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Structured abstractLay abstract In this study, we aimed to elucidate the therapeutic mechanism of miRNA (miR)-498 in autophagy and macrophage polarization to M2-like phenotype in esophageal cancer. This study reports lower miR-498 expression in esophageal cancer tissues compared with adjacent normal tissues. According to the experimental results, miR-498 negatively targets MDM2 by binding to its 3′UTR, which leads to attenuated ubiquitination and degradation of ATF3 induced by MDM2. Specifically, overexpressed miR-498 reduces ratio of LC3II (a marker that is commonly utilized to detect cell autophagy) to LC3I and increases p62 (a common cargo receptor for autophagy) accumulation in KYSE-150 cells, and elevates macrophage polarization to M2-like phenotype by depressing MDM2-mediated ATF3 degradation. The present study deepened our understanding of the causes of esophageal cancer and provided at least three novel therapeutic targets for the development of effective targeted therapy for esophageal cancer.

Objectives: Cisplatin-based concurrent chemoradiotherapy has been identified as the primary and standard treatment for locally advanced nasopharyngeal carcinoma (NPC). The side effects of cisplatin affect the compliance to therapy. Thus, the search for a platinum-based substitute for NPC has always been a research focus. However, there is a variability in the efficacy of different platinum-based chemotherapy in the treatment of NPC. We performed a meta-analysis to compare between the efficacy and safety of the cisplatin-based regimens and the other platinum-based derivatives (carboplatin, nedaplatin, and lobaplatin) for locally advanced NPC. Methods: PubMed, EMBASE, Cochrane Library, Web of Science, and ClinicalTrials.gov were systematically searched for all potentially eligible clinical trials as of February 15, 2022. The pooled hazard ratios, risk ratio, and 95% confidence interval were calculated using the Review Manager Software version 5.4. Results: A total of 1,907 patients with locally advanced NPC were eligible from the 1,265 retrieved records. This systematic review included eight articles, six of which were randomized controlled clinical trials. There was no significant difference in the 3- and 5-years overall survival, progression-free survival, distant metastasis-free survival, and locoregional relapse-free survival between cisplatin-based chemotherapy and other platinum-based chemotherapy. Severe acute hematological side effects (≥ grade 3) during treatment, such as neutropenia, leukopenia, and thrombocytopenia, are equivalent in both groups. However, the incidence of anemia is higher in patients receiving other platinum-based chemotherapy. Moreover, the risks of nausea, vomiting and weight loss were higher in the cisplatin group but there was no significant difference in the other non-hematological and late side effects between the two groups. Conclusion: Other types of platinum-based chemotherapy are as effective as cisplatin-based chemotherapy in the treatment of locally advanced NPC, thus acting as potential alternatives to cisplatin. Further studies providing high-level evidence are needed.

Background: Platinum compounds are commonly used for lung cancer treatment. However, the severe side effects and relatively poor prognosis limit their therapeutic effect. Therefore, developing novel platinum derivative and treatment strategy are critical for current lung cancer therapy. Methods: Flow cytometry, HMGB1 and ATP release, and immunoblotting were performed to evaluate the Oxaliplatin-induced immunogenic cell death (ICD) in two lung carcinoma cells. Vaccination approach and subcutaneous tumor models were created to analyze the tumor regression effect of Oxaliplatin. PD-L1 mRNA and protein levels were detected in LLC (Lewis lung carcinoma). Enhanced therapeutic efficacy of LLC was assessed by co-administration Oxaliplatin and aPD-L1 in murine lung tumor model. Results: Oxaliplatin induced robust ICD in LLC cells, activated dendritic cells (DCs, CD80+CD86+) and enhanced cytotoxic T cells (CD8+) in LLC tumor tissues, which resulted in tumor regression. Co-administration of Oxaliplatin and checkpoint inhibitor, aPD-L1, could enhance the therapeutic efficacy of LLC in murine lung carcinoma. Conclusion: This study reveals Oxaliplatin can induce robust ICD in tumor tissues and suppress tumor growth by activating DCs and enhancing T-cell infiltration. Notably, the Oxaliplatin-induced ICD provides an immunogenic microenvironment, which enhances the checkpoint inhibitor therapeutic efficacy of LLC.

Background This research aimed to analyze the effects of stellate nerve block with different drugs on the curative effect, stress responses, and the circulatory system of patients with hypertensive trigeminal neuralgia (TN). Methods A retrospective analysis of 82 patients with hypertensive TN admitted to our hospital from January 2019 to January 2021 was conducted, and the patients were divided into a control group and an observation group according to different drugs. The pain visual analogue scale (VAS) scores were determined between the 2 groups before treatment and at 1, 2, 3, 7, and 30 d after treatment. The mean arterial pressure (MAP) and heart rate (HR) were measured in the 2 groups of patients before treatment and immediately after treatment (T0), half an hour after treatment (T1), 1 h after treatment (T2), and 6 h after treatment (T3). The left ventricular wall thickness (LVWT), left ventricular end systolic volume (LVESV), left ventricular ejection fraction (LVEF), and fraction shortening (FS) were detected in the 2 groups before treatment and at T0-T2. Patient satisfaction was also scored, and the incidence of adverse reactions was assessed. Results The VAS scores of the 2 groups of patients decreased significantly after treatment at 1, 2, 3, 7, and 30 d. The MAP and HR indicators of the 2 groups decreased gradually at T0-T2, and gradually recovered to levels before treatment at the T3 time point. The MAP and HR indicators of the observation group were significantly lower than those of the control group at T0-T2. After treatment, the levels of LVWT, LVESV, LVEF, and FS in the observation group at the T0-T2 time points were significantly lower than those of the control group. Additionally, after treatment, the satisfaction of the observation group was significantly higher than that of the control group. The total incidence of adverse reactions in the observation group was significantly lower than that in the control group. Conclusions For patients with hypertensive TN, a single ropivacaine stellate nerve block can significantly relieve pain, and has little effect on heart function.

Tangningtongluo (TNTL), a traditional Chinese medicine, has been widely used in clinics for decades in southwest China. Its pharmacological properties and underlying molecular mechanisms remain unclear. The main goal of ethnopharmacology is to identify novel bioactive compounds derived from plants for use in indigenous medical practice. This knowledge can be used to develop novel pharmaceuticals. In the present study, hyperglycemic C57BL/KsJ‑db/db (db/db) mice were used to test the effect of TNTL on microvasculature of the retina and hypoglycemia. Metformin (Met) was selected as a positive control. 26‑week‑old mice were randomly assigned to receive either the anti‑diabetic agent Met [140 mg/kg body weight (BW)], 1.8, 0.9 or 0.45 g/kg BW TNTL, or a placebo. The fasting blood glucose, serum insulin and glycated hemoglobin levels were measured. Histopathologic examination of the pancreas was performed to confirm the hypoglycemic effect. Fluorescein angiography was applied to detect diabetes‑induced retinal angioma in the db/db mice. TNTL intake significantly decreased the fasting blood glucose level in a dose‑dependent manner. Additionally, TNTL intervention resulted in a significant decrease in the insulin resistance index. Notably, TNTL treatment markedly reduced the speed of retinal degeneration and mildly reversed microvascular caliber degeneration. Western blot analysis indicated that upregulation of phosphorylated insulin receptor substrate‑1 (p‑IRS‑1) by the administration of TNTL may be strongly involved in the improvement of insulin resistance. In conclusion, TNTL exerted a strong hypoglycemic effect and reversed retinal degeneration via upregulation of ISR‑1. The present findings provide important scientific evidence supporting TNTL as an effective alternative approach for the management of Type 2 diabetes mellitus.

As the foremost common female malignancy, breast cancer (BC) poses a significant public health stumbling block. Although treatment protocols have improved over the years, the overall prognosis of BC remains unsatisfactory. Extensive investigations have taken place into long non coding RNAs (lncRNAs) pertaining to their involvement in carcinogenesis. The current study in connection with bioinformatics tools aimed to identify the myocardial infarction associated transcript (MIAT) as a BC-related differentially expressed lncRNA in an attempt to elucidate the effect of MIAT in BC cells. MIAT was initially overexpressed while DLG3 was down-regulated in BC. BC cells were subsequently treated with si-MIAT or/and si-DLG3, after which the expressions of DLG3 and the Hippo signaling pathway-related proteins were evaluated to analyze their regulatory mechanism in BC, which indicated that MIAT inhibition up-regulated DLG3 and activated the Hippo signaling pathway to suppress proliferation and promote apoptosis of BC cells. MS-PCR and RIP assays demonstrated that MIAT bound to the methylation proteins DNMT1, DNMT3A and DNMT3B, promoted the methylation of CpG islands in DLG3 promoter and inhibited the DLG3 expression. Moreover, our data suggested that DLG3 could bind to MST2 and regulate LAST1, which prevented the nuclear translocation of YAP. The in vitro results were further verified via the in vivo findings. Taken together, the central findings of our study demonstrate that MIAT silencing inhibits BC progression by means of up-regulating DLG3 via activation of the Hippo signaling pathway, highlighting a novel potential therapeutic target for the treatment of the BC.

Background Myocardial injury caused by myocardial ischemia (MI) is still a severe condition that can result in apoptosis, oxidative stress, and inflammation. Remifentanil is a selective, ultra-short-acting, µ-opioid receptor agonist opioid. It can improve sinusoidal heart rate patterns in the fetus, for bupivacaine-induced cardiotoxicity, and with lipopolysaccharide (LPS)-induced cardiomyocytes injuries. This study aimed to explore the cardioprotective effects of remifentanil in MI model rats. Methods Sprague Dawley (SD) rats were split into five groups at random, including a control group, Isop group, low-dose remifentanil treatment group (10 µg/kg), medium-dose remifentanil treatment group (20 µg/kg), and a high-dose remifentanil treatment group (40 µg/kg). The MI model was achieved by subcutaneously injecting rats with isoproterenol (85 mg/kg) for two consecutive days. With the expression of apoptotic molecules, myocardial systolic function index, inflammation, antioxidant enzymes, and the myocardial enzyme taken into account, the data was analyzed. Results After treatment with remifentanil, the left ventricular wall thickness (LVWT), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), fraction shortening (FS), and heart rate (HR) were significantly increased in comparison with the Isop group. Creatine kinase-MB (CK-MB), Mb, and cTnl expressions were decreased. Meanwhile, the levels of cleaved caspase-3 and caspase-9 were decreased. Remarkably, the levels of reactive oxidative species (ROS), malondialdehyde (MDA), and lactate dehydrogenase (LDH) were observed to be repressed, while the levels of superoxide dismutase (SOD) was significantly increased. More importantly, the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and interferon (IFN)-γ were decreased. Conclusions Remifentanil has significant potential as a therapeutic intervention strategy for ameliorating myocardial injury after MI and these findings provide the rationale for further clinical studies.

To investigate the relationship between OPRM1 118A/G gene polymorphism and oxycodone analgesic dose in patients with cancer pain.DNA sequencing was used to detect the genotypies of OPRM1 118 A/G site in 203 patients with moderate and severe cancer pain, and to compare the relationship between the pain degree and the dose of oxycodone at 3 and 30 days after treatment in patients with different genotypes.The fequencies of AA, AG and GG genotypes at the OPRM1 118 A/G site were 34.78%, 52.70%, and 12.52%, respectively. The dosage of oxycodone in GG genotype was significantly higher than that in AA genotype and AG genotype (15.44±10.19 vs. 10.25±4.53, 10.49±5.26; 89.15±27.69 vs. 43.59±12.19, 48.27±18.79) on the 3 and 30 day after treatment, difference was statistically significant (P0.05).For cancer pain patients with GG genotype of OPRM1 118A/G site, if they need to achieve the same analgesic effect as patients with AA and AG genotype, the dose of oxycodone should be increased.

Objective To evaluate the effect of Wuwei Wentong Chubi (WWWTCB) Capsule on the PI3K/AKT/mTOR signaling pathway in the synovial tissues of adjuvant-induced arthritis (AA) rats, and investigate its potential pharmacological mechanisms of treating rheumatoid arthritis. Methods Sixty Sprague Dawley (SD) rats were randomly assigned into six groups evenly: normal group, model group, WWWTCB groups at 0.80, 1.60, 3.20 g/kg body mass, and tripterygium glycosides tablet (TPT) group at 40 mg/kg body mass. Except for the normal group, the other five groups were induced into AA models with Complete Freund's Adjuvant (CFA). The WWWTCB or TPT, was administrated from day 12 after injection of CFA by gavage, once a day for 12 days. After that, unaffected ankle-joint tissues from the AA rats were collected for histopathological examination. The mRNA levels of PI3K, AKT, mTOR, p70s6 and beclin1 in the synovial tissue were detected by real-time quantitative PCR. Meanwhile, the protein levels of PI3K, AKT, p-AKT, mTOR, p-mTOR, p70s6, p-p70s6 and beclin1 were determined by immunofluorescence histochemical staining and/or Western blotting. Results Compared with the model group, WWWTCB (1.60, 3.20 g/kg body mass) groups showed less ankle-joint injury and decreased proliferation of synovial cells in the ankle-joint tissues. In addition, the administration of WWWTCB decreased the mRNA and protein levels of PI3K, AKT, p-AKT, mTOR, p-mTOR, p70s6 and p-p70s6, while increased the level of beclin1. Conclusion WWWTCB ameliorated AA in rats. The improvement might be closely related to the inhibitory effect of WWWTCB on the PI3K/AKT/mTOR signaling pathway and its promoting effect on the autophagy activity of synovial cells.

Hexokinase-II (HK-II) confers protection against cell death and this study was designed to investigate the effect of mangiferin on the regulation of mitochondrial HK-II. In vessel endothelial cells, saturated fatty acid palmitate (PA) stimulation induced HK-II detachment from mitochondria due to cellular acidification. Mangiferin reduced lactate accumulation by improving pyruvate dehydrogenase activity, promoted Akt translocation to HK-II and prevented HK-II detachment from mitochondria. Knockdown of Akt2 diminished the protective effect of mangiferin on mitochondrial HK-II, confirming the role of Akt in the regulation of HK-II. Mangiferin prevented mitochondrial permeability transition pore opening, restored mitochondrial membrane potential and thereby protected cell from apoptosis. In high-fat diet fed mice, oral administration of mangiferin induced Akt phosphorylation, increased HK-II binding to mitochondria and resultantly protected vessel endothelial function, demonstrating its protective effect on endothelial integrity in vivo. This finding provided a novel strategy for the protection of mitochondrial function in the endothelium.

This paper studies the adaptive full state hybrid projective synchronization method. Based on the Lyapunov stability theory, an adaptive controller is designed. It is proved theoretically that the controller can make the states of the dynamical system and the response system with known or unknown parameters asymptotically full state hybrid projective synchronized. A unified chaotic system is used as an example and numerical simulations show the effectiveness of the scheme.