A review on recent advances on nobiletin in central and peripheral nervous system diseases.

In recent years, the role of nobiletin in neuronal disorders has received extensive attention. However, the study of nobiletin in the peripheral nervous system is limited. Nobiletin, as a compound with high fat solubility, high bioavailability and low toxicity, has been extensively studied. Accumulating scientific evidence has shown that nobiletin has a variety of biological functions in the nervous system, such as inhibiting the expression of inflammatory factors, reducing the neurotoxic response, improving the antioxidant capacity, promoting the survival of nerve cells, promoting axon growth, reducing blood‒brain barrier permeability, reducing brain oedema, promoting cAMP response element binding protein expression, improving memory, and promoting mild depolarization of nerve cell mitochondria to improve antioxidative stress capacity. Accumulating studies have shown that nobiletin also protects enteric nervous system, spinal cord and sciatic nerve. To explore the new therapeutic potential of nobiletin in the nervous system, recent and relevant research progress is reviewed in this article. This will provide a new research idea for nobiletin in the nervous system.

Mitochondria-associated regulation in adipose tissues and potential reagents for obesity intervention.

Introduction: A systematic review analysis was used to assess the profile of mitochondrial involvement in adipose tissue regulation and potential reagents to intervene in obesity through the mitochondrial pathway. Methods: Three databases, PubMed, Web of Science, and Embase, were searched online for literature associated with mitochondria, obesity, white adipose tissue, and brown adipose tissue published from the time of their creation until June 22, 2022, and each paper was screened. Results: 568 papers were identified, of which 134 papers met the initial selection criteria, 76 were selected after full-text review, and 6 were identified after additional searches. A full-text review of the included 82 papers was performed. Conclusion: Mitochondria play a key role in adipose tissue metabolism and energy homeostasis, including as potential therapeutic agents for obesity.

Development and validation of a clinical cure marker based on negative lymph nodes for gastric cancer after gastrectomy.

Objective: To explore lymph node (LN)-related derived indicators as clinical cure markers for gastric cancer (GC) after gastrectomy. Methods: Data of resected GC patients were extracted from the SEER database and our own department. Propensity score matching (PSM) was used to balance the baseline differences between the clinical cure and the nonclinical cure groups. The area under the curve (AUC) and decision curve analysis (DCA) were used to choose the optimal marker, and survival analysis was used to validate the clinical value of the most effective marker. Results: After PSM, the differences in age, sex, race, location, surgical type, and histologic type between the two groups were significantly reduced (all P > 0.05), and the AUCs of examined LNs (ELNs), negative LNs (NLNs), ESR (ELNs/tumor size), ETR (ELNs/T-stage), NSR (NLNs/tumor size), NTR (NLNs/T-stage), EPR (ELNs/PLNs) and NPR (NLNs/PLNs) were 0.522, 0.625, 0.622, 0.692, 0.706, 0.751, 7.43, and 7.50, respectively. When NTR was 5.9, the Youden index of 0.378 was the highest. The sensitivity and specificity were 67.5% and 70.3% in the training group and 66.79% and 67.8% in the validation group, respectively. DCA showed that NTR had the largest net clinical benefit, and patients with NTR greater than 5.9 had significantly prolonged overall survival in our own cohort. Conclusion: NLNs, NTR, NSR, ESR, ETR, NPR and EPR can be used as clinical cure markers. However, NTR was the most effective, and the best cutoff value was 5.9.

Nobiletin protects enteric nerves and ameliorates disordered bowel motility in diet-induced obese mice via increasing Trem2 expression.

Nobiletin can regulate lipid metabolism and protect the central nervous system. However, its role in the enteric nervous system (ENS) of obese subjects is still unclear. To investigate the ENS protective effects and mechanism of nobiletin in obese mice, male C57BL/6 mice were fed a chow diet and a high-fat diet (HFD) for 8 weeks. The identified obese and control mice were grouped and administered vehicle, nobiletin 40 mg/kg, 100 mg/kg or 200 mg/kg daily for 4 weeks. The major indexes of obesity, intestinal transit rate, PGP9.5, nNOS, TNF-α, IL-1ß, IL-6, IL-10, Bcl2 and Bax were measured. The full-length transcriptome was used to analyze differentially expressed genes (DEGs) in the colon. The results indicated that nobiletin effectively improved major indexes of obesity and bowel motility function, suppressed the expression of TNF-α, IL-1ß, IL-6 and Bax, and upregulated the expression of IL-10, Bcl2, PGP9.5 and nNOS. Based on full-length transcriptome sequencing, nobiletin regulated lipid metabolism and inflammation via the PPAR and NOD-like receptor signaling pathways. Trem2 expression was significantly reduced in obese mice. However, Trem2 expression was significantly increased after nobiletin treatment in obese mice. The enrichment analysis showed that Trem2 plays an important role in enteric neuroinflammation. In conclusion, nobiletin regulates lipid metabolism and inflammation in obese mice. Trem2 is a potential target of nobiletin for ENS protection in obese mice.

Potential novel biomarkers in small intestine for obesity/obesity resistance revealed by multi-omics analysis.

BACKGROUND: Although obesity is caused by different factors, individual susceptibility to obesity differs among people under the same circumstances. The microbiota in the caecum or fresh faeces and metabolites in blood or urine contribute to obesity resistance; however, the microbiota or metabolites in the small intestine have not been extensively studied. METHODS: To investigate the relationship between the microbiota or metabolites in the small intestine and susceptibility to obesity, eighty-eight male C57BL/6 mice were fed a high-fat diet (HFD) for 8 weeks to establish two models of obesity and obesity resistance. For further study, six mice were chosen from among the obesity models, and twelve mice were randomly chosen from among the obesity resistance models. After fasting plasma glucose and behavioural testing, the mice were fed in single cages for another 4 weeks to observe their weight and food intake. All mice were sacrificed at 20 weeks of age. Serum ALT, AST, HDL, LDL, TG and TC levels were measured using an automatic biochemical analyser. The microbiota and metabolites in the small intestine contents were analysed using 16 S sequencing and an ultrahigh-performance liquid chromatographic system, respectively. Transcripts in the jejunum were evaluated using full-length transcriptome sequencing and verified by qPCR. RESULTS: The results showed that HFD induced depression and anxiety behaviours and higher fasting plasma glucose, ALT, AST, HDL, LDL, TG and TC levels in the obese mice; however, these levels were improved in obese resistance mice. The correlation analysis showed that the phosphatidylcholine, TG, and phosphatidylethanolamine levels were higher in obese mice and correlated positively with intestinal microflora (Desulfovibrio and Gemella) and the Cxcl10 gene. A higher abundance of Clostridium_sensu_stricto_1 in obesity-resistant mice correlated negatively with the metabolite contents (neuromedin N and enkephalin L) and Pck1 gene expression and correlated positively with certain metabolites (5-hydroxy-L-tryptophan, cinnamyl alcohol and 1 H-indole-3-acetamide) and genes expression (Gdf15, Igfbp6 and Spp1). CONCLUSION: Clostridium_sensu_stricto_1, neuromedin N, enkephalin L, Pck1, 5-hydroxy-L-tryptophan, Cxcl10 and cinnamyl alcohol may be novel biomarkers in the small intestine for obesity/obesity resistance. These might be helpful for obesity prevention or for treating obese patients.

Survival comparison between endoscopic and surgical resection for non-ampullary duodenal neuroendocrine tumor (1-2 cm).

The treatment plan for non-ampullary duodenal neuroendocrine tumors (d-NETs) with diameters 1-2 cm remains controversial. We therefore aimed to compare the prognostic effects of endoscopic treatment and surgical resection on non-ampullary d-NETs with 1-2 cm diameters. A total of 373 eligible patients were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was performed to match patients 1:1 according to clinicopathological characteristics. Disease-specific survival (DSS) and overall survival (OS) were calculated. Before PSM, there was no significant difference in DSS or OS (all P > 0.05), but the T stage, N stage, and TNM stage were significantly different between the two surgical methods (all P < 0.05). After 1:1 PSM, the differences in clinicopathological characteristics were significantly reduced (all P > 0.05). Survival analysis showed that tumor grade was correlated with DSS and that age was correlated with OS (all P < 0.05); however, the surgical method and other clinicopathological characteristics were not correlated with prognosis (all P > 0.05). Subgroup survival analysis of patients with T2N0M0 disease and tumors invading the lamina propria or submucosa showed that the 5-year DSS and OS rates were not significantly different according to the surgical approach (all P > 0.05). The surgical approach has no significant effect on the prognosis of patients with non-ampullary d-NETs with 1-2 cm diameters, especially those with T2N0M0 disease. This suggests that endoscopic treatment may be a preferred option for these patients.

Taxifolin suppresses the malignant progression of gastric cancer by regulating the AhR/CYP1A1 signaling pathway.

The development of novel approaches for the treatment of gastric cancer is of utmost importance. Taxifolin (Tax) has been reported to possess biological activities against a number of types of cancer. The objective of the present study was to examine the effects of Tax on gastric cancer and to explore its potential mechanisms of action. For this purpose, AGS and NCI­N87 cells, as well as BALB/c mice with gastric cancer cell­derived tumors were treated with Tax. Cell Counting Kit­8 and colony formation assays were performed to detect cell viability and proliferation, respectively. Wound­healing and Transwell assays were also conducted to determine the cell migratory and invasive abilities, respectively. Western blot analysis was performed to determine protein expression in vitro and in vivo. The results revealed that Tax significantly inhibited the viability, proliferation, migration and invasion of gastric cancer cells through the aryl hydrocarbon receptor (AhR)/cytochrome P450 1A1 (CYP1A1) signaling pathway. SB203580, an AhR agonist, partly abolished the inhibitory effects of Tax on gastric cancer cell viability, proliferation, migration and invasion. In addition, Tax also suppressed tumor growth in vivo. Collectively, the present study demonstrated that Tax significantly suppressed the tumor characteristics of gastric cancer. Tax may thus prove to be a potential therapeutic strategy for gastric cancer.

Role of Removed Lymph Nodes on the Prognosis of M0 Small-Bowel Neuroendocrine Tumors: a Propensity Score Matching Analysis from SEER Database.

BACKGROUND: Current studies on the number of removed lymph nodes (LNs) and their prognostic value in small-bowel neuroendocrine tumors (SBNETs) are limited. This study aimed to clarify the prognostic value of removed LNs for SBNETs. METHODS: SBNET patients without distant metastasis from 2004 to 2017 in the SEER database were included. The optimal cutoff values of examined LNs (ELNs) and negative LNs (NLNs) were calculated by the X-tile software. Propensity score matching (PSM) was done to match patients 1:1 on clinicopathological characteristics between the two groups. The Kaplan-Meier method with log-rank test and multivariable Cox proportional-hazards regression model were used to evaluate the prognostic effect of removed LNs. RESULTS: The cutoff values of 14 for ELNs and 9 for NLNs could well distinguish patients with different prognoses. After 1:1 PSM, the differences in clinicopathological characteristics between the two groups were significantly reduced (all P > 0.05). Removal of more than one LN significantly improved the prognosis of the patients (P < 0.001). The number of lymphatic metastasis in the sufficiently radical resection group (SRR, 3.74 ± 3.278, ELN > 14 and NLN > 9) was significantly more than that in the insufficiently radical resection group (ISRR, 2.72 ± 3.19, ELN < 14 or NLN < 9). The 10-year overall survival (OS) of the SRR was significantly better than that of the ISRR (HR = 1.65, P = 0.001, 95% CI: 1.24-2.19). CONCLUSION: Both ELNs and NLNs can well predict the OS of patients. Systematic removal of more than 14 LNs and more than 9 NLNs can increase the OS of SBNET patients.

Critical prognostic value of the log odds of negative lymph nodes/tumor size in rectal cancer patients.

BACKGROUND: The number of negative lymph nodes (NLNs) and tumor size are associated with prognosis in rectal cancer patients undergoing surgical resection. However, little is known about the prognostic significance of the NLN count after adjusting for tumor size. AIM: To assess the prognostic impact of the log odds of NLN/tumor size (LONS) in rectal cancer patients. METHODS: Data of patients with stage I-III rectal cancer were extracted from the Surveillance, Epidemiology, and End Results Program database. These patients were randomly divided into a training cohort and a validation cohort. Univariate and multivariate Cox regression analyses were used to determine the prognostic value of the LONS. The optimal cutoff values of LONS were calculated using the "X-tile" program. Stratified analysis of the effect of LONS on cancer-specific survival (CSS) and overall survival (OS) were performed. The Kaplan-Meier method with the log-rank test was used to plot the survival curve and compare the survival data among the different groups. RESULTS: In all, 41080 patients who met the inclusion criteria were randomly divided into a training cohort (n = 28775, 70%) and a validation cohort (n = 12325, 30%). Univariate and multivariate analyses identified the continuous variable LONS as an independent prognostic factor for CSS [training cohort: Hazard ratio (HR) = 0.47, 95% confidence interval (CI): 0.44-0.51, P < 0.001; validation cohort: HR = 0.46, 95%CI: 0.41-0.52, P < 0.001] and OS (training cohort: HR = 0.53, 95%CI: 0.49-0.56, P < 0.001; validation cohort: HR = 0.52, 95%CI: 0.42-0.52, P < 0.001). The X-tile program indicated that the difference in CSS was the most significant for LONS of -0.8, and the cutoff value of -0.4 can further distinguish patients with a better prognosis in the high LONS group. Stratified analysis of the effect of the categorical variable LONS on CSS and OS revealed that LONS was also an independent predictor, independent of pN stage, pT stage, tumor-node-metastasis stage, site, age, sex, the number of examined lymph nodes, race, preoperative radiotherapy and carcinoembryonic antigen level. CONCLUSION: LONS is associated with improved survival of rectal cancer patients independent of other clinicopathological factors.

The log odds of negative lymph nodes/T stage: a new prognostic and predictive tool for resected gastric cancer patients.

PURPOSE: When only the TNM classification is used to predict survival in gastric cancer (GC) patients, the impact of the degree of lymphadenectomy on the prognosis is neglected. This study aimed to establish a more effective nomogram based on the log odds of negative lymph nodes/T stage ratio (LONT) to predict survival in surgically treated GC patients. METHODS: The data of resected GC patients were extracted from the Surveillance, Epidemiology, and End Results Program (SEER) database. Univariate and multivariate Cox regression analyses were used to identify the significant prognostic factors. The prognostic performance was assessed using a calibration plot, concordance index (C-index), and area under the (time-dependent receiver operating characteristic) curve (AUC) to compare the predicted survival probability based on the nomogram score groups. RESULTS: The results showed LONT as an independent prognostic factor for cancer-specific survival (CSS) and overall survival (OS), independent of clinicopathological factors. After removing potential redundancy, only LONT, T stage, N stage, location and age were used in the final nomogram model. The model had a higher C-index (0.736 ± 0.012) and AUC (0.798) than the TNM staging system (0.685 ± 0.012 and 0.744). The nomogram score could predict a significant survival difference between any two adjacent groups in terms of CSS and OS. CONCLUSION: High LONT is associated with improved survival of gastric cancer patients, independent of other clinicopathological factors. The prognostic nomogram model based on LONT could effectively predict CSS and OS for resectable GC patients.

Electroacupuncture modulates stromal cell-derived factor-1α expression and mobilization of bone marrow endothelial progenitor cells in focal cerebral ischemia/reperfusion model rats.

Stromal cell-derived factor-1α(SDF-1α) plays a crucial role in regulating the mobilization, migration and homing of endothelial progenitor cells(EPCs). Electroacupuncture(EA), a modern version of Traditional Chinese Medicine, can improve neurological recovery and angiogenesis in cerebral ischemic area. This study aimed to investigate the effects of electroacupuncture(EA) on the mobilization and migration of bone marrow EPCs and neurological functional recovery in rats model after focal cerebral ischemia/reperfusion and the potentially involved mechanisms. Sprague-Dawley rats received filament occlusion of the right middle cerebral artery for 2h followed by reperfusion for 12h, 1d, 2d, 3d, 7d respectively. Rats were randomly divided into sham group, model group and EA group. After 2h of the reperfusion, EA was given at the "Baihui" (GV 20)/Siguan ("Hegu" (LI 4)/"Taichong" (LR 3)) acupoints in the EA group. Modified neurological severity score (mNSS) was used to assess the neurological functional recovery. EPCs number and SDF-1α level in bone marrow(BM) and peripheral blood(PB) were detected by using fluorescence-activated cell sorting (FACS) analysis and quantitative real time polymerase chain reaction (qRT-PCR) respectively. An mNSS test showed that EA treatment significantly improved the neurological functional outcome. EPCs number in PB and BM were obviously increased in the EA group. After cerebral ischemia, the SDF-1α level was decreased in BM while it was increased in PB, which implied a gradient of SDF-1α among BM and PB after ischemia. It suggested that the forming of SDF-1α concentration gradient can induce the mobilization and homing of EPCs. Eletroacupuncture as a treatment can accelerate and increase the forming of SDF-1α concentration gradient to further induce the mobilization of EPCs and angiogenesis in ischemic brain and improve the neurological function recovery.

High-mobility group box 1 released from astrocytes promotes the proliferation of cultured neural stem/progenitor cells.

Astrocytes are major components of the adult neurogenic niche and play a crucial role in regulating neural stem cell proliferation and differentiation. Following brain injury, astrocytes become reactive and release high-mobility group box 1 (HMGB1), which plays a crucial role in the inflammatory process. However, although it has been reported that HMGB1 promotes neural stem/progenitor cell (NS/PC) proliferation in the developing brain, whether HMGB1 released by reactive astrocytes regulates NS/PC proliferation remains unknown. In this study, we aimed to investigate whether HMGB1 released from reactive astrocytes enhances NS/PC proliferation and to elucidate the possible mechanisms involved in this process. To evaluate the effects of HMGB1 on NS/PC proliferation, NS/PCs were cultured in HMGB1 culture medium and astrocyte-conditioned medium with or without reactive astrocyte-derived HMGB1 by RNA interference (RNAi). To explore the possible mechanisms, the HMGB1 receptor for advanced glycation endproducts (RAGE) in the NS/PCs was blocked with anti-RAGE antibody, and c-Jun N-terminal protein kinase (JNK) in the NS/PCs was inhibited using the potent JNK inhibitor, SP600125. Our results suggested that HMGB1 released from reactive astrocytes promoted NS/PC proliferation in vitro, and the blockade of RAGE or the inhibition of the JNK signaling pathway in the NS/PCs prevented the HMGB1-induced NS/PC proliferation. Our findings demonstrated that HMGB1 released by reactive astrocytes promoted NS/PC proliferation by binding RAGE and enhancing the phosphorylation of the JNK signaling pathway. These findings support a previously described mechanism of a crosstalk between astrocytes and NS/PCs, and suggest that reactive astrocyte-derived HMGB1 plays an important role in the repair of the central nervous system following brain injury.

[Effect of electroacupuncture on CD 34+ endothelial progenitor cell counts in bone marrow and peripheral blood in focal cerebral ischemia/reperfusion rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on CD 34+ endothelial progenitor cells (EPCs) in bone marrow and peripheral blood and the expression of p-AKT protein in bone marrow in focal cerebral ischemia/reperfusion (CI/R) rats, so as to investigate its mechanism underlying improvement of cerebral ischemia. METHODS: A total of 108 male SD rats were randomly divided into sham operation (sham) group, model (CI/R) group, and EA group which were further divided into 12, 24, 48 h subgroups (n = 12/group, 6 rats for biochemical analysis and the other 6 rats for Western blot analysis). Cl/R model was established by occlusion of the right middle cerebral artery for 2 hours followed by reperfusion. EA (2 Hz/20 Hz) was applied to "Baihui"(GV 20), left "Hegu" (LI 4) and left "Taichong" (LR 3) acupoints for 30 min, once daily. The neurological deficit scores were evaluated using Longa 5-grade standards. Flow cytometer was used to detect the percentages of CD 34+ EPCs in bone marrow and peripheral blood. The expression of p-AKT protein of bone marrow was detected by Western blot. RESULTS: In comparison with the CIl/R model group, the neurological deficit score were gradually and significantly decreased 48 h after CI/R in the EA group (P<0. 05), suggesting an improvement of the neurological function after EA. Compared with the sham group, the percentages of CD 34+ EPCs in bone marrow and peripheral blood and the expression level of bone-marrow p-AKT protein were significantly up-regulated in the model group at the three time-points after CI/R (P<0. 01, P<0. 05). Following EA intervention, the percentages of CD 34+ EPCs at the three time-points in the peripheral blood, and at time-points of 12 h and 24 h in the bone marrow, and the expression levels of p-AKT protein at the three time-points were significantly further up-regulated in the EA group in comparison with the model group (P<0.05, P<0.01). CONCLUSION: EA can effectively up-regulate the percentages of CD 34+ EPCs in the bone marrow and peripheral blood, and increase p-AKT protein expression in the bone marrow in CI/R rats, which may contribute to its effect in improving neurological function.