Background Nerve growth factor (NGF) is a novel target of pain therapeutics for oral cancer, and it plays a main role in the nociception of chronic pain. Surgery, along with chemotherapy or radiotherapy, is the gold standard for treating patients, but the side effects are significant as well. Newer effective interventions with natural phytochemicals could improve patient compliance and enhance the quality of life among patients with oral cancer. A literature search revealed a positive correlation between NGF and oral cancer pain. Nigella sativa (N. sativa) and Cuscuta reflexa (C. reflexa) have proven anticancer effects, but their activity with NGF is unexplored. Aims and objectives We aimed to identify the potential phytochemicals in N. sativa and C. reflexa. We also checked the NGF-blocking activity of the phytochemicals. Molecular docking and molecular dynamic (MD) simulations evaluated the binding energy and stability between the NGF protein and selected phytochemical ligands. Materials and methods We obtained protein NGF structure from UniProt (ID: 4EDX, P01138, Beta-nerve growth factor), ligand (thymoquinone) structure using PubChem ID: 10281, and ligand (cuscutin) structure using PubChem ID: 66065. Maestro protein (Schrödinger Inc., Mannheim, Germany) was used for molecular docking. Desmond Simulation Package (Schrödinger Inc., Mannheim, Germany) was used to model MD for 100 nanoseconds (ns). We have assessed the interaction between the protein and ligands by root mean square deviation (RMSD) values.  Results The interaction of thymoquinone and cuscutin with NGF was assessed. While interacting with thymoquinone, there was mild fluctuation from 0.6 Å to 2.5 Å up to 80 ns and ended up at 4.8 Å up to 100 ns. While interacting with cuscutin, mild fluctuation was seen from 0.8 Å to 4.8 Å till 90 ns and ended at 6.4 Å up to 100 ns. We found a stable interaction between our drug combination and the NGF receptor. Conclusion We have identified a stable interaction between thymoquinone, cuscutin, and NGF by our MD simulations. Hence, it could be used as an NGF inhibitor for pain relief and to control tumor progression. Further in vitro and in vivo evaluations of this novel drug combination with phytochemicals will help us understand their biological activities and potential clinical applications in oral cancer therapeutics.

The emergence of the Nerve Growth Factor (NGF) has promoted the development of neuroprotective therapy; however, it has little effect on cerebral ischemia because of its poor Blood-Brain Barrier (BBB) permeability. Specific Mode Electroacupuncture Stimulation (SMES) can open BBB safely and effectively; however, it has shown inconclusive clinical effects and indirect clinical evidence in the recovery phase. Hence, the authors conducted a multicentre, randomized, placebo-controlled, assessor-blinded clinical trial to assess the effectiveness and safety of SMES combined with NGF treatment used during ischaemic stroke recovery.
A total of 288 stroke patients from three hospitals will be recruited and randomly allocated to four groups: acupuncture + placebo, acupuncture + NGF, SMES + placebo, and SMES + NGF, in a 1:1:1:1 ratio. Assessment data will be collected at baseline, 2-weeks, and 4-weeks during the treatment period, as well as at the 4-week and 8-week follow-up after treatment completion. The primary outcome measure will be the basic cure rate. The secondary outcome measures include the simplified Modified Barthel Index, Timed Up and Go Test, Fugl-Meyer Assessment of Motor Function Score, Tinetti Performance Oriented Mobility Assessment, Montreal Cognitive Assessment, and Loewenstein Occupational Therapy Cognitive Assessment. Moreover, resting-state functional magnetic resonance imaging and Functional near-infrared spectroscopy can detect changes in cerebral blood flow and brain function and investigate the relationship between the clinical efficacy and mechanism of the prescribed interventions.
This study will provide clinical evidence for the efficacy and safety of SMES combined with NGF in the treatment of stroke patients.

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.
BACKGROUND: NCT03982368; registered May 23, 2019.

OBJECTIVE: An overexpression of nerve growth factor (NGF) in the urothelium is discussed to lead to neuronal hyperinnervation of the bladder detrusor. The aim was to assess the sensory and sympathetic innervation of the detrusor in unclosed exstrophic bladders patients with known overexpression of NGF in the urothelium.
METHODS: Full-thickness bladder biopsies were prospectively obtained from 34 infants at delayed primary bladder closure between 01/2015 and 04/2020. The bladder biopsies were immunohistochemically stained with antibodies against S100, calcitonin gene-related peptide (anti-CGRP), Neurofilament 200 (anti-NF200), and tyrosine-hydroxylase (anti-TH). Specimens from 6 children with congenital vesicoureterorenal reflux (VUR) served as controls.
RESULTS: There was no statistically significant difference in nerve fiber density in any of the immunohistochemical assessments (anti-S100 [p = 0.210], anti-CGRP [p = 0.897], anti-NF200 [p = 0.897]), and anti-TH [p = 0.956]) between patients with BE and patients with VUR. However, we observed a trend toward lower nerve fiber densities in exstrophic detrusor.
CONCLUSIONS: Overall our results showed an unharmed innervation pattern in this cohort but a lower density of nerve fibers in the detrusor compared to controls. Further studies in patients after successful primary closure are needed to clarify the potential impact of the urothelial overexpression of NGF modulating the innervation pattern in exstrophic bladders.

UNASSIGNED: In observational studies, sepsis and circulating levels of cytokines have been associated with unclear causality. This study used Mendelian randomization (MR) to identify the causal direction between circulating cytokines and sepsis in a two-sample study.
UNASSIGNED: An MR analysis was performed to estimate the causal effect of 41 cytokines on sepsis risk. The inverse-variance weighted random-effects method, the weighted median-based method, and MR-Egger were used to analyze the data. Heterogeneity and pleiotropy were assessed using MR-Egger regression and Cochran\'s Q statistic.
UNASSIGNED: Genetically predicted beta-nerve growth factor (OR = 1.12, 95% CI [1.037-1.211], P = 0.004) increased the risk of sepsis, while RANTES (OR = 0.92, 95% CI [0.849-0.997], P = 0.041) and fibroblast growth factor (OR = 0.869, 95% CI [0.766-0.986], P = 0.029) reduced the risk of sepsis. These findings were robust in extensive sensitivity analyses. There was no clear association between the other cytokines and sepsis risk.
UNASSIGNED: The findings of this study demonstrate that beta-nerve growth factor, RANTES, and fibroblast growth factor contribute to sepsis risk. Investigations into potential mechanisms are warranted.

We reviewed fundamental studies on muscular pain, encompassing the characteristics of primary afferent fibers and neurons, spinal and thalamic projections, several muscular pain models, and possible neurochemical mechanisms of muscle pain. Most parts of this review were based on data obtained from animal experiments, and some researches on humans were also introduced. We focused on delayed-onset muscle soreness (DOMS) induced by lengthening contractions (LC), suitable for studying myofascial pain syndromes. The muscular mechanical withdrawal threshold (MMWT) decreased 1-3 days after LC in rats. Changing the speed and range of stretching showed that muscle injury seldom occurred, except in extreme conditions, and that DOMS occurred in parameters without muscle damage. The B2 bradykinin receptor-nerve growth factor (NGF) route and COX-2-glial cell line-derived neurotrophic factor (GDNF) route were involved in the development of DOMS. The interactions between these routes occurred at two levels. A repeated-bout effect was observed in MMWT and NGF upregulation, and this study showed that adaptation possibly occurred before B2 bradykinin receptor activation. We have also briefly discussed the prevention and treatment of DOMS.

Objective: Immaturity of the digestive tract and enteric nervous system is a widely accepted theory for infantile colic (IC) etiopathogenesis. The study aimed to show whether neurotrophins that are necessary for normal functioning and development of the gastrointestinal system have a role in the pathogenesis of IC. Materials and Methods: The IC group (n = 75) comprising the mothers of infants with IC and the control group (n = 75) were included to this cross-sectional case-control study. Brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), and nerve growth factor (NGF) levels of breast milk samples were evaluated by immunosorbent analysis method. Results: The mean age of infants with IC was 7.3 ± 2.8 weeks, while the mean age of the control group was 8.1 ± 2.9 weeks (p = 0.110). No significant difference was found between the breast milk BDNF, GDNF, CNTF, and NGF levels of two groups (p = 0.941, p = 0.510, p = 0.533, p = 0.839, respectively). Conclusions: This is the first report comparing the neurotrophin levels of the breast milk samples taken from the mothers of infants with and without IC. The study demonstrated that breast milk neurotrophin levels of the mothers did not differ significantly between the infants with and without IC.

To measure the therapeutic effect of an anti-oxidant, edaravone (EDV), or neurotrophic treatment with nerve growth factor (NGF) as an add-on treatment for alcohol-related brain damage (ARBD).
Multi-centre, randomised, single-blinded, comparative clinical trial.
One hundred and twenty-two inpatients recruited from seven hospitals in different regions of China, all diagnosed with ARBD and aged 18 to 65 years old; among them, only two were female.
Patients were randomly assigned to receive one of three treatments for 2 weeks: 40 patients, treatment as usual (TAU: a combination of intramuscular injections of thiamine, intravenous infusions of other B vitamins with vitamin C and oral medication with vitamin E per day); 40, EDV add-on treatment to TAU (intravenous infusion with 30 mg of EDV twice per day); and 42, NGF add-on treatment to TAU (intramuscular injection of 20 μg of NGF per day). The patients underwent follow-up for 24 weeks.
The primary outcome was the composite score of executive cognitive function in the 2nd week after treatment, which was measured as the mean of the Z scores of the assessments, including the digit symbol substitute test (DSST), digit span memory test-forward (DST-F), digit span memory test-reverse (DST-R) and space span memory test (SSMT). The secondary outcomes were the composite scores at later follow-ups, the score for each component of cognitive function, global cognitive function measured by the Montreal Cognitive Assessment (MoCA), craving for alcohol and the safety of the therapies.
EDV add-on treatment improved the composite score of executive cognitive function better than TAU in the 2nd week (adjusted mean difference: 0.24, 95% confidence interval 0.06 to 0.41; P = 0.008), but NGF add-on treatment did not (adjusted mean difference: 0.07, 95% confidence interval -0.09 to 0.24; P = 0.502). During the follow-up to 24 weeks, EDV add-on treatment improved the composite score of executive cognitive function and DST-R score better than TAU (both P < 0.01). Craving for alcohol was relieved in all three groups. No severe adverse events were observed.
The short-term addition of edaravone to supplementary therapy treatment for alcohol-related brain damage (ARBD) improved executive cognitive function in patients with ARBD.

UNASSIGNED: A stereological and histopathological study in an animal model.
UNASSIGNED: This study explores the effects of the nerve growth factor and photobiomodulation therapy on the damaged nerve tissue and fracture healing.
UNASSIGNED: A total of 24 rabbits were divided into 4 groups: control group (n = 5), nerve growth factor (NGF) group (n = 7), photobiomodulation (PBMT) group (n = 6), and nerve growth factor and photobiomodulation therapy (NGF+PBMT) group (n = 6). The vertical fracture was performed between the mental foramen and the first premolar, and the mental nerve was crushed for 30 seconds with a standard serrated clamp with a force of approximately 50 N in all groups. The control group received an isotonic solution (.02 mL, .09% NaCl) to the operation site locally. The NGF group received 1 μg human NGF-β/.9% .2 mL NaCl solution for 7 days locally. The PBMT group received PBMT treatment (GaAlAs laser, 810 nm, .3 W, 18 J/cm2) every 48 hours for 14 sessions following the surgery. The NGF+PBMT group received both NGF and PBMT treatment as described above. After 28 days, the bone tissues and mental nerves from all groups were harvested and histologically and stereologically analyzed.
UNASSIGNED: According to the stereological results, the volume of the new vessel and the volume of the new bone were significantly higher in the PBMT group than in other groups (P < .001). According to the histopathological examinations, higher myelinated axons were observed in experimental groups than in the control group.
UNASSIGNED: As a result, PBMT has beneficial effects on bone regeneration. Based on the light microscopic evaluation, more regenerated axon populations were observed in the NGF group than in the PBMT and PBMT + NGF groups in terms of myelinated axon content.

Observational studies have reported an association between circulating cytokines and sepsis. However, the precise causal relationship between these factors remains unclear. The objective of this study was to explore the causal link between circulating cytokines and sepsis using genetic data within the framework of Mendelian Randomization (MR).
We performed a two-sample MR analysis to investigate this causality relationship in individuals of European ancestry. The publicly available genome-wide association studies (GWAS) statistics were used. We selected eligible instrumental single nucleotide polymorphisms (SNPs) that were significantly related to the circulating cytokines. Multiple MR analysis approaches were carried out, which included inverse variance weighted (IVW), Weighted Median, MR-Egger, Weighted Mode, Simple Mode, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods.
We found evidence to support the causal role of genetically predicted circulating levels on decreased risk of sepsis, including RANTES (OR = 0.920, 95% CI: 0.849-0.997, P = 0.041) and basic fibroblast growth factor (basic-FGF) (OR = 0.869, 95% CI: 0.766-0.986, P = 0.029). Additionally, MR analysis positive causal association of between beta-nerve growth factor (β-NGF) and sepsis (OR = 1.120, 95% CI: 1.037-1.211, P = 0.004). The results of MR-Egger, Weighted Median, Weighted Mode, and Simple Mode methods were consistent with the IVW estimates. Sensitivity analysis showed no horizontal pleiotropy to bias the causal estimates.
This MR study provides first novel evidence that genetically predicted causal association of circulating levels of RANTES, basic-FGF, and β-NGF with altered sepsis risk. The findings shed light on the potential involvement of these cytokines in sepsis pathogenesis. Although requiring additional confirmation, the results contribute new insights into cytokine mediators in sepsis and suggest promising future research directions.