ULK1-dependent phosphorylation of PKM2 antagonizes O-GlcNAcylation and regulates the Warburg effect in breast cancer.

Pyruvate kinase M2 (PKM2) is a central metabolic enzyme driving the Warburg effect in tumor growth. Previous investigations have demonstrated that PKM2 is subject to O-linked ß-N-acetylglucosamine (O-GlcNAc) modification, which is a nutrient-sensitive post-translational modification. Here we found that unc-51 like autophagy activating kinase 1 (ULK1), a glucose-sensitive kinase, interacts with PKM2 and phosphorylates PKM2 at Ser333. Ser333 phosphorylation antagonizes PKM2 O-GlcNAcylation, promotes its tetramer formation and enzymatic activity, and decreases its nuclear localization. As PKM2 is known to have a nuclear role in regulating c-Myc, we also show that PKM2-S333 phosphorylation inhibits c-Myc expression. By downregulating glucose consumption and lactate production, PKM2 pS333 attenuates the Warburg effect. Through mouse xenograft assays, we demonstrate that the phospho-deficient PKM2-S333A mutant promotes tumor growth in vivo. In conclusion, we identified a ULK1-PKM2-c-Myc axis in inhibiting breast cancer, and a glucose-sensitive phosphorylation of PKM2 in modulating the Warburg effect.

Needle retaining after electroacupuncture combined with cognitive training for post-stroke cognitive impairment: a multi-center randomized controlled trial. / ç”µé’ˆåŽç•™é’ˆè”åˆè®¤çŸ¥è®­ç»ƒæ²»ç–—è„‘å’ä¸­åŽè®¤çŸ¥åŠŸèƒ½éšœç¢ï¼šå¤šä¸­å¿ƒéšæœºå¯¹ç §è¯•éªŒ.

OBJECTIVES: To compare the efficacy of needle retaining after electroacupuncture combined with cognitive training and electroacupuncture combined with cognitive training in the treatment of post-stroke cognitive impairment (PSCI). METHODS: A total of 206 patients with PSCI were randomized into a needle retaining group (103 cases, 9 cases dropped out) and an electroacupuncture group (103 cases, 6 cases dropped out). In addition to the conventional basic medical treatment and the rehabilitation treatment, in the needle retaining group, electroacupuncture at Shenting (GV 24) and Baihui (GV 20) was applied, with continuous wave of 50 Hz in the first 15 min and with disperse-dense wave of 2 Hz/50 Hz in the last 15 min, the needles were continuously retained for 1 h after electroacupuncture, during which cognitive training was adopted; in the electroacupuncture group, cognitive training was performed after the same electric stimulation exerted for 30 min, without additional needles retaining. The treatment was given once a day, 5 times a week for totally 8 weeks in the two groups. Before and after 8-week treatment, the TCM syndrome score was observed; before and after 4,8-week treatment, the scores of mini-mental state examination (MMSE), Montreal cognitive assessment (MoCA) and ability of daily living were observed in the two groups. The clinical efficacy of the two groups was evaluated after 8-week treatment. RESULTS: After 8-week treatment, the TCM syndrome scores were increased compared with those before treatment in both groups (P<0.05); the TCM syndrome score in the needle retaining group was higher than that in the electroacupuncture group (P<0.05).After 4,8-week treatment, the scores of MMSE, MoCA and ability of daily living were increased compared with those before treatment in both groups (P<0.05); MMSE, MoCA scores after 4,8-week treatment and ability of daily living score after 8-week treatment in the needle retaining group were higher than those in the electroacupuncture group (P<0.05). The total effective rate was 90.4% (85/94) in the needle retaining group, which was superior to 82.5% (80/97) in the electroacupuncture group (P<0.05). CONCLUSIONS: Both needle retaining after electroacupuncture combined with cognitive training and electroacupuncture combined with cognitive training can effectively treat PSCI, improve the clinical symptom, cognitive function and ability of daily living in PSCI patients. Needle retaining after electroacupuncture combined with cognitive training has a better therapeutic effect.

Bibliometric analysis: Research trends of acupuncture treatment to cognitive impairment in recent 15 years.

Objectives: Acupuncture therapy has been used for cognitive impairment-related diseases, however, there are still few studies on the overall trend of acupuncture therapy on cognitive impairment based on bibliometric analysis. The purpose of this study was to explore the research trend of the impact of acupuncture on cognitive impairment in the past 15 years, analyze the research trends and hotspots, and provide new ideas and theoretical basis for future research directions. Methods: From the Web of Science Core Collection (WoSCC), the relevant literature on the treatment of cognitive impairment with acupuncture from 2007 to 2022 was retrieved. Then, based on the CiteSpace and VOSviewer software of the Java platform, the cooperation between countries and institutions in this field, the co-citation of journals and documents, and the cooperation between authors and authors, etc. were analyzed. In addition, the co-occurrence and burst analysis of keywords are also carried out, and a visual knowledge map is drawn. Results: As of August 08, 2022, a total of 394 records related to the treatment of cognitive impairment with acupuncture were identified. The analysis results show: The number and rate of annual publications have steadily increased, with some fluctuations from year to year. The countries that contribute the most to this field are China and the USA. Among them, Beijing University of Chinese Medicine and Capital Medical University are tied for first place in terms of the number of published papers. Tao Jing is the most prolific author and the number one cited author. Conclusions: The number of publications on acupuncture for cognitive impairment is expected to increase rapidly in future research, suggesting a bright future for the field. Future research hotspots will focus on pain, injury, protocol, diagnosis, guidelines, etc. It is also necessary to strengthen cross-regional and cross-country cooperation among various academic groups.

Electroacupuncture of Baihui and Shenting ameliorates cognitive deficits via Pten/Akt pathway in a rat cerebral ischemia injury model.

Cerebral ischemic stroke is a huge threat to the health and life of many people. Electroacupuncture (EA) at Baihui (GV20) and Shenting (GV24) acupoints can notably alleviate cerebral ischemia/reperfusion injury (CIRI). However, the molecular basis underlying the effectiveness of EA at the GV20 and GV24 acupoints for CIRI remains largely unknown. Our present study demonstrated that EA treatment at the GV20 and GV24 acupoints markedly alleviated middle cerebral artery occlusion/reperfusion (MCAO/R)-induced cognitive deficits and cerebral infarction in rats. Proteomics analysis revealed that 195 and 218 proteins were dysregulated in rat hippocampal tissues in the MCAO/R vs. sham group and thhhe EA vs. MCAO/R group, respectively. Moreover, 62 proteins with converse alteration trends in MCAO/R vs. sham and EA vs. MCAO/R groups were identified. These proteins might be implicated in the EA-mediated protective effect against MCAO/R-induced cerebral injury. GO enrichment analysis showed that 39 dysregulated proteins in the MCAO/R vs. sham group and 40 dysregulated proteins in the EA vs. MCAO/R group were related to brain and nerve development. Protein-protein interaction analysis of the abovementioned dysregulated proteins associated with brain and nerve development suggested that Pten/Akt pathway-related proteins might play major roles in regulating EA-mediated protective effects against MCAO/R-induced brain and nerve injury. Western blot assays demonstrated that Pak4, Akt3, and Efnb2 were expressed at low levels in the MCAO/R group vs. the sham group but at high levels in the EA group vs. the MCAO/R group. In conclusion, multiple proteins related to the protective effect of EA at the GV20 and GV24 acupoints against CIRI were identified in our study.

Acupuncture ameliorates breast cancer-related fatigue by regulating the gut microbiota-gut-brain axis.

Cancer-related fatigue (CRF) is the most common side effect of chemotherapy for breast cancer (BC). Acupuncture treatment has an anti-fatigue effect and can regulate gut microbiota disturbance in fatigue patients. Related studies have shown that the gut microbiota-gut-brain axis is closely related to the occurrence of CRF. In this study, we first investigated the alterations of acupuncture on fatigue-like behavior, gut microbiota, gut inflammation and neuroinflammation response, gut barriers, HPA axis, and serum metabolomics in CRF mice after BC chemotherapy. Then, the correlation analysis of gut microbiota and other indicators was discussed. Our results showed that acupuncture treatment could exert an anti-fatigue effect and ameliorate the gut barrier, gut inflammation, neuroinflammation, and dysfunction of the HPA axis in CRF mice after chemotherapy for BC. 16S rRNA sequencing showed that acupuncture treatment could enhance the abundance of Candidatus Arthromitus, Lactobacillus, and Clostridia_UCG-014_unclassified and decrease the abundances of Escherichia-Shigella, Burkholderia-Caballeronia-Paraburkholderia, and Streptococcus. Serum metabolomics analysis showed that acupuncture treatment could regulate the differential metabolites N-methylnicotinamide, beta-glycerophosphoric acid, geranyl acetoacetate, serotonin and phenylalanine, tyrosine and tryptophan biosynthesis, taurine and hypotaurine, and beta-alanine metabolic pathways. Correlation analysis indicated that there are certain correlations between gut microbiota and gut inflammation, neuroinflammation, gut barrier, HPA axis function and serum metabolites. In conclusion, our findings revealed that the anti-fatigue mechanism of acupuncture treatment may be closely related to the gut microbiota-gut-brain axis. This study also provided a new reference for basic and clinical research on CRF after breast cancer chemotherapy.

The Clinical Observation and Mechanism of Acupuncture on Cancer-Related Fatigue of Breast Cancer Based on "Gut-Brain Axis": Study Protocol for a Randomized Controlled Trial.

Background. Cancer-related fatigue (CRF) is a painful, persistent feeling of physical and cognitive subjective fatigue related to cancer or cancer remedy. The occurrence of CRF may be related to the hypothalamic-pituitary-adrenaline (HPA) axis, inflammatory mediator theory, and gut microbiota. Moreover, acupuncture could play a vital part in the therapy of CRF. The study will evaluate whether acupuncture can improve fatigue symptoms of CRF patients after breast cancer chemotherapy by regulating the gut-brain axis. Methods/design. Seventy patients with CRF will be enrolled in this study, with 35 patients randomly assigned to each group. Blood and feces will be collected at the beginning and end of treatment. Piper fatigue scale, KPS score scale, and quality-of-life scale will be used to observe the changes of fatigue symptoms and life quality of CRF patients and to evaluate the effect of acupuncture on CRF. Then, the method of ELISA will be used to explore the regulatory effect of acupuncture on the HPA axis and inflammatory cytokines. Moreover, based on 16SrDNA, the changes of gut microbiota structure and flora of CRF patients will be observed. Ultimately, the correlation analysis of gut microbiota can be related to inflammatory cytokines, HPA axis, and clinical efficacy evaluation. Discussion. This study will identify the effect and the mechanism of acupuncture therapy in CRF. And it will offer an alternative treatment modality for the treatment of CRF after chemotherapy for breast cancer. Furthermore, it will also provide the clinical and theoretical bases for the extensive application of acupuncture therapy in tumor rehabilitation. Trial Status. Protocol version number and date: V2.0, 6 May 2021. The trial is registered with the Chinese Clinical Trial Registry on 20 June 2021 (trial identifier: ChiCTR2100047510).

Effects of Exercise on Parkinson's Disease: A Meta-Analysis of Brain Imaging Studies.

BACKGROUND: Exercise is increasingly recognized as a key component of Parkinson's disease (PD) treatment strategies, but the underlying mechanism of how exercise affects PD is not yet fully understood. OBJECTIVE: The activation likelihood estimation (ALE) method is used to study the mechanism of exercise affecting PD, providing a theoretical basis for studying exercise and PD, and promoting the health of patients with PD. METHODS: Relevant keywords were searched on the PubMed, Cochrane Library, and Web of Science databases. Seven articles were finally included according to the screening criteria, with a total sample size of 97 individuals. Using the GingerALE 3.0.2 software, an ALE meta-analysis was performed using seven studies that met the requirements, and the probability of the cross-experiment activation of each voxel was calculated. RESULTS: The meta-analysis produced seven clusters, and major activations were found in the cerebellum, occipital lobe, parietal lobe, and frontal lobe brain regions. CONCLUSION: Exercise for PD mainly results in the enhanced activation of the cerebellum, occipital lobe, parietal lobe, and frontal lobe. Exercise for PD does not cause a change in the activation of a single brain area, and the observed improvement may result from coordinated changes in multiple brain areas.

Retracted Article: Panax notoginseng saponins regulate VEGF to suppress esophageal squamous cell carcinoma progression via DVL3-mediated Wnt/ß-catenin signaling.

Panax notoginseng saponins (PNS) have recently attracted increasing attention for their anti-tumor activities. The aim of this study was to explore the functional role and underlying mechanisms of PNS on the progression of esophageal squamous cell carcinoma (ESCC). The mRNA levels of vascular endothelial growth factor (VEGF), ß-catenin and dishevelled-3 (DVL3) were assessed using qRT-PCR. Western blot was performed to detect the expression levels of VEGF, ß-catenin and DVL3. Cell viability and proliferation abilities were determined using MTT assay. Transwell assays were used to evaluate cell migration and invasion capacities. Our data revealed that PNS hampered the viability of ESCC cells. VEGF silencing weakened proliferation, migration and invasion in ESCC cells. Mechanistically, PNS time-dependently reduced VEGF expression and PNS hampered ESCC cell proliferation, migration and invasion through VEGF. Moreover, ß-catenin and DVL3 were upregulated in ESCC tissues and cells and positively correlated with VEGF level in ESCC tissues. VEGF regulated DVL3 via the Wnt/ß-catenin signaling pathway in ESCC cells. Furthermore, PNS repressed DVL3 expression through VEGF in ESCC cells. Our study suggested that PNS suppressed ESCC progression at least partly through repressing VEGF via the DVL3-mediated Wnt/ß-catenin signaling pathway, indicating that PNS might be promising anti-tumor agents for ESCC treatment.

HIF­1α promotes the stemness of oesophageal squamous cell carcinoma by activating the Wnt/ß­catenin pathway.

Hypoxia­inducible­factor 1α (HIF­1α) is a marker for poor prognosis in the majority of the cancer types, and it has been revealed to be essential for maintaining cancer stem cells (CSCs). In the present study, it was determined that the expression of HIF­1α and CSC­related genes under hypoxic conditions was upregulated. Stable knockdown of HIF­1α significantly inhibited cell proliferation, migration and tumour growth in vivo in oesophageal squamous cell carcinoma (ESCC). A previous study revealed that the Wnt/ß­catenin pathway may play a key role in maintenance and progression of CSCs. Therefore, it was also revealed that stable knockdown of HIF­1α reduced the formation of spheroid body cells, the expression of CSC­related genes and Wnt/ß­catenin pathway­related target genes, as well as the activity of the Wnt/ß­catenin pathway. Collectively, the present results indicated that HIF­1α may regulate the stemness of ESCC by activating the Wnt/ß­catenin pathway.

Association between metformin and the risk of gastric cancer in patients with type 2 diabetes mellitus: a meta-analysis of cohort studies.

OBJECTIVES: The objective of this study was to evaluate the association between metformin therapy and the incidence of gastric cancer (GC) in patients with type 2 diabetes mellitus (T2DM). METHODS: We systemically searched the following databases for studies published between the databases' dates of inception and Nov. 2016: PubMed, Embase, the Cochrane Library, the Web of Science, and the China National Knowledge Infrastructure (CNKI). Hazard ratios (HR)and corresponding 95% confidence intervals (CIs) for the association between metformin therapy and the incidence of GC in patients with T2DM were the outcome measures assessed in this study. STATA 12.0 (Stata Corporation, College Station, Texas, USA) was used to conduct the statistical analysis. RESULTS: A total of seven cohort studies including 591,077 patients met all the criteria for inclusion in the analysis. Our data showed that metformin therapy was associated with a significantly lower incidence of GC in patients with T2DM than other types of therapy (HR=0.763, 95% CI: 0.642˜0.905). Subgroup analysis showed that patients living in Taiwan benefitted more from metformin therapy than patients living in any other region, as metformin significantly decreased the risk of GC in patients living in Taiwan but did not significantly decrease the risk of GC in patients living in other regions (HR=0.514, 95% CI: 0.384-0.688). The results of the present analysis support the idea that metformin facilitates reductions in the risk of T2DM-related GC. CONCLUSIONS: The risk of GC among patients with T2DM is lower in patients receiving metformin therapy than in patients not receiving metformin therapy.

Expression and functional regulation of stemness gene Lgr5 in esophageal squamous cell carcinoma.

Cancer stem cells (CSCs) are defined as a rare subpopulation of undifferentiated cells with biological characteristics that include the capacity for self-renewal, differentiation into various lineages, and tumor initiation. To explore the mechanism of CSCs in esophageal squamous cell carcinoma (ESCC), we focused on Leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), a target gene of the Wnt signaling pathway, which has been identified as a marker of intestinal stem cells and shown to be overexpressed in several human malignancies. Lgr5 expression was significantly correlated with lymph node metastasis, increased depth of invasion, increased tumor size, advanced differentiation, higher AJCC stage and poorer survival. Silencing of Lgr5 expression in the ESCC cell line KYSE450 by small interfering RNA (siRNA) strongly inhibited cell proliferation, migration and invasion ability, the expression of CSCs-related genes and Wnt/ß-catenin signaling. In addition, Lgr5 was highly expressed in ESCC spheroid body cells, which were identified by high expression of CSCs-related genes, and high tumorigenicity in vivo. Taken together, these results demonstrate that Lgr5 activation of Wnt/ß-catenin signaling is a potential mechanism to promote the progression of ESCC and ESCC stem cell renewal, and Lgr5 may be used as a molecular target for the development of treatments for ESCC.

Metformin inhibited esophageal squamous cell carcinoma proliferation in vitro and in vivo and enhanced the anti-cancer effect of cisplatin.

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with poor prognosis in China. Chemotherapy now is one of the most frequently used treatments for patients with ESCC in middle or late stage, however the effects were often limited by increased chemoresistance or treatment toxicity. So it is urgent to find new drugs to treat ESCC patients. Metformin with low cost and toxicity has proved to have anti-cancer effects in a numerous cancers, while its role and mechanism in ESCC has seldom been studied. In the present study, we found that metformin exhibited not only an anti-proliferation ability in a dose and time dependent manner but also a proapoptosis effect in a dose dependent manner in ESCC cell line KYSE450. Our in vivo experiment also showed that metformin markedly inhibited KYSE450 xenograft tumors growth compared to those treated with normal saline. What's more, no obvious toxic reactions were observed. To further explore the underlying mechanism, we found that metformin treatment could significantly damp the expression of 4EBP1 and S6K1 in KYSE 450 cells in vitro and in vivo, furthermore, the p-4EBP1 and p-S6K1 expression in KYSE 450 cells were also inhibited greatly in vitro and in vivo. During the therapy of cancer, in order to overcome side effects, combination therapy was often used. In this paper, we demonstrated that metformin potentiated the effects of cisplatin via inhibiting cell proliferation and promoting cell apoptosis. Taken together, metformin owned the potential anti-cancer effect on ESCC in monotherapy or was combined with cisplatin and these results laid solid basis for the use of metformin in ESCC.