growth factor signaling pathway", indicating changes in vesicle and cell homeostasis. In contrast to the spiral ganglion, where important changes in tinnitus are characterized by processes at the level of cells, important biological changes in the CN take place at the level of synapses and transcription. [ABSTRACT FROM AUTHOR]

Abstract Background With the rapid growth of the ageing population, chronic diseases such as osteoarthritis have become one of the major diseases affecting the quality of life of elderly people. The main pathological manifestation of osteoarthritis is articular cartilage damage. Alleviating and repairing damaged cartilage has always been a challenge. The application of cartilage tissue engineering methods has shown promise for articular cartilage repair. Many studies have used cartilage tissue engineering methods to repair damaged cartilage and obtained good results, but these methods still cannot be used clinically. Therefore, this study aimed to investigate the effect of incorporating nerve growth factor (NGF) into a silk fibroin (SF)/chitosan (CS) scaffold containing bone marrow-derived mesenchymal stem cells (BMSCs) on the repair of articular cartilage defects in the knees of rabbits and to explore the possible underlying mechanism involved. Materials and methods Nerve growth factor-loaded sustained-release microspheres were prepared by a double emulsion solvent evaporation method. SF/CS scaffolds were prepared by vacuum drying and chemical crosslinking. BMSCs were isolated and cultured by density gradient centrifugation and adherent culture. NGF-SF/CS-BMSC composites were prepared and implanted into articular cartilage defects in the knees of rabbits. The repair of articular cartilage was assessed by gross observation, imaging and histological staining at different time points after surgery. The repair effect was evaluated by the International Cartilage Repair Society (ICRS) score and a modified Wakitani score. In vitro experiments were also performed to observe the effect of different concentrations of NGF on the proliferation and directional differentiation of BMSCs on the SF/CS scaffold. Results In the repair of cartilage defects in rabbit knees, NGF-SF/CS-BMSCs resulted in higher ICRS scores and lower modified Wakitani scores. The in vitro results showed that there was no significant correlation between the proliferation of BMSCs and the addition of different concentrations of NGF. Additionally, there was no significant difference in the protein and mRNA expression of COL2a1 and ACAN between the groups after the addition of different concentrations of NGF. Conclusion NGF-SF/CS-BMSCs improved the repair of articular cartilage defects in the knees of rabbits. This repair effect may be related to the early promotion of subchondral bone repair.

Abstract Background Dry eye disease (DED) includes neurosensory abnormalities as part of its multifactorial etiology. Nerve growth factor is important for maintaining corneal nerve integrity and wound healing. Cenegermin (recombinant human nerve growth factor) is a topical biologic that promotes corneal healing in patients with neurotrophic keratitis. The purpose of this study was to evaluate efficacy and safety of cenegermin in moderate-to-severe DED and identify an optimal dosing strategy. Methods This was a phase II, multicenter, randomized, double-masked, vehicle-controlled, dose-ranging clinical trial in patients with moderate-to-severe DED, including Sjögren’s DED (NCT03982368). Patients received 1 drop of cenegermin 3 times daily (t.i.d.; 20 mcg/mL), cenegermin 2 times daily (b.i.d.; 20 mcg/mL) and vehicle once daily, or vehicle t.i.d. for 4 weeks. Follow-up continued for 12 additional weeks. The primary endpoint was change in Schirmer I score from baseline to week 4. Other key endpoints included rate of responders (Schirmer I test > 10 mm/5 min) after treatment and change in Symptoms Assessment iN Dry Eye (SANDE) scores from baseline to end of follow-up. A 1-sided test (α = 0.025) was used to evaluate statistical significance. Results At week 4, mean changes in Schirmer I scores were not statistically significantly different in either cenegermin group versus vehicle (cenegermin vs vehicle [treatment difference; 95% CI]: t.i.d., 2.60 mm and b.i.d., 3.99 mm vs 1.68 mm [t.i.d.: 0.93; −1.47 to 3.32, P = 0.078; b.i.d.: 2.31; −0.08 to 4.70, P = 0.066]). More patients responded to treatment with cenegermin t.i.d. and b.i.d. versus vehicle (t.i.d.: 25.9% [21/81, P = 0.028]; b.i.d.: 29.3% [24/82, P = 0.007] vs 11.9% [10/84]), with statistical significance (set at P

A preclinical model of human adolescent binge drinking, adolescent intermittent ethanol exposure (AIE) recreates the heavy binge withdrawal consummatory patterns of adolescents and has identified the loss of basal forebrain cholinergic neurons as a pathological hallmark of this model. Cholinergic neurons of the nucleus basalis magnocellularis (NbM) that innervate the prefrontal cortex (PFC) are particularly vulnerable to alcohol related neurodegeneration. Target derived neurotrophins (nerve growth factor [NGF] and brain-derived neurotrophic factor [BDNF]) regulate cholinergic phenotype expression and survival. Evidence from other disease models implicates the role of immature neurotrophin, or proneurotrophins, activity at neurotrophic receptors in promoting cholinergic degeneration; however, it has yet to be explored in adolescent binge drinking. We sought to characterize the pro- and mature neurotrophin expression, alongside their cognate receptors and cholinergic markers in an AIE model. Male and female Sprague Dawley rats underwent 5 g/kg 20% EtOH or water gavage on two-day-on, two-day-off cycles from post-natal day 25–57. Rats were sacrificed 2 h, 24 h, or 3 weeks following the last gavage, and tissue were collected for protein measurement. Western blot analyses revealed that ethanol intoxication reduced the expression of BDNF and vesicular acetylcholine transporter (vAChT) in the PFC, while NGF was lower in the NbM of AIE treated animals. During acute alcohol withdrawal, proNGF in the PFC was increased while proBDNF decreased, and in the NbM proBDNF increased while NGF decreased. During AIE abstinence, the expression of neurotrophins, their receptors, and vAChT did not differ from controls in the PFC. In contrast, in the NbM the expression of both NGF and choline acetyltransferase (ChAT) were reduced long-term following AIE. Taken together these findings suggest that AIE alters the expression of proneurotrophins and neurotrophins during intoxication and withdrawal that favor prodegenerative mechanisms by increasing the expression of proNGF and proBDNF, while also reducing NGF and BDNF. • Adolescent ethanol exposure causes neurotrophin dysregulation. • There is disruption in the ratio of proNGF to mature NGF. • Cholinergic markers are also impacted by adolescent intermittent ethanol exposure. • Changes in pro- and mature NGF contributes to alcohol-related brain damage in an adolescent model. [ABSTRACT FROM AUTHOR]

Brain metastases are one of the most serious clinical problems in breast cancer (BC) progression, associated with lower survival rates and a lack of effective therapies. Thus, to dissect the early stages of the brain metastatic process, we studied the impact of brain organotropic BC cells' secretomes on the establishment of the brain pre‐metastatic niche (PMN). We found that BC cells with specific tropism to the brain caused significant blood–brain barrier (BBB) disruption, as well as microglial activation, in both in vitro and in vivo models. Further, we searched for a brain‐organotropic metastatic signature, as a promising source for the discovery of new biomarkers involved in brain metastatic progression. Of relevance, we identified VGF (nerve growth factor inducible) as a key mediator in this process, also impacting the BBB and microglial functions both in vitro and in vivo. In a series of human breast tumors, VGF was found to be expressed in both cancer cells and the adjacent stroma. Importantly, VGF‐positive tumors showed a significantly worse prognosis and were associated with HER2 (human epidermal growth factor receptor 2) overexpression and triple‐negative molecular signatures. Further clinical validation in primary tumors from metastatic BC cases showed a significant association between VGF and the brain metastatic location, clearly and significantly impacting on the prognosis of BC patients with brain metastasis. In conclusion, our study reveals a unique secretome signature for BC with a tropism for the brain, highlighting VGF as a crucial mediator in this process. Furthermore, its specific impact as a poor prognostic predictor for BC patients with brain metastasis opens new avenues to target VGF to control the progression of brain metastatic disease. © 2024 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

The article concerns the problem of molecular mechanisms of memory formation. In this study the effects of polyclonal antibodies to serotonin-modulating anticonsolidation protein (SMAP) complex and its component dihydropyrimidinase-related protein 2 (DRP2) have been analyzed. Intra-cerebral administration of polyclonal anti-SMAP antibody significantly enhanced elaboration and strengthened memory formation in two complex behavioral conditioned models. At the same time, intra-cerebral administration of anti-SMAP antibody resulted in an increase of the content of nerve growth factor (NGF) in the water-soluble fraction of the hippocampus while intra-cerebral administration of anti-DRP2 antibody caused a decrease in the content of β-III tubulin (a marker of differentiated neurons) in the hippocampus and in the left parietal cortex of untrained rats. The obtained results indicate that DRP2 might participate in regulation of the processes of back remodeling of mature nerve cells of adult organisms, occurring during training of rats in the behavioral paradigm used in this study under the effects of anti-SMAP and anti-DRP2 antibodies. Conclusion is made that back remodeling (dedifferentiation) of mature nerve cells, apparently, is engaged in memory formation.

Objective(s): Despite the many benefits of mesenchymal stem cell (MSC) transplantation for tissue regeneration, there are some limitations to using them, including the high costs, applying invasive procedures, the possibility of transplant rejection, and cell malignancy. This study aimed to investigate the effect of secretions of bone marrow stromal cells (BMSCs) with the cell-free strategy on damaged sciatic nerve with an emphasis on the role of apoptosis and the expression of myelin protein zero (MPZ) and nerve growth factor (NGF) proteins.Materials and Methods: BMSCs were cultured and a 25-fold concentrated conditioned medium (CM) from the cells was provided. After creating a crush injury in the left sciatic nerve of male rats, BMSCs or CM were injected into the injured site of the nerve. Four weeks later, the expression of MPZ, NGF, Bax, and Bcl-2 proteins in the sciatic nerve and histological parameters of the sciatic nerve and gastrocnemius muscle were assessed.Results: The results demonstrated that injection of CM decreased apoptosis and increased expression of MPZ and NGF proteins, improving remyelination and regeneration of the sciatic nerve almost as much as the transplantation of the BMSCs themselves compared to the control group.Conclusion: The results suggest that BMSC secretions may improve remyelination and regeneration of damaged sciatic nerve by increasing the expression of MPZ and NGF and decreasing apoptosis.