Effect of electroacupuncture stimulation of "Sibai"(ST2) and "Quanliao"(SI18) on excitatory neurons of sensorimotor cortex in mice. / 电针"四白"和"颧髎"æ¿€æ´»å°é¼ èº¯ä½“æ„Ÿè§‰è¿åŠ¨çš®å±‚çš„å ´å¥‹æ€§ç¥žç»å ƒ.

OBJECTIVES: To observe the activation state and neuronal types of somatosensory cortex and the primary motor cortex induced by electroacupuncture (EA) stimulation of "Sibai" (ST2) and "Quanliao" (SI18) acupoints in mice. METHODS: Male C57BL/6J mice were randomly divided into blank control and EA groups, with 6 mice in each group. Rats of the EA group received EA stimulation (2 Hz, 0.6 mA) at ST2 and SI18 for 30 minutes. Samples were collected after EA intervention, and immunofluorescence staining was performed to quantify the expression of the c-Fos gene (proportion of c-Fos positive cells) in the somatosensory cortex and primary motor cortex. The co-labelled cells of calcium/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) and gamma-aminobutyric acid (GABA) in the somatosensory cortex and primary motor cortex were observed and counted by using microscope after immunofluorescence staining. Another 10 mice were used to detect the calcium activity of excitatory neurons in the somatosensory cortex and primary motor cortex by fiber photometry. RESULTS: In comparison with the blank control group, the number of c-Fos positive cells, and the proportion of c-Fos and CaMKⅡ co-labelled cells in both the somatosensory cortex and primary motor cortex were significantly increased after EA stimulation (P<0.05). No significant changes were found in the proportion of c-Fos and GABA co-labeled cells in both the somatosensory cortex and primary motor cortex after EA. Results of fiber optic calcium imaging technology showed that the spontaneous calcium activity of excitatory neurons in both somatosensory cortex and primary motor cortex were obviously increased during EA compared with that before EA (P<0.01), and strikingly reduced after cessation of EA compared with that during EA (P<0.05). CONCLUSIONS: Under physiological conditions, EA of ST2 and SI18 can effectively activate excitatory neurons in the somatosensory cortex and primary motor cortex.

Identifying promising GSK3ß inhibitors for cancer management: a computational pipeline combining virtual screening and molecular dynamics simulations.

Glycogen synthase kinase-3 (GSK3ß), a serine/threonine protein kinase, has been discovered as a novel target for anticancer drugs. Although GSK3ß is involved in multiple pathways linked to the etiology of various cancers, no specific GSK3ß inhibitor has been authorized for cancer therapy. Most of its inhibitors have toxicity effects therefore, there is a need to develop safe and more potent inhibitors. In this study, a library of 4,222 anti-cancer compounds underwent rigorous computational screening to identify potential candidates for targeting the binding pocket of GSK3ß. The screening process involved various stages, including docking-based virtual screening, physicochemical and ADMET analysis, and molecular dynamics simulations. Ultimately, two hit compounds, BMS-754807 and GSK429286A, were identified as having high binding affinities to GSK3ß. BMS-754807 and GSK429286A exhibited binding affinities of -11.9, and -9.8 kcal/mol, respectively, which were greater than that of the positive control (-7.6 kcal/mol). Further, molecular dynamics simulations for 100 ns were employed to optimize the interaction between the compounds and GSK3ß, and the simulations demonstrated that the interaction was stable and consistent throughout the study. These hits were also anticipated to have good drug-like properties. Finally, this study suggests that BMS-754807 and GSK429286A may undergo experimental validation to evaluate their potential as cancer treatments in clinical settings.

DDTC-Cu(I) based metal-organic framework (MOF) for targeted melanoma therapy by inducing SLC7A11/GPX4-mediated ferroptosis.

Disulfiram (DSF), a drug for alcohol withdrawal, has attracted extensive scientific attention due to its potential to treat cancer. The metabolite of DSF, diethyl dithiocarbamate (DDTC), forms a Cu-DDTC complex in vivo with copper ions, which has been shown to be a proteasome inhibitor with high antitumor activity. However, the in vivo stability of Cu-DDTC complexes remains a challenge. In this study, the nanomedicine Cu-BTC@DDTC with high antitumor activity was prepared by using the nanoscale metal-organic framework (MOF) Cu-BTC as a carrier and loading diethyldithiocarbamate (DDTC) through coordination interaction. The results showed that Cu-BTC@DDTC had high drug loading and adequate stability, and exhibited DDTC-Cu(I) chemical valence characteristics and polycrystalline structure features. In vitro cytocompatibility investigation and animal xenograft tumor model evaluation demonstrated the anti-cancer potential of Cu-BTC@DDTC, especially the combination of Cu-BTC@DDTC with low-dose cisplatin showed significant antitumor effect and biosafety. This study provides a feasible protocol for developing antitumor drugs based on the drug repurposing strategy.

[Empirical analysis on lumbar disc herniation treated with "sinew-bone three needling technique" of Chinese medicine].

The paper presents professor WU Han-qing's experience in treatment of lumbar disc herniation (LDH) with "sinew-bone three needling technique" of Chinese medicine. Based on the theory of meridian sinew, the points are located by "three-pass method" in terms of the distribution of meridian sinew and syndrome/pattern differentiation. The cord-like muscles and adhesion are relieved by relaxing technique to work directly on the affected sites and alleviate the local compression to the nerve root. The needle technique is operated flexibly according to the affected regions involved, due to which, the needling sensation is increased while the safety ensured. As a result, the meridian qi is enhanced, the mind and qi circulation is regulated; and the clinical effect is improved.

Quantitative analysis and visualization of literature on acupuncture and related TCM therapies for the treatment of colorectal cancer based on CiteSpace.

Objective: We analyzed the literature describing the results of treatment of colorectal cancer (CRC) using acupuncture in the past three decades from the Web of Science (WoS) and Chinese databases (including CNKI, WANGFANG and VIP), and summarized the current development of CRC treatment as well as future research directions through the presentation of maps and visualization analysis. Methods: We searched the WoS and Chinese databases. Relevant articles were exported, and the data were organized using Excel software and was visualized and analyzed using CiteSpace software. Results: A total of 355 articles from the WoS and 95 articles from Chinese databases were selected for inclusion in the analysis. The articles in WoS were sourced from 174 journals, 1274 institutions, and 66 countries, and covered 299 keywords. The articles in the Chinese databases were sourced from 43 journals, 111 institutions, and 3 countries, and included 126 keywords. The article with the most citations in the WoS was cited 128 times and in the Chinese databases, the article with the most citations was cited 120 times. Acupuncture, CRC, rectal cancer, apoptosis, warm acupuncture, traditional Chinese medicine (TCM) and gastrointestinal function were mentioned most frequently in the WoS. CRC, electroacupuncture, gastrointestinal function, rectal cancer, acupuncture and moxibustion, acupuncture, and colon cancer were mentioned most frequently in the Chinese databases. Conclusion: Both the WoS and Chinese databases showed a gradual increase in the number of articles related to acupuncture treatment for CRC, indicating a growing interest in this area. Acupuncture treatments are diverse, including warm acupuncture, auricular acupuncture, acupuncture injection, and electroacupuncture. They are often used in combination with drugs to treat symptoms such as depression, nausea and vomiting, pain, diarrhea, and urinary and fecal incontinence, which are commonly associated with CRC.

Fucoidans from Cucumaria frondosa ameliorate renal interstitial fibrosis via inhibition of the PI3K/Akt/NF-κB signaling pathway.

The effects of Cucumaria frondosa polysaccharides (CFPs) on renal interstitial fibrosis by regulating the phosphatidylinositol-3-hydroxykinase/protein kinase-B/nuclear factor-κB (PI3K/AKT/NF-κB) signaling pathway were investigated in vivo and in vitro in this research. The common unilateral urethral obstruction (UUO) model was used to examine the renoprotective effect and its mechanism in vivo. Compared to the UUO group, CFP administration could ameliorate renal function, inhibit inflammation and fibrosis, and reduce the deposition of the extracellular matrix and epithelial-mesenchymal transition. Mechanistic results indicated that CFPs could inhibit the expression of the total protein of PI3K and the conversion of the AKT and NF-κB p65 phosphorylated proteins, thereby inhibiting the transduction of the PI3K/AKT/NF-κB pathway. In addition, CFP treatment could improve inflammation and fibrosis in HK-2 cells induced by TGF-ß1, and its in vitro mechanism was also verified to inhibit the PI3K/Akt/NF-κB signaling pathway. Overall, these results showed that CFP could alleviate renal interstitial fibrosis related to the PI3K/AKT/NF-κB signaling pathway.

Low-frequency electroacupuncture improves disordered hepatic energy metabolism in insulin-resistant Zucker diabetic fatty rats via the AMPK/mTORC1/p70S6K signaling pathway.

BACKGROUND AND AIM: Disordered hepatic energy metabolism is found in obese rats with insulin resistance (IR). There are insufficient experimental studies of electroacupuncture (EA) for IR and type 2 diabetes mellitus (T2DM). The aim of this study was to probe the effect of EA on disordered hepatic energy metabolism and the adenosine monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase, 70-kDa (p70S6K) signaling pathway. METHODS: Zucker Diabetic Fatty (ZDF) rats were randomly divided into three groups: EA group receiving EA treatment; Pi group receiving pioglitazone gavage; and ZF group remaining untreated (n = 8 per group). Inbred non-insulin-resistant Zucker lean rats formed an (untreated) healthy control group (ZL, n = 8). Fasting plasma glucose (FPG), fasting insulin (FINS), C-peptide, C-reactive protein (CRP) and homeostatic model assessment of insulin resistance (HOMA-IR) indices were measured. Hematoxylin-eosin (H&E) staining was used to investigate the liver morphologically. The mitochondrial structure of hepatocytes was observed by transmission electron microscopy (TEM). Western blotting was adopted to determine protein expression of insulin receptor substrate 1 (IRS-1), mTOR, mTORC1, AMPK, tuberous sclerosis 2 (TSC2) and p70S6K, and their phosphorylation. RT-PCR was used to quantify IRS-1, mTOR, mTORC1, AMPK and p70S6K mRNA levels. RESULTS: Compared with the ZF group, FPG, FINS, C-peptide, CRP and HOMA-IR levels were significantly reduced in the EA group (p < 0.05, p < 0.01). Evaluation of histopathology showed improvement in liver appearances following EA. Phosphorylation levels of AMPK, mTOR and TSC2 decreased, and IRS-1 and p70S6K increased, in hepatocytes of the ZF group, while these negative effects appeared to be alleviated by EA. CONCLUSIONS: EA can effectively ameliorate IR and regulate energy metabolism in the ZDF rat model. AMPK/mTORC1/p70S6K and related molecules may represent a potential mechanism of action underlying these effects.

Acupuncture for cancer pain: an evidence-based clinical practice guideline.

BACKGROUND: This study aims to develop an evidence-based clinical practice guideline of acupuncture in the treatment of patients with moderate and severe cancer pain. METHODS: The development of this guideline was triggered by a systematic review published in JAMA Oncology in 2020. We searched databases and websites for evidence on patient preferences and values, and other resources of using acupuncture for treatment of cancer pain. Recommendations were developed through a Delphi consensus of an international multidisciplinary panel including 13 western medicine oncologists, Chinese medicine/acupuncture clinical practitioners, and two patient representatives. The certainty of evidence, patient preferences and values, resources, and other factors were fully considered in formulating the recommendations. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was employed to rate the certainty of evidence and the strength of recommendations. RESULTS: The guideline proposed three recommendations: (1) a strong recommendation for the treatment of acupuncture rather than no treatment to relieve pain in patients with moderate to severe cancer pain; (2) a weak recommendation for the combination treatments with acupuncture/acupressure to reduce pain intensity, decrease the opioid dose, and alleviate opioid-related side effects in moderate to severe cancer pain patients who are using analgesics; and (3) a strong recommendation for acupuncture in breast cancer patients to relieve their aromatase inhibitor-induced arthralgia. CONCLUSION: This proposed guideline provides recommendations for the management of patients with cancer pain. The small sample sizes of evidence limit the strength of the recommendations and highlights the need for additional research.

[Acupoint selection for cancer pain: based on current evidence and Delphi method].

Based on literature research and Delphi expert consensus method, the important acupoints for cancer pain was summarized to provide evidence basis for the formulation of Clinical Practice Guide of Acupuncture in the Treatment of Cancer Pain. Through systematic search of Chinese and English databases, 28 clinical studies regarding acupuncture for cancer pain were included. The acupoint selection methods and high-frequency acupoints were summarized and analyzed. Based on this, a Delphi questionnaire was designed and two rounds of questionnaire survey on 30 experts in acupuncture and tumor related fields in China and abroad were conducted. As a result, it was suggested that the individualized acupoint selection should be adopted for acupuncture treatment of cancer pain, with Zusanli (ST 36), Hegu (LI 4), Taichong (LR 3), Sanyinjiao (SP 6), Yanglingquan (GB 34) and ashi points as the main acupoints. Combined with clinical research evidence and expert consensus, the important acupoints for cancer pain were identified. However, clinical acupoint selection still needed further research and refinement.

Electroacupuncture ameliorates beta-amyloid pathology and cognitive impairment in Alzheimer disease via a novel mechanism involving activation of TFEB (transcription factor EB).

Alzheimer disease (AD) is the most prevalent neurodegenerative disorder leading to dementia in the elderly. Unfortunately, no cure for AD is available to date. Increasing evidence has proved the roles of misfolded protein aggregation due to impairment of the macroautophagy/autophagy-lysosomal pathway (ALP) in the pathogenesis of AD, and thus making TFEB (transcription factor EB), which orchestrates ALP, as a promising target for treating AD. As a complementary therapy, acupuncture or electroacupuncture (EA) has been commonly used for treating human diseases. Although the beneficial effects of acupuncture for AD have been primarily studied both pre-clinically and clinically, the real efficacy of acupuncture on AD remains inconclusive and the underlying mechanisms are largely unexplored. In this study, we demonstrated the cognitive-enhancing effect of three-needle EA (TNEA) in an animal model of AD with beta-amyloid (Aß) pathology (5xFAD). TNEA reduced APP (amyloid beta (A4) precursor protein), C-terminal fragments (CTFs) of APP and Aß load, and inhibited glial cell activation in the prefrontal cortex and hippocampus of 5xFAD. Mechanistically, TNEA activated TFEB via inhibiting the AKT-MAPK1-MTORC1 pathway, thus promoting ALP in the brains. Therefore, TNEA represents a promising acupuncture therapy for AD, via a novel mechanism involving TFEB activation.Abbreviations Aß: ß-amyloid; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; AKT1: thymoma viral proto-oncogene 1; ALP: autophagy-lysosomal pathway; APP: amyloid beta (A4) precursor protein; BACE1: beta-site APP cleaving enzyme 1; CQ: chloroquine; CTFs: C-terminal fragments; CTSD: cathepsin D; EA: electroacupuncture; FC: fear conditioning; GFAP: glial fibrillary acidic protein; HI: hippocampus; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAPK1/ERK2: mitogen-activated protein kinase 1; MAPT: microtubule-associated protein tau; MTORC1: mechanistic target of rapamycin kinase complex 1; MWM: Morris water maze; NFT: neurofibrillary tangles; PFC: prefrontal cortex; PSEN1: presenilin 1; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TNEA: three-needle electroacupuncture.

Cigarette Smoking and Risk of Different Pathologic Types of Stroke: A Systematic Review and Dose-Response Meta-Analysis.

OBJECTIVES: To quantify the association of cigarette smoking, including cigarettes per day and quitting duration, with the risk of different types of stroke morbidity and mortality in the general population, and to clarify the shape of the dose-response relations. STUDY SELECTION: Prospective cohort studies and reported on the association between smoking, quitting and the incidence or mortality of stroke were included. DATA EXTRACTION AND SYNTHESIS: All available data were converted uniformly to odds ratios (ORs) and were pooled using random-effects meta-analysis with inverse variance weighting. A dose-response meta-analysis was performed to explore the quantitative relationship between different smoking characteristics and the risk of different pathologic types of stroke incidence. RESULTS: Twenty-five studies with 3,734,216 individuals were included. Compared to never smokers, the pooled ORs of stroke morbidity and mortality were 1.45 (1.24-1.70) and 1.44 (1.23-1.67) among ever smokers and 1.90 (1.55-2.34) and 1.70 (1.45-1.98) among current smokers. The risk of different pathologic types of stroke was also increased among ever and current smokers. There was a significant non-linear dose-response association between the number of cigarette smoking and the risk of stroke incidence. Comparing no smoking, the ORs for smoking five and 35 cigarettes per day were 1.44 (1.35-1.53) and 1.86 (1.71-2.02). Other pathologic types of stroke have a similar dose-response relationship. There was also non-linear dose-response association between the length of time since quitting and risk of stroke. The risk of stroke decreased significantly after quitting for 3 years [OR = 0.56 (0.42-0.74)]. CONCLUSION: The risk of different types of stroke among smokers is remarkably high. Our findings revealed a more detailed dose-response relationship and have important implications for developing smoking control strategies for stroke prevention. SYSTEMATIC REVIEW REGISTRATION: https://inplasy.com/inplasy-2020-6-0062/, identifier: INPLASY202060062.

Electroacupuncture Attenuates Inflammation after Ischemic Stroke by Inhibiting NF-κB-Mediated Activation of Microglia.

Microglial activation and microglia-mediated inflammation play an important role in the occurrence, development, and outcome of stroke. Brain injury induces the activation and release of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin- (IL-) 1ß, and IL-6. Many studies have confirmed that acupuncture is effective in treating ischemic stroke. However, its protective mechanism against ischemic brain injury is complex and multifactorial. In this study, we observed the effects of electroacupuncture at Baihui (GV20) and Dazhui (GV14) on microglial activation and inflammation in the cortical ischemic penumbra (IP) of permanent middle cerebral artery occlusion (pMCAO) rats. It was found that electroacupuncture inhibited the degeneration and necrosis of microglia in the cortical IP and ameliorated mitochondrial damage. Immunofluorescence and western blot analysis showed that microglia were in a resting state or weakly activated in the normal brain. After cerebral ischemia, the expression of microglial markers (Iba-1 and CD11b) increased, and NF-κB p65, IL-1ß, and TNF-α expression gradually increased. The dynamic changes were generally temporally consistent. Electroacupuncture downregulated the expressions of Iba-1 and CD11b. Additionally, it inhibited the expression of NF-κB p65, IL-1ß, and TNF-α and reduced the conversion of microglia to the M1 phenotype after ischemia. Electroacupuncture regulated the activation of microglia and microglia-mediated inflammation after cerebral ischemia, confirming the relevant theories regarding the effect of acupuncture treatment on cerebral ischemia and guiding clinical practice.

Effect of Different Frequencies of Electroacupuncture on Post-Stroke Dysphagia in Mice.

The aim of this study was to determine the optimum frequency of electroacupuncture (EA) for the treatment of dysphagia after stroke. Male C57BL/6 J mice were randomly divided into five groups: normal, model, 2 Hz, 50 Hz, and 100 Hz groups. All mice received a photochemical ischemia, except the normal group. The EA parameters were 1 mA for 15 min, with different frequencies (2, 50, and 100 Hz) applied. After a three day treatment, neuronal activation was detected by the expression of c-Fos. A multi-channel electrophysiological technique was used to assess the discharge of contralateral neurons and the neuron types in each group. The concentration of brain-derived neurotrophic factor (BDNF) in the contralateral neurons was also examined. In addition, the dysfunction of swallowing in mice was calculated according to the lick counts and the lick-lick interval within a certain period of time. The number of c-Fos neurons (P < 0.05) and the expression of BDNF (P < 0.05) increased after the 2 Hz EA treatment. The total frequency of neuron discharge in the 2 Hz group increased compared with the model group (P < 0.05). The pattern of sorted neuron populations was similar between the normal and 2 Hz groups. Consistent with these results, the lick counts increased (P < 0.05) and the lick-lick interval decreased after the 2 Hz EA treatment, which indicated a functional improvement in swallowing. These results indicated that the 2 Hz EA treatment had a good effect on dysphagia after stroke.

Effect of Metformin Nanoparticle-Mediated Thioredoxin Interacting Protein Expression on Oxaliplatin-Induced Peripheral Neuralgia.

Oxaliplatin (LOHP) is an approved anti-cancer drug that often accumulates in the peripheral nerves during the treatment of cancer. Metformin is a prescription drug with a wide range of pharmacological effects, which can augment the anti-cancer efficacy of chemotherapy drugs. Recent studies suggest that metformin is a potential drug that can relieve oxaliplatin induced neuralgia, and autophagy plays an important role in it. This study aims at exploring the effect and mechanism of action of metformin on oxaliplatin-induced peripheral neuropathic pain. To explore the underlying mechanism of metformin on peripheral nerves, neuropathic pain model was developed by intraperitoneal injection of oxaliplatin into mice. Metformin nanoparticles encapsulated by PLGA were used to intervene the pain in the model mice. RT-qPCR and immunoblotting were used to detect the effects of metformin on the expression of TXNIP and autophagy associated genes-BECN1 and LC3B in the sciatic nerves of pain model mice. Hematoxylin and eosin staining were used to detect the pathological changes in the sciatic nerve. Flow cytometry and Annexin V-FITC/PI apoptosis detection kit were used to detect the apoptosis of sciatic nerve cells. The effect of metformin on the pain perception of mice was detected by thermal and mechanical stimulation experiments. The results showed that the expression of TXNIP and autophagy related indexes-BECN1 and LC3B in sciatic nerve decreased significantly after oxaliplatin treatment. However, metformin intervention resulted in significant up-regulation of TXNIP and autophagy related indexes, and augmented the threshold of thermal sensitivity and mechanical tingling. Thus, our study has identified TXNIP as a novel target for oxaliplatin induced peripheral nerve pain. We have shown that oxaliplatin inhibits TXNIP expression, regulates autophagy, thereby affecting neuralgia. In contrast, metformin promotes the expression of TXNIP and autophagy of cells thereby inhibiting neural sensitivity and thus results in pain relief.

CBS-Induced H2S Generation in Hippocampus Inhibits EA-Induced Analgesia.

Hydrogen sulfide (H2S) is an important mediator participating in both physiological and pathological systems and related to the inflammatory process. Acupuncture has a therapeutic effect on inflammatory pain. However, whether H2S generated in the central nervous system (CNS) is a mediator of electroacupuncture (EA) treatment for inflammatory pain is unknown. We injected complete Freund's adjuvant (CFA) to induce inflammatory pain and applied EA treatment as an interventional strategy for pain relief. The results presented here show that S-adenosyl-l-methionine (SAM), an allosteric activator of cystathionine-ß-synthetase (CBS), may reverse the therapeutic effect of EA. CBS-induced H2S generation might get involved in the mechanism of EA-induced analgesia in the hippocampus on chronic inflammatory pain.

Electroacupuncture improves cognitive deficits and insulin resistance in an OLETF rat model of Al/D-gal induced aging model via the PI3K/Akt signaling pathway.

To investigate the effect of electroacupuncture (EA) on cognitive function and insulin resistance (IR) in an Al/D-gal-induced aging model for Alzheimer's disease (AD) using Ostuka Long-Evans Tokushima Fatty (OLETF) rats. The Al/D-gal-OLETF rats for AD were randomly divided into the EA and non-EA groups. Cognitive function was assessed using the Morris water maze (MWM). The morphology of the hippocampal neurons was observed using hematoxylin & eosin (H&E) staining. Aß and total Tau in the hippocampus and cerebrospinal fluid (CSF) were detected using western blotting (WB) and enzyme-linked immunosorbent assay (ELISA). Fasting blood glucose (FPG) was determined using the glucose oxidase method. Plasma fasting insulin (FINS), serum C-peptide (C-P), and CSF insulin were detected using ELISA. The expression of the genes and proteins in the PI3K signaling pathway was detected using quantitative real-time PCR and WB. After EA intervention, the hippocampal Aß and total Tau protein levels, body weight, FPG, FINS, and C-P were significantly decreased. The MWM showed that the percentage of time in the target quadrant of the EA group was elevated in the probe test. The protein levels of p-IRS1, p-IRS2, IDE, and p-GSK3ß were significantly increased, while p-PI3K-p85α and p-Akt were decreased. In conclusion, EA improves cognitive function and insulin resistance in rat models of AD. The PI3K/Akt signaling pathway is involved in those changes.

A small molecule transcription factor EB activator ameliorates beta-amyloid precursor protein and Tau pathology in Alzheimer's disease models.

Accumulating studies have suggested that targeting transcription factor EB (TFEB), an essential regulator of autophagy-lysosomal pathway (ALP), is promising for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). However, potent and specific small molecule TFEB activators are not available at present. Previously, we identified a novel TFEB activator named curcumin analog C1 which directly binds to and activates TFEB. In this study, we systematically investigated the efficacy of curcumin analog C1 in three AD animal models that represent beta-amyloid precursor protein (APP) pathology (5xFAD mice), tauopathy (P301S mice) and the APP/Tau combined pathology (3xTg-AD mice). We found that C1 efficiently activated TFEB, enhanced autophagy and lysosomal activity, and reduced APP, APP C-terminal fragments (CTF-ß/α), ß-amyloid peptides and Tau aggregates in these models accompanied by improved synaptic and cognitive function. Knockdown of TFEB and inhibition of lysosomal activity significantly inhibited the effects of C1 on APP and Tau degradation in vitro. In summary, curcumin analog C1 is a potent TFEB activator with promise for the prevention or treatment of AD.

Effects of Exercise During or Postchemotherapy in Cancer Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Exercise may effectively reduce side effects caused by chemotherapy. However, no meta-analyses of exercise during or postchemotherapy for cancer patients have been definitely performed to guide clinical practice. AIMS: To evaluate and summarize available scientific evidence to provide recommendations of an exercise intervention for cancer patients undergo chemotherapy. METHODS: A systematic review and meta-analysis were performed with databases searching of MEDLINE, Cochrane Library, and Embase from their inception to October 15, 2017. Literature was selected to identify randomized controlled trials of exercise during or postchemotherapy for cancer patients. Risk-of-bias assessment was performed by two reviewers independently. Data were analyzed using the Cochrane Collaboration's RevMan 5.3 (Review Man, Copenhagen, Denmark). RESULTS: A total of 10 trials with 838 participants were included in our study. Exercise could have a beneficial effect in cancer patients undergo chemotherapy in the outcome of physical fitness (MD: 0.16, 95% CI: 0.08-0.25, p < .01 and MD: 2.46, 95% CI: 1.44-3.47, p < .01) and depression (MD: -1.36, 95% CI: -2.68 to -0.04, p = .04), but not in FACT-G, FACT-B, anxiety, weight, and BMI (all p > .05). Exercise sequence (during or postchemotherapy) did not influence the effect of exercise for cancer patients undergo chemotherapy. In total, six studies were assessed as an overall low risk of bias. Subgroup analyses and sensitivity analyses reached results similar to those of the meta-analyses, which reflected our results were reliable and robust. LINKING EVIDENCE TO ACTION: Exercise seems to have a beneficial effect on physical fitness and depression, but not on quality of life, anxiety, weight, and BMI. More specific and detailed description of the implementation of exercise programs should be proposed in the future.

Nonpharmacological Interventions for Cancer-Related Fatigue: A Systematic Review and Bayesian Network Meta-Analysis.

BACKGROUND: Nonpharmacological interventions are the first recommendation for cancer-related fatigue, according to current guidelines. There are many forms of nonpharmacological interventions for addressing cancer-related fatigue, but the preferred means remain controversial and are not stated in the guidelines. Therefore, we evaluated the comparative effects and ranks of all major nonpharmacological interventions, according to different assessment methods, in cancer patients with fatigue. METHODS: Medline, Embase, Cochrane Library, and Allied and Complementary Medicine Database were searched for randomized controlled trials on nonpharmacological treatments for cancer-related fatigue. We assessed the trials' methodological quality using the Cochrane Risk of Bias tool. A Bayesian network meta-analysis and a comparative effects ranking were performed with Aggregate Data Drug Information System software. RESULTS: A total of 16,675 items were obtained from the databases, and 182 studies comprising 18,491 participants were included in the analysis. Based on the ranking probabilities, multimodal therapy and qigong ranked best with a Brief Fatigue Inventory; for a Functional Assessment of Cancer Therapy-fatigue scale, combined psychosocial therapies and bright white light therapy ranked best; for the Piper Fatigue Scale, resistance exercise and mindfulness-based stress reduction ranked best; for a multidimensional fatigue inventory, multimodal therapy and cognitive behavioral therapy (CBT) ranked best; for the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), acupuncture and CBT ranked best; and for the Profile of Mood States Fatigue Subscale, multimodal therapy, qigong, aerobic exercise, and CBT ranked best. Comprehensive analysis of the results indicated that multimodal therapy, CBT, and qigong might be the optimum selections for reducing cancer-related fatigue. Most of the included studies had low risk of methodological quality problems; however, 59 studies had low methodological quality. LINKING EVIDENCE TO ACTION: Different interventions have their own sets of advantages for addressing cancer-related fatigue. These results can be utilized as evidence-based interventions for healthcare workers and patients to manage cancer-related fatigue.

Transcatheter arterial chemoembolisation followed by three-dimensional conformal radiotherapy versus transcatheter arterial chemoembolisation alone for primary hepatocellular carcinoma in adults.

BACKGROUND: Hepatocellular carcinoma, also called malignant hepatoma, is a primary malignancy of the liver. Despite regular surveillance conducted in high-risk populations, most people with hepatocellular carcinoma are diagnosed at an advanced stage. Consequently, only a minority of people with the disease are suitable for surgical resection when diagnosed. OBJECTIVES: To compare the beneficial and harmful effects of transcatheter arterial chemoembolisation (TACE) followed by three-dimensional conformal radiotherapy (3-DCRT) versus TACE alone in adults with primary hepatocellular carcinoma, considered unsuitable for surgical resection. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index - Science up to 31 May 2018. We checked reference lists for all included studies and related reviews for further relevant articles. SELECTION CRITERIA: We included all randomised clinical trials comparing TACE followed by 3-DCRT versus TACE alone in people with primary hepatocellular carcinoma. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as suggested by Cochrane. We presented the results of the fixed-effect model in the absence of statistical heterogeneity. Otherwise, we reported the results from the random-effects model meta-analysis. We assessed risk of bias of the included trials using bias risk domains and presented the review results incorporating the methodological quality of the trials using GRADE. Our main conclusions were based on the analysis up to three years' follow-up. MAIN RESULTS: We identified eight randomised clinical trials (632 participants) that fulfilled our inclusion criteria. All eight trials were at high risk of bias, and we rated the evidence as low to very low certainty. The mean age ranged from 16 years to 78 years. The proportion of men ranged from 60% to 75% and the proportion of people with stage III primary hepatocellular carcinoma ranged from 22% to 85%. The median follow-up duration was 12 months (2 months to 38 months).TACE followed by 3-DCRT compared with TACE alone may have reduced all-cause mortality at three years' follow-up (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.73 to 0.88; 552 participants; 7 trials; low-certainty evidence). TACE followed by 3-DCRT compared with TACE alone may reduce the proportion of participants without tumour response (complete response plus partial response) (RR 0.49, 95% CI 0.39 to 0.61; 632 participants; 8 trials; low-certainty evidence). Data, from one trial on health-related quality of life, favoured the TACE followed by 3-DCRT group, but the provided data were ill-defined (very low-certainty evidence). None of the trials reported serious adverse events. The results on non-serious adverse events were as follows: TACE followed by 3-DCRT compared with TACE alone showed no difference in the results for proportion of participants with leukopenia (RR 1.12, 95% CI 0.92 to 1.34; 438 participants; 5 trials; very low-certainty evidence) and serum transaminases elevation (RR 1.67, 95% CI 0.66 to 4.27; 280 participants; 4 trials; very low-certainty evidence). However, the proportion of participants with total bilirubin elevation was larger in the TACE followed by 3-DCRT group than in the TACE alone group (RR 2.69, 95% CI 1.34 to 5.40; 172 participants; 2 trials; very low-certainty evidence). The rate of participants with serum alpha-fetoprotein (AFP) without decline or normalisation was significantly lower in the TACE followed by 3-DCRT group than in the TACE group, but these data were from one trial only (Chi² = 7.24, P = 0.007; very low-certainty evidence). AUTHORS' CONCLUSIONS: TACE followed by 3-DCRT may be associated with lower all-cause mortality and increased tumour response, despite the increased toxicity expressed by a higher rise of total bilirubin. Our review findings should be considered with caution because of the methodological weaknesses in the included trials, resulting in low- to very low-certainty evidence. Data on serious adverse events and health-related quality of life are lacking. We are also very much uncertain in the results of the reported non-serious adverse events. High-quality trials are needed to assess further the role of TACE followed by 3-DCRT for unresectable hepatocellular carcinoma.