UNASSIGNED: Neuroplasticity as a mechanism to overcome central nervous system injury resulting from different neurological diseases has gained increasing attention in recent years. However, deficiency of these repair mechanisms leads to the accumulation of neuronal damage and therefore long-term disability. To date, the mechanisms by which remyelination occurs and why the extent of remyelination differs interindividually between multiple sclerosis patients regardless of the disease course are unclear. A member of the neurotrophins family, the brain-derived neurotrophic factor (BDNF) has received particular attention in this context as it is thought to play a central role in remyelination and thus neuroplasticity, neuroprotection, and memory.
UNASSIGNED: To analyse the current literature regarding BDNF in different areas of multiple sclerosis and to provide an overview of the current state of knowledge in this field.
UNASSIGNED: To date, studies assessing the role of BDNF in patients with multiple sclerosis remain inconclusive. However, there is emerging evidence for a beneficial effect of BDNF in multiple sclerosis, as studies reporting positive effects on clinical as well as MRI characteristics outweighed studies assuming detrimental effects of BDNF. Furthermore, studies regarding the Val66Met polymorphism have not conclusively determined whether this is a protective or harmful factor in multiple sclerosis, but again most studies hypothesized a protective effect through modulation of BDNF secretion and anti-inflammatory effects with different effects in healthy controls and patients with multiple sclerosis, possibly due to the pro-inflammatory milieu in patients with multiple sclerosis. Further studies with larger cohorts and longitudinal follow-ups are needed to improve our understanding of the effects of BDNF in the central nervous system, especially in the context of multiple sclerosis.

BACKGROUND: Circulating cytokines can represent non-invasive biomarkers to improve prediction of clinical outcomes of cancer patients. Here, plasma levels of IL-8, CCL4, osteopontin, LIF and BDNF were determined at baseline (T0), after 2 months of therapy (T2) and, when feasible, at progression (TP), in 70 melanoma patients treated with BRAF and MEK inhibitors. The association of baseline cytokine levels with clinical response, progression-free survival (PFS) and overall survival (OS) was evaluated.
METHODS: Cytokine concentrations were measured using the xMAP technology. Their ability to discriminate between responding (Rs) and non-responding (NRs) patients was assessed by Receiver Operating Characteristics analysis. PFS and OS were estimated with the Kaplan-Meier method. The Cox proportional hazard model was used in the univariate and multivariate analyses to estimate crude and adjusted hazard ratios with 95% confidence intervals.
RESULTS: CCL4 and LIF were undetectable in the majority of samples. The median osteopontin concentration at T0 and T2 was significantly higher in NRs than in Rs. The median T0 and T2 values of IL-8 were also higher in NRs than in Rs, although the statistical significance was not reached. No differences were detected for BDNF. In 39 Rs with matched T0, T2, and TP samples, osteopontin and IL-8 significantly decreased from T0 to T2 and rose again at TP, while BDNF levels remained unchanged. In NRs, none of the cytokines showed a significant decrease at T2. Only osteopontin demonstrated a good ability to discriminate between Rs and NRs. A high IL-8 T0 level was associated with significantly shorter PFS and OS and higher risk of progression and mortality, and remained an independent negative prognostic factor for OS in multivariate analysis. An elevated osteopontin T0 concentration was also significantly associated with worse OS and increased risk of death. Patients with high IL-8 and high osteopontin showed the lowest PFS and OS, and in multivariate analysis this cytokine combination remained independently associated with a three- to six-fold increased risk of mortality.
CONCLUSIONS: Circulating IL-8 and osteopontin appear useful biomarkers to refine prognosis evaluation of patients undergoing targeted therapy, and deserve attention as potential targets to improve its clinical efficacy.

Temporal lobe epilepsy (TLE) is a type of focal epilepsy characterized by spontaneous recurrent seizures originating from the hippocampus. The epigenetic reprogramming hypothesis of epileptogenesis suggests that the development of TLE is associated with alterations in gene transcription changes resulting in a hyperexcitable network in TLE. DNA 5-methylcytosine (5-mC) is an epigenetic mechanism that has been associated with chronic epilepsy. However, the contribution of 5-hydroxymethylcytosine (5-hmC), a product of 5-mC demethylation by the Ten-Eleven Translocation (TET) family proteins in chronic TLE is poorly understood. 5-hmC is abundant in the brain and acts as a stable epigenetic mark altering gene expression through several mechanisms. Here, we found that the levels of bulk DNA 5-hmC but not 5-mC were significantly reduced in the hippocampus of human TLE patients and in the kainic acid (KA) TLE rat model. Using 5-hmC hMeDIP-sequencing, we characterized 5-hmC distribution across the genome and found bidirectional regulation of 5-hmC at intergenic regions within gene bodies. We found that hypohydroxymethylated 5-hmC intergenic regions were associated with several epilepsy-related genes, including Gal, SV2, and Kcnj11 and hyperdroxymethylation 5-hmC intergenic regions were associated with Gad65, TLR4, and Bdnf gene expression. Mechanistically, Tet1 knockdown in the hippocampus was sufficient to decrease 5-hmC levels and increase seizure susceptibility following KA administration. In contrast, Tet1 overexpression in the hippocampus resulted in increased 5-hmC levels associated with improved seizure resiliency in response to KA. These findings suggest an important role for 5-hmC as an epigenetic regulator of epilepsy that can be manipulated to influence seizure outcomes.

OBJECTIVE: To study the effects of resveratrol on heroin addiction-related behaviors and to preliminarily explore the possible intervention mechanism of resveratrol in heroin dependence.
METHODS: The effects of resveratrol on heroin withdrawal symptoms were observed by naloxone; The effect of resveratrol on heroin reward memory acquisition was detected by CPP paradigm; The effect of resveratrol on the mental excitability of heroin was tested by open field experiment; The effect of resveratrol on heroin spatial learning and memory was tested by water maze test. Western blot was used to detect Sirtuin 1 (SIRT1) Expression of brain-derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), and postsynaptic density protein (PSD95).
RESULTS: The behavioral results showed that the withdrawal behavior of the resveratrol intervention group was reduced compared with the heroin chronic dependence group (P<0.05), and the shift score of the conditioned place preference test of the resveratrol intervention group was reduced compared with the heroin chronic dependence group (P<0.05) The spatial learning and memory ability of the water maze in the resveratrol intervention group was improved compared with the heroin chronic dependence group (P<0.05), and the mental excitability of the resveratrol intervention group was lower than that of the heroin chronic dependence group (P<0.05), but higher than that of the saline group (P<0.05); SIRT1 The expression levels of BDNF, GDNF and PSD95 protein were significantly increased (P<0.05).
CONCLUSIONS: The behavioral results of this study suggest that resveratrol can be used as a potential drug to treat heroin dependence. At the same time, SIRT1 The expression of BDNF, GDNF, and PSD95 increased; SIRT1, BDNF, GDNF, and PSD95 play an essential role in heroin addiction.

BACKGROUND: Endometriosis is a chronic inflammatory disease that affects ∼ 10 % of women. A significant fraction of patients experience limited or no efficacy with current therapies. Tissue adjacent to endometriosis lesions often exhibits increased neurite and vascular density, suggesting that disease pathology involves neurotrophic activity and angiogenesis.
OBJECTIVE: We aim to evaluate the potential for key tyrosine-kinase-receptor-coupled neurotrophic molecules to contribute to endometriosis-associated pain in mice.
METHODS: Peritoneal fluid was collected from endometriosis patients undergoing surgery and the levels of NGF and VEGFR1 regulators (VEGFA, VEGFB, PLGF, and sVEGFR1) were quantified by ELISA. VEGFR1 regulator concentrations were used to calculate VEGFR1 occupancy. We used genetic depletion, neutralizing antibodies, and pharmacological approaches to specifically block neurotrophic ligands (NGF or BDNF) or receptors (VEGFR1, TRKs) in a murine model of endometriosis-associated pain. Endometriosis-associated pain was measured using von Frey filaments, quantification of spontaneous abdominal pain-related behavior, and thermal discomfort. Disease parameters were evaluated by lesion size and prevalence. To evaluate potential toxicity, we measured the effect of entrectinib dose and schedule on body weight, liver and kidney function, and bone structure (via micro-CT).
RESULTS: We found that entrectinib (pan-Trk inhibitor) or anti-NGF treatments reduced evoked pain, spontaneous pain, and thermal discomfort. In contrast, even though calculated receptor occupancy revealed that VEGFR1 agonist levels are sufficient to support signaling, blocking VEGFR1 via antibody or tamoxifen-induced knockout did not reduce pain or lesion size in mice. Targeting BDNF-TrkB with an anti-BDNF antibody also proved ineffective. Notably, changing dosing schedule to once weekly eliminated entrectinib-induced bone-loss without decreasing efficacy against pain.
CONCLUSIONS: This suggests NGF-TrkA signaling, but not BDNF-TrkB or VEGF-VEGFR1, mediates endometriosis-associated pain. Moreover, entrectinib blocks endometriosis-associated pain and reduces lesion sizes. Our results also indicated that entrectinib-like molecules are promising candidates for endometriosis treatment.

Previous research have reported that modulating the gut microbiome composition by fecal microbiota transplantation and probiotic administration can alleviate seizure occurrence and severity. Saccharomyces boulardii (SB) is a yeast probiotic that has demonstrated ameliorating effects on anxiety, memory and cognitive deficit, and brain amyloidogenesis. In this research, our goal was to examine the anti-seizure effects of SB on the pentylenetetrazole (PTZ)-kindled male Wistar rats. The animals were randomly categorized into four test groups. The rats were orally administered with saline (control and PTZ groups) or S. boulardii (SB + PTZ and SB groups) for 57 days. From the 29th day of the experiment, the animals received intraperitoneally saline (control and SB groups) or PTZ (PTZ and SB + PTZ groups) on alternate days for 30 days. The administration dose of SB and PTZ was 1010 CFU/ml/day and 35 mg/kg, respectively. We assessed animal seizure behavior, neuroinflammation, oxidative stress, and the levels of matrix metalloproteinase-9 (MMP-9) and brain-derived neurotrophic factor (BDNF) in the hippocampus tissue. S. boulardii hindered the PTZ-induced kindling development. SB treatment elevated glutathione (GSH) and total antioxidant capacity (TAC) and reduced malondialdehyde (MDA) levels. SB also lessened the hippocampal levels of BDNF and MMP-9. Following SB supplementation, proinflammatory cytokines interleukin-1 beta (IL-1β) and IL-6 were lowered, and anti-inflammatory cytokine IL-10 was enhanced. Overall, our data indicated, for the first time, the positive impact of SB on the PTZ-kindled seizure rat model. The anti-seizure activity of SB was mediated by modulating oxidative stress, neuroinflammation, and MMP-9 and BDNF levels.

UNASSIGNED: It aims to explore the effect of target task-oriented phase training on fibrinogen (Fbg), angiopoietin (Ang-1), vascular endothelial growth factor (VEGF), serum brain-derived neurotrophic factor (BDNF), and quality of life in post-operative patients with brain trauma.
UNASSIGNED: 142 patients with brain trauma who were operated on in neurosurgery of our hospital from March 2020 to March 2023 were chosen and separated into two groups by random number table. The control group (n=71) received routine post-operative training. The experimental group (n=71) received target task-oriented training based on the control group, and the serum cell levels of nursing for 3, 7, and 14 days were compared. Improvement of limb function and quality of life after 2, 4, and 6 weeks of nursing care is observed.
UNASSIGNED: Cilj ovog istraživanja je bio da se ispita efekat ciljanih zadatih treninga u fazi rehabilitacije na nivoe fibrinogena (Fbg), angiopoetina-1 (Ang-1), vaskularnog endotelijalnog faktora rasta (VEGF), serumskog faktora neurotrofnog mozga (BDNF) i na kvalitet života kod pacijenata nakon operacije u vezi sa povredom mozga.
UNASSIGNED: Odabrano je 142 pacijenata sa povredom mozga koji su operisani na odeljenju neurohirurgije naše bolnice od marta 2020. do marta 2023. godine i koji su podeljeni u dve grupe slučajnim izborom. Kontrolna grupa (n=71) je imala rutinske postoperativne treninge, dok je eksperimentalna grupa (n=71) dobijala ciljane zadate treninge na osnovu kontrolne grupe, a nivoi faktora u serumu su praćeni tokom 3, 7 i 14 dana. Posmatrano je poboljšanje funkcije udova i kvaliteta života posle 2, 4 i 6 nedelja nege.
UNASSIGNED: Pre nege, upoređivanje nivoa faktora u serumu, rezultata za funkciju udova i rezultata za kvalitet života između dve grupe bilo je sa P>0,05. Nakon 3, 7 i 14 dana nege, Fbg u kontrolnoj grupi je bio viši nego u eksperimentalnoj grupi. Nivoi Ang-1, VEGF i BDNF u eksperimentalnoj grupi su bili viši nego u kontrolnoj grupi (P<0,05). Nakon 2, 4 i 6 nedelja nege, FMA rezultati za gornje i donje udove u kontrolnoj grupi su bili niži nego u eksperimentalnoj grupi, sa P<0,05. Rezultati na fiziološkom, psihološkom, socijalnom polju i na polju životnog okruženja kod kontrolne grupe su bili niži nego u eksperimentalnoj grupi, sa P<0,05.
UNASSIGNED: Primena ciljanih zadatih treninga u fazi rehabilitacije kod pacijenata sa povredom mozga nakon operacije može da pomogne u podizanju nivoa Fbg, Ang-1, VEGF i BDNF u serumu, da poboljša funkciju udova i unapredi kvalitet života.

UNASSIGNED: The threat of hearing loss has become a universal reality. Gentamycin (GM) can lead to ototoxicity and may result in permanent hearing loss. This study aimed to elucidate whether the hypolipidemic drug Ezetimibe (EZE) has a possible underlying mechanism for protecting rats from GM-induced ototoxicity.
UNASSIGNED: 30 male Wister albino rats were separated into three groups, ten in each group: control, GM, and GM + EZE. At the end of the experiment, rats underwent hearing threshold evaluation via auditory brainstem response (ABR), carotid artery blood flow velocity (CBV), and resistance (CVR) measurement, in addition to a biochemical assessment of serum malondialdehyde (MDA), nitric oxide (NO), catalase (CAT), hemeOxygenase-1 (HO-1), and tumor necrosis factor-α (TNF-α). Also, real-time PCR was employed to quantify the levels of brain-derived neurotrophic factor (BDNF). Cochlea was also studied via histological and immunohistochemical methods. GM revealed a significant increase in CVR, MDA, NO, and TNF-α and a significant decrease in ABR, CBV, CAT, HO-1, and cochlear BDNF expression. EZE supplementation revealed a significant rise in ARB in addition to CBV and a decline in CVR and protected cochlear tissues via antioxidant, anti-inflammatory, and antiapoptotic mechanisms via downregulating Caspase-3 immunoreaction, upregulating proliferating cellular nuclear antigen (PCNA) immunoreaction, and upregulating of the cochlear BDNF expression. Correlations were significantly negative between BDNF and MDA, NO, TNF-α, COX 2, and caspase-3 immunoreaction and significantly positive with CAT, HO-1, and PCNA immunoreaction.
UNASSIGNED: EZE can safeguard inner ear tissues from GM via antioxidant, anti-inflammatory, and antiapoptotic mechanisms, as well as upregulation of BDNF mechanisms.

Exercise provides a range of cognitive benefits, including improved memory performance. Previously, we demonstrated that 14 days of continuous voluntary wheel-running exercise enables learning in a hippocampus-dependent Object Location Memory (OLM) task under insufficient, subthreshold training conditions in adult mice. Whether similar exercise benefits can be obtained from consistent intermittent exercise as continuous exercise is unknown. Here, we examine whether intermittent exercise (the weekend warrior effect: 2 days of exercise a week for 7 weeks) displays similar or distinct cognitive benefits as previously examined with 14 days of continuous exercise. We find that both continuous and intermittent exercise parameters similarly enable hippocampus-dependent OLM compared to the 2-day exercise control group. Mice receiving intermittent exercise maintained cognitive benefits following a 7-day sedentary delay, whereas mice that underwent 14 continuous days of exercise showed diminished cognitive benefits as previously reported. Further, compared to continuous exercise, intermittent exercise mice exhibited persistently elevated levels of the genes Acvr1c and Bdnf which we know to be critically involved in hippocampus-dependent long-term memory in the dorsal hippocampus. Together findings suggest that consistent intermittent exercise persistently enables hippocampal-dependent long-term memory. Understanding the optimal parameters for persistent cognitive function and the mechanisms mediating persistent effects will aid in therapeutic pursuits investigating the mitigation of cognitive ailments.

UNASSIGNED: Previous studies in different populations have shown that vitamin D supplementation may reduce depression levels. In adolescents, vitamin D deficiency has been identified as a factor contributing to the onset of depression. This study aimed to establish a model of adolescent depression in mice by using the scientific unpredictable chronic mild stress (UCMS) model and to preliminarily evaluate the effect of vitamin D on the occurrence and development of depression and whether it is related to the protein expression of the BDNF pathway.
UNASSIGNED: The UCMS method was used to establish a model of adolescent depression in 4-week-old C57BL/6 male mice, randomly divided into five groups: Control group, Stress group, Stress+ low-dose group, Stress+ medium-dose group, Stress+ high-dose group. At the same time as chronic stress, the administration groups were given intramuscular injections of different doses of vitamin D. After 8 weeks, behavioral tests, including the forced swimming test (FST) and open field test (OFT), were performed on each group of mice, along with recording of indicators, blood vitamin D level detection, and brain tissue western blot analysis.
UNASSIGNED: The results showed a significant difference in vitamin D levels among mice in different groups after 8 weeks (P=0.012). The results of behavioral testing showed a significant difference in the static time of forced swimming among the groups (P<0.001). Compared with the UCMS group, the static time of mice with vitamin D injection was significantly reduced (P<0.001). The total number of times mice entered the central area, the total distance of movement, and the time spent in the central area significantly increased after vitamin D injection compared with the UCMS-only group (all P<0.001). There was no significant difference in the expression of BDNF in the brain tissues of experimental mice (P>0.05).
UNASSIGNED: In conclusion, in the mouse adolescent depression model, appropriate vitamin D supplementation can reduce the occurrence of stress-induced depression. Furthermore, vitamin D deficiency may also serve as a potential risk factor for depression.