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PURPOSE: This research aimed to explore prognostic factors for early-onset colorectal cancer (EO-CRC) patients with liver metastasis (LM) and develop nomogram for predicting cancer-specific survival (CSS) probability quantitatively. METHODS: Our study included 4368 EO-CRC patients with LM registered in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2017. Potential prognostic factors for EO-CRC patients with LM were identified by multivariable Cox regression analysis. Prognostic nomogram was subsequently constructed based on these prognostic factors. The discriminative ability, calibration, and clinical usefulness of the nomogram were assessed by the area under the receiver operating characteristic (ROC) curves (AUC), calibration curves, and decision curve analysis (DCA). RESULTS: In the training cohort, marital status, primary tumor location, histopathological grade, T stage, number of metastatic organs, carcinoembryonic antigen (CEA), perineural invasion (PI), surgery of primary site, chemotherapy, radiation therapy, and metastatic lymph nodes ratio (LNR) were prognostic factors for cancer-specific mortality of EO-CRC patients with LM. The 1-, 2-, and 3-year AUC values of the prognostic nomogram were 0.777, 0.781, and 0.788, respectively. Calibration curves indicated acceptable agreement between nomogram-predicted survival and actual observed survival at 1, 2, and 3 years. DCA curves exhibited good positive net benefits in the prognostic model in most threshold probabilities at different time points. All of these results were reproducible in the validation cohort. CONCLUSIONS: This study identified prognostic factors for EO-CRC patients with LM and developed a prognostic nomogram with good performance and clinical usability, which may help clinicians make better treatment decisions.

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BACKGROUND: Insomnia is a common but frequently overlooked sleep disorder after stroke, and there are limited effective therapies for insomnia following stroke. Traditional Chinese medicine (TCM), including acupuncture and the Chinese herbal medication (CHM) Suanzaoren decoction (SZRD), has been reported as an alternative option for insomnia relief after stroke in China for thousands of years. Here, this study aims to investigate the efficacy and safety of electroacupuncture (EA) in combination with SZRD in the treatment of insomnia following stroke. METHODS: A total of 240 patients with post-stroke insomnia will be included and randomized into four groups: the EA group, SZRD group, EA & SZRD group, and sham group. The same acupoints (GV20, GV24, HT7, and SP6) will be used in the EA group, EA & SZRD group, and sham group, and these patients will receive the EA treatment or sham manipulation every other day for 4 consecutive weeks. SZRD treatments will be given to participants in the SZRD group and EA & SZRD group twice a day for 4 consecutive weeks. The primary outcome measures include Pittsburgh Sleep Quality Index scores and polysomnography. Secondary outcome measures include the Insomnia Severity Index, the National Institutes of Health Stroke Scale, the Hospital Anxiety and Depression Scale, brain magnetic resonance imaging, functional magnetic resonance imaging, and nocturnal melatonin concentrations. The primary and secondary outcomes will be assessed at baseline (before treatment), during the 2nd and 4th weeks of the intervention, and at the 8th and 12th weeks of follow-up. Safety assessments will be evaluated at baseline and during the 4th week of the intervention. DISCUSSION: This study will contribute to assessing whether the combination of these two therapies is more beneficial for post-stroke insomnia than their independent use, and the results of this clinical trial will improve our understanding of the possible mechanisms underlying the effects of combination therapies. TRIAL REGISTRATION: Chinese Clinical Trials Register ChiCTR2000031413 . Registered on March 30, 2020.

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OBJECTIVES: Preclinical research is essential to the advancement of science but susceptible to insufficient reporting and methodological shortcomings, which compromise internal validity. We aimed to systematically assess the methodological and reporting quality of studies conducted on acupuncture for experimental cerebral ischemia/reperfusion injury (CIRI). METHODS: A comprehensive search in six databases was performed for animal research concerning acupuncture for CIRI. Two authors independently selected articles, extracted data, and assessed the methodological and reporting quality of identified articles using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tool, and Animal Research: Reporting In Vivo Experiments (ARRIVE) guideline, respectively. RESULTS: A total of 24 studies were identified. Only 1 article (4%) achieved a decent overall rating in using SYRCLE (percentage of items with "low risk" ⩾50%). Of the 22 items on the SYRCLE tool, only 8 items (37%) were rated as "low risk" of bias in more than 50% of the included studies. Of the 39 items of ARRIVE, 20 (51%) items were rated as "low risk" in more than 50% of the included studies. CONCLUSIONS: The methodological and reporting quality of included studies was generally low, which demands further improvement. These findings should inform the development of evidence-based guidelines for future preclinical research assessing the effect of acupuncture on CIRI.

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Cerebral ischemia/reperfusion (CIR) injury occurs when blood flow is restored in the brain, causing secondary damage to the ischemic tissues. Previous studies have shown that electroacupuncture (EA) treatment contributes to brain protection against CIR injury through modulating autophagy. Studies indicated that SIRT1-FOXO1 plays a crucial role in regulating autophagy. Here we investigated the mechanisms underlying the neuroprotective effect of EA and its role in modulating autophagy via the SIRT1-FOXO1 signaling pathway in rats with CIR injury. EA pretreatment at "Baihui", "Quchi" and "Zusanli" acupoints (2/15Hz, 1mA, 30 min/day) was performed for 5 days before the rats were subjected to middle cerebral artery occlusion, and the results indicated that EA pretreatment substantially reduced the Longa score and infarct volume, increased the dendritic spine density and lessened autophagosomes in the peri-ischemic cortex of rats. Additionally, EA pretreatment also reduced the ratio of LC3-II/LC3-I, the levels of Ac-FOXO1 and Atg7, and the interaction of Ac-FOXO1 and Atg7, but increased the levels of p62, SIRT1, and FOXO1. The above effects were abrogated by the SIRT1 inhibitor EX527. Thus, we presume that EA pretreatment elicits a neuroprotective effect against CIR injury, potentially by suppressing autophagy via activating the SIRT1-FOXO1 signaling pathway.

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Geum japonicum Tunb. var. chinense (GJ) is a traditional Chinese medicine usually used for the alleviation of dizziness and headache. Previous studies have reported that the GJ extracts could alleviate cerebral I/R injury by reducing apoptosis in vivo. To further elucidate the positive role and underlying mechanism of the GJ extracts in cerebral I/R injury, the current study investigated the effects of the GJ extracts on oxygen-glucose deprivation and re-oxygenation (OGD/R)-induced astrocytes injury in light of BDNF/PI3K/Akt/CREB signaling pathway with seropharmacological method. In the present study, the LC-MS profiling of the GJ extracts, obtain by reflux extraction, led to the identification of three possible active components were 5-desgalloylstachyurin, tellimagrandin II (TG II) and 3,4,5-Trihydroxybenzaldehyde (THBA). Drug-containing serum was collected from rats given different doses of the GJ extracts (0, 1.75 g/kg, 7 g/kg). Data indicated that the GJ extracts could increase the cell viability and decrease apoptosis and the expression of glial fibrillary acidic protein (GFAP) in OGD/R-induced astrocytes. In addition, the detection of apoptosis-related factors showed that the GJ extracts could obviously increase the expression of Bcl-2 and reduce the expression of Bax, Caspase-3 and cleaved-Caspase-3. Furthermore, the GJ extracts markedly increased the expression of BDNF, TrkB, PI3K, p-Akt and p-CREB. All these effects of the GJ extracts could be significantly reversed by LY294002, an inhibitor of PI3K. These data indicated that the GJ extracts could protect astrocytes against OGD/R-induced injury by inhibiting astrocytes reactivity and apoptosis, owing to the activation of the BDNF/PI3K/Akt/CREB pathway. The results support the application of the GJ extracts in the treatment of ischemic stroke and other ischemic encephalopathy.

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OBJECTIVE: To investigate the effect of electroacupuncture (EA) preconditioning on autophagy in cerebral cortex tissues of rats with cerebral ischemia-reperfusion injury (CIRI), so as to explore its mechanisms underlying improvement of CIRI. METHODS: Thirty-three male Sprague-Dawley rats were randomly divided into sham operation, model and EA groups (n=11 in each group). EA (2 Hz/15 Hz, 1 mA) was applied to "Baihui"(GV20), "Quchi" (LI11) and "Zusanli" (ST36) for 30 min, once daily for 5 days, followed by establishment of CIRI model by occlusion of the middle cerebral artery (MCAO) for 1.5 h and reperfusion for 24 h. The neurological deficit score was assessed in reference to Longa's methods, and the infarct volume assessed by 2,3,5-triphenyltetrazolium chloride staining. The density of dendrite spines of neurons in the ischemic cerebral cortex tissue was detected by Golgi's staining, the autophagosome observed by electron microscopy, and the expression levels of microtubule-associated protein 1 light chain 3 (LC3) and p62 (a selective autophagy substrate) were detected by Western blot. RESULTS: Compared with the sham operation group, the neurological deficit score and infarct volume were significantly increased (P<0.01), the number of autophagosomes and the ratio of LC3-Ⅱ/LC3-Ⅰ also significantly increased (P<0.01), while the expression level of p62 was notably decreased in the model group (P<0.01). Following the intervention and in comparison with the model group, the neurological deficit score and infarct volume were significantly reduced (P<0.01), the number of autophagosomes and the ratio of LC3-Ⅱ/LC3-Ⅰ obviously decreased (P<0.01), and the expression of p62 was significantly up-regulated in the EA group (P<0.01). CONCLUSION: EA pretreatment is effective in improving CIRI in rats, which may be realized through suppressing autophagy in the ischemic cerebral cortex tissue.

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Cerebral ischemia injury, the leading cause of morbidity and mortality worldwide, initiates sequential molecular and cellular pathologies that underlie ischemic encephalopathy (IE), such as ischemic stroke, Alzheimer disease (AD), Parkinson's disease (PD), epilepsy, etc. Targeted therapeutic treatments are urgently needed to tackle the pathological processes implicated in these neurological diseases. Recently, accumulating studies demonstrate that microRNA-124 (miR-124), the most abundant miRNA in brain tissue, is aberrant in peripheral blood and brain vascular endothelial cells following cerebral ischemia. Importantly, miR-124 regulates a variety of pathophysiological processes that are involved in the pathogenesis of age-related IE. However, the role of miR-124 has not been systematically illustrated. Paradoxically, miR-124 exerts beneficial effects in the age-related IE via regulating autophagy, neuroinflammation, oxidative stress, neuronal excitability, neurodifferentiation, Aß deposition, and hyperphosphorylation of tau protein, while it may play a dual role via regulating apoptosis and exerts detrimental effects on synaptic plasticity and axonal growth. In the present review, we thus focus on the paradoxical roles of miR-124 in age-related IE, as well as the underlying mechanisms. A great understanding of the effects of miR-124 on the hypoxic-ischemic brain will open new avenues for therapeutic approaches to protect against cerebral ischemia injury.

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Excessive autophagy is one of the crucial factors of cerebral ischemia-reperfusion injury (CIRI), which has been demonstrated to be one of the targets for acupuncture treatment of ischemic stroke. In the present paper, we make a review about the development of acupuncture intervention induced improvement of CIRI (such as reducing the infarction area, improving learning-memory ability and motor function) by regulating autophagy in animal studies. Outcomes showed that acupuncture intervention can function in 1) inhibiting CIRI-induced increase of the number of lysosomes and autophagic lysosomes, and relieving structural injury of mitochondria, and reducing the number of autophagosome in the central region of the ischemic cerebral cortex tissue; 2) down-regulating the expression of microtubule-associated protein Ⅱ light chain 3 (LC3Ⅱ) and the ratio of LC3-Ⅱ/LC3-Ⅰ in the ischemic cerebral region, and 3) regulating the expression of Beclin 1 (autophagy-related gene), promoting the expression of P62 (autophagy-related adaptor protein). In addition, acupuncture can also regulate phosphoinositide 3 kinase (PI3K)- protein kinase B (AKT)- mammalian target of rapamycin complex 1(mTOR) signaling at different time-points (down-regulation at the early stage and up-regulation at the later stage), and activating AMP-activated protein kinase (AMPK)-mTOR- UNC51-like kinase-1 signaling to relieve cerebral ischemic injury. These results reveal some mechanisms of acupuncture therapy underlying improvement of CIRI and provide experimental basis for clinical application of acupuncture therapy in the treatment of ischemic stroke.

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OBJECTIVE: To explore the effect of electrical stimulation at auricular points (EAS) combined with sound masking on the expression of cAMP-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) in the auditory cortex of tinnitus rats. METHODS: A total of 27 adult male SD rats were randomly divided into a control group, a model group and an EAS group. The rats in the model group and the EAS group were intervened with intraperitoneal injection of sodium salicylate to induce tinnitus model, while the rats in the control group were intervened with injection of 0.9% NaCl solution. After the model was successfully established, the rats in the EAS group were treated with electrical stimulation at "Shenmen" (TF4) and "Yidan" (CO11), combined with sound masking; the treatment was given once a day for 15 days. The gap prepulse inhibition of acoustic startle (GPIAS) and prepulse inhibition (PPI) testing were performed using the acoustic startle reflex starter package for rats. The expression of BDNF, TrkB, CREB and p-CREB in the auditory cortex of each group were measured with Western Blot analysis. RESULTS: ① Compared with the control group, the GPIAS values in 12 kHz, 16 kHz, 20 kHz and 28 kHz were significantly decreased in the model group (all P<0.05); compared with the model group, GPIAS values in 12 kHz, 16 kHz, 20 kHz and 28 kHz were significantly increased in the EAS group (all P<0.05). ② Compared with the control group, the expression of BDNF and p-CREB in the model group was significantly increased (P<0.01), and the expression of TrkB in the model group was significantly increased (P<0.05); the differences of expression of BDNF, TrkB, CREB and p-CREB between the model group and the EAS group had no statistics significance (all P>0.05). CONCLUSION: EAS could improve the GPIAS values of high-frequency background sound in tinnitus rats, which may be related with the upregulation of the BDNF/TrkB/CREB signaling pathway in the auditory cortex, leading to the reversion of the maladaptive plasticity.

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Electroacupuncture is known as an effective adjuvant therapy in ischemic cerebrovascular disease. However, its underlying mechanisms remain unclear. Studies suggest that autophagy, which is essential for cell survival and cell death, is involved in cerebral ischemia reperfusion injury and might be modulate by electroacupuncture therapy in key ways. This paper aims to provide novel insights into a therapeutic target of electroacupuncture against cerebral ischemia/reperfusion injury from the perspective of autophagy. Here we review recent studies on electroacupuncture regulation of autophagy-related markers such as UNC-51-like kinase-1 complex, Beclin1, microtubule-associated protein-1 light chain 3, p62, and autophagosomes for treating cerebral ischemia/reperfusion injury. The results of these studies show that electroacupuncture may affect the initiation of autophagy, vesicle nucleation, expansion and maturation of autophagosomes, as well as fusion and degradation of autophagolysosomes. Moreover, studies indicate that electroacupuncture probably modulates autophagy by activating the mammalian target of the rapamycin signaling pathway. This review thus indicates that autophagy is a therapeutic target of electroacupuncture treatment against ischemic cerebrovascular diseases.

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Geum japonicum Thunb. var. chinense (GJ) is a type of wild vegetable found in China and other Asian countries; it has been reported that its extracts possess a neuroprotective effect against cerebral ischemia reperfusion (CIR) injury. The aim of this study is to explore the effect GJ extracts on transient focal CIR injury and neurons apoptosis and to clarify its possible underlying mechanisms in vivo. Our results indicated that pretreatment with GJ extracts significantly ameliorated the infarct volume, decreased neurological deficits, lessened neural cells apoptosis, downregulated GFAP activity level, and increased surviving neurons. Moreover, GJ extracts preadministration increased Bcl-2 levels and attenuated the increase in the expressions of Bax and it also lowered the cleaved caspase-3 activity in ischemic cortex tissues which was caused by CIR and increased the expression of PI3K and p-Akt. The above effects of high dose of GJ (GJ-H) group were much better than those of low dose of GJ (GJ-L), which indicated that GJ extracts may be helpful in the suppression of CIR injury with a dose-dependent manner.