Influence of glutamine metabolism on diabetes Development:A scientometric review.

Objective: "Metabolism affects function" is the consensus of researchers at present. It has potential clinical application value to study the effects of regulating glutamine (Gln) metabolism on diabetes physiology or pathology. Our research aimed to summarize the latest research progress, frontier hot topics and future development trends in this field from the perspective of scientometrics. Methods: Relevant literatures and reviews were obtained from the Web of Science (WoS) between January 1, 2001 and May 31, 2022. An online analysis platform of bibliometrics, CiteSpace, and VOS viewer software were used to generate visual knowledge network graphs, including publication countries, institutions and authors partnership analysis, co-occurrence analysis, co-citation analysis, as well as citations and keywords burst detection to acquire research trends and hotspots. Results: Our results showed that a total of 945 publications in the WoS database met the analysis requirements, with articles being the main type. The overall characteristics showed an increasing trend in the number of publications and citations. The United States was leading the way in this research and was a hub for aggregating collaborations across countries. Vanderbilt University delivered high-quality impact with the most published articles. DeBerardinis, RJ in this field was the most representative author and his main research contents were Gln metabolism and mitochondrial glutaminolysis. Significantly, there was a relative lack of collaboration between institutions and authors. In addition, "type 2 diabetes", "glutamine", "metabolism", "gene expression" and "metabolomics" were the keywords categories with high frequency in co-citation references and co-occurrence cluster keywords. Analysis of popular keywords burst detection showed that "branched chain", "oxidative phosphorylation", "kinase", "insulin sensitivity", "tca cycle", "magnetic resonance spectroscopy" and "flux analysis" were new research directions and emerging methods to explore the link between Gln metabolism and diabetes. Overall, exploring Gln metabolism showed a gradual upward trend in the field of diabetes. Conclusion: This comprehensive scientometric study identified the general outlook for the field and provided valuable guidance for ongoing research. Strategies to regulate Gln metabolism hold promise as a novel target to treat diabetes, as well as integration and intersection of multidisciplinary provides cooperation strategies and technical guarantees for the development of this field.

Styrax (Liquidambar orientalis Mill.) promotes mitochondrial function and reduces cardiac damage following myocardial ischemic injury: the role of the AMPK-PGC1α signaling pathway.

OBJECTIVES: To explore the effect of extract of Styrax (ES) on myocardial ischemic injury and its molecular mechanism, indirectly providing a theoretical basis for the development of ES. METHODS: In order to assess the impact of ES treatment on ischemic heart disease, both a left anterior descending ligation-induced myocardial infarction (MI) model and an ischemia/hypoxia (I/H)-induced H9c2 cell injury model have been constructed. Specifically, Sprague-Dawley rats were randomly assigned to the following groups (n = 8) and administered intragastrically once a day for seven consecutive days: Sham group, MI group, ES-L (0.2 g/kg) group, ES-M (0.4 g/kg) group, ES-H (0.8 g/kg) group, and trimetazidine (TMZ, 0.02 g/kg) group. The cardiac functions and biochemical assessment of rats were detected. Then, we validated experimentally the targets and mechanism of ES on these pathological processes in I/H-induced H9c2 cell injury model. KEY FINDINGS: These results showed that different doses of ES (0.2 g/kg, 0.4 g/kg, 0.8 g/kg, intragastric) significantly improved myocardial structure and function when compared to the MI group. The results of 2,3,5-triphenyltetrazolium chloride (TTC), hematoxylin-eosin, and masson staining indicated that ES could significantly reduce infarct size, inhibit myocardium apoptosis, and decrease myocardial fibrosis. Moreover, ES distinctly suppressed the serum levels of lactate dehydrogenase (LDH), cardiac troponin T (cTnT), and creatine kinase-MB (CK-MB), alleviated myocardial mitochondrial morphology, and stimulated adenosine triphosphate (ATP) production, increased the level of succinate dehydrogenase (SDH), complex I and complex V activity. Different doses of ES (5 µg/ml, 10 µg/ml, 20 µg/ml) also improved cardiomyocyte morphology and decreased the apoptosis rate in H9c2 cells that had been exposed to I/H. Furthermore, the results of western blotting and qRT-PCR indicated that ES promoted the expression of proteins and mRNA related to energy metabolism, including phosphorylated adenosine monophosphate activated protein kinase (p-AMPK), peroxisome proliferator activated receptor gamma coactivator 1 alpha (PCG-1α), nuclear respiratory factor 1, and mitochondrial transcription factor A (TFAM). Mechanically, after the administration of Compound C (dorsomorphin), an AMPK inhibitor, these effects of myocardial protection produced by ES were reversed. CONCLUSIONS: Collectively, these results demonstrated that ES could improve myocardial mitochondrial function and reduce ischemic injury by activating AMPK/PCG-1α signaling pathway, while indicating its potential advantages as a dietary supplement.

Protective effect and mechanism of styrax on ischemic stroke rats: metabonomic insights by UPLC-Q/TOF-MS analysis.

CONTEXT: Styrax is used for prevention and treatment of cerebrovascular diseases. However, the underlying mechanism remains unclear. OBJECTIVE: To elucidate styrax's anti-ischemic stroke protective effects and underlying mechanisms. MATERIALS AND METHODS: An ischemic-stroke rat model was established based on middle cerebral artery occlusion (MCAO). Sprague-Dawley rats were randomly assigned to the following groups (n = 10) and administered intragastrically once a day for 7 consecutive days: sham, model, nimodipine (24 mg/kg), styrax-L (0.1 g/kg), styrax-M (0.2 g/kg) and styrax-H (0.4 g/kg). Neurological function, biochemical assessment, and ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS)-based serum metabonomics were used to elucidate styrax's cerebral protective effects and mechanisms. Pearson correlation and western blot analyses were performed to verify. RESULTS: The addition of 0.4 g/kg styrax significantly reduced cerebral infarct volume and neurobehavioral abnormality score. Different doses of styrax also decrease MDA, TNF-α, IL-6, and IL-1ß, and increase SOD and GSH-Px in ischemic-stroke rats (p < 0.05; MDA, p < 0.05 only at 0.4 g/kg dose). Biochemical indicators and metabolic-profile analyses (PCA, PLS-DA, and OPLS-DA) also supported styrax's protective effects. Endogenous metabolites (22) were identified in ischemic-stroke rats, and these perturbations were reversible via styrax intervention, which is predominantly involved in energy metabolism, glutathione and glutamine metabolism, and other metabolic processes. Additionally, styrax significantly upregulated phosphorylated AMP-activated protein kinase and glutaminase brain-tissue expression. CONCLUSION: Styrax treatment could ameliorate ischemic-stroke rats by intervening with energy metabolism and glutamine metabolism. This can help us understand the mechanism of styrax, inspiring more clinical application and promotion.

First-line treatments for advanced hepatocellular carcinoma: a network meta-analysis and cost-effectiveness analysis in China and the United States.

Background: Various therapeutic strategies are available for the first-line treatment of patients with advanced hepatocellular carcinoma (aHCC). But which approach is the most cost-effective remains uncertain. Objectives: This study aims to evaluate the cost-effectiveness of first-line strategies in aHCC patients from the perspective of Chinese and US payers. Design: A network meta-analysis (NMA) and cost-effectiveness study. Data sources and methods: A NMA was conducted to collect all first-line strategies with aHCC from 1 October 1 2018 until 1 January 2022. The relevant randomized controlled trial literature in PubMed, Embase, and Cochrane Library for the last 3 years were searched. The abstracts of meetings of the American Society of Clinical Oncology, European Society of Medical Oncology, and American Association for Cancer Research were also reviewed. A Markov model that included three states was developed. One-way sensitivity and probabilistic sensitivity analysis were performed to investigate the uncertainty of the economic evaluation. Scenario analysis was conducted to explore the economic benefits of treatment strategies in low-income populations. Results: Base-case analysis in China included 1712 patients showed that atezolizumab combined with bevacizumab, sintilimab combined with bevacizumab, lenvatinib (LEVA), and sorafenib (SORA) added 0.46, 1.25, 0.77, and -1.08 quality-adjusted life-years (QALYs), respectively, compared with donafenib, resulting in an incremental cost-effective ratio of $85607.88, $12109.27, and $1651.47 per QALY at a willingness-to-pay (WTP) of $11101.70/QALY. In the United States, only the incremental cost-effectiveness ratios (ICERs) of SORA was higher that were lower than the WTP threshold ($69375/QALY), and LEVA was the most cost-effective strategy with the ICERs were 25022.13/QALY. Conclusion: The NMA and cost-effectiveness analysis revealed that LEVA is the favorite choice in the first-line treatment of Chinese aHCC patients and US payers' perspective when the WTP was $11101.70/QALY in China and $69375.0/QALY in the United States. Registration: This study has been registered on the PROSPERO database with the registration number CRD42021286575.

Knowledge Mapping of the Links Between the Gut Microbiota and Heart Failure: A Scientometric Investigation (2006-2021).

Background: There is considerable research value and extensive application perspectives to explore the link between gut microbiota and heart failure. The purpose of this study is to provide an overview of overall characteristics, evolutionary pathways, frontier research hotspots, and future trends in this field. Methods: Research datasets were acquired from the Web of Science Core Collection (WoSCC) between January 1, 2006 and December 31, 2021. Three different analysis tools including one online platform, VOS viewer V1.6.17.0, and CiteSpace V5.8.R2 software were used in order to conduct collaboration network analysis, co-cited analysis, co-occurring analysis, and citation burst detection. Results: A total of 873 publications in the WoSCC database met the requirement. The overall characteristics analysis showed that a steady growth trend in the number of publications and citations, with the predominant literature type being articles and the most frequent subject category being cardiac cardiovascular systems. The United States was the most prolific country and the center of national collaboration. Cleveland Clinic and Nathalie M. Delzenne provided the leading influence with publications, the cooperation between the institutes and authors were relatively weak. Moreover, gut microbiota, heart failure, risk factor, obesity, and inflammation were the keywords that appeared more frequently in the clustering analysis of reference co-citation and keyword co-occurrence. Burst detection analysis of top keywords showed that trimethylamine N-oxide (TMAO), bile acid, blood pressure, hypertension, and fermentation were the new research foci on the association between gut microbiota and heart failure. Strategies to improve gut microbiota hold promise as a new approach to treat heart failure. Conclusion: The comprehensive bibliometric study indicates that the structured information may be helpful in understanding research trends in the link between gut microbiota and heart failure, and locating research hotspots and gaps in this domain, especially further advances in this field will lead to significant breakthroughs in the development of novel therapeutic tools for metabolic modulation of heart failure.

Corrigendum to "Salvia miltiorrhiza and the Volatile of Dalbergia odorifera Attenuate Chronic Myocardial Ischemia Injury in a Pig Model: A Metabonomic Approach for the Mechanism Study".

[This corrects the article DOI: 10.1155/2021/8840896.].

Salvia miltiorrhiza and the Volatile of Dalbergia odorifera Attenuate Chronic Myocardial Ischemia Injury in a Pig Model: A Metabonomic Approach for the Mechanism Study.

Salvia miltiorrhiza (SM) coupled with Dalbergia odorifera (DO) has been used to relieve cardiovascular diseases in China for many years. Our previous studies have integrated that SM-the volatile oil of DO (SM-DOO)-has a cardioprotective effect on chronic myocardial ischemia based on a pharmacological method, but the cardioprotective mechanism has not been elucidated completely in the metabonomic method. In the present study, a metabonomic method based on high-performance liquid chromatography time-of-flight mass spectrometry (HPLC-Q-TOF-MS) was performed to evaluate the effects of SM-DOO on chronic myocardial ischemia induced by an ameroid constrictor, which was placed on the left anterior descending coronary artery (LAD) of pigs. Pigs were divided into three groups: sham, model, and SM-DOO group. With multivariate analysis, a clear cluster among the different groups was obtained and the potential biomarkers were recognized. These biomarkers were mainly related to energy metabolism, glucose metabolism, and fatty acid metabolism. Furthermore, the protein expressions of phosphorylated AMP-activated protein kinase (p-AMPK) and glucose transporter-4 (GLUT4) were significantly upregulated by SM-DOO. The result indicated that SM-DOO could regulate the above biomarkers and metabolic pathways, especially energy metabolism and glucose metabolism. By analyzing and verifying the biomarkers and metabolic pathways, further understanding of the cardioprotective effect of SM-DOO with its mechanism was evaluated. Metabonomic is a reliable system biology approach for understanding the cardioprotective effects of SM-DOO on chronic myocardial ischemia and elucidating the mechanism underlying this protective effect.

Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma.

Intratumoral heterogeneity (ITH) is a fundamental property of cancer; however, the origins of ITH remain poorly understood. We performed single-cell transcriptome profiling of peritoneal carcinomatosis (PC) from 15 patients with gastric adenocarcinoma (GAC), constructed a map of 45,048 PC cells, profiled the transcriptome states of tumor cell populations, incisively explored ITH of malignant PC cells and identified significant correlates with patient survival. The links between tumor cell lineage/state compositions and ITH were illustrated at transcriptomic, genotypic, molecular and phenotypic levels. We uncovered the diversity in tumor cell lineage/state compositions in PC specimens and defined it as a key contributor to ITH. Single-cell analysis of ITH classified PC specimens into two subtypes that were prognostically independent of clinical variables, and a 12-gene prognostic signature was derived and validated in multiple large-scale GAC cohorts. The prognostic signature appears fundamental to GAC carcinogenesis and progression and could be practical for patient stratification.

Frequency and Implications of Paratracheal Lymph Node Metastases in Resectable Esophageal or Gastroesophageal Junction Adenocarcinoma.

OBJECTIVE: We aimed to evaluate the frequency of paratracheal lymph nodes (LN) metastases and their prognostic influence. SUMMARY BACKGROUND DATA: Paratracheal LNs are considered regional nodes in the esophageal cancer classification, but their metastatic rate and influence on survival remain unclear. METHODS: One thousand one hundred ninety-nine patients with resectable esophageal or gastroesophageal junction adenocarcinoma (EAC) (January 2002 and December 2016) in our Gastrointestinal Medical Oncology Database were analyzed. Paratracheal LNs were defined as1R, 1L, 2R, 2L, 4R, and 4L, according to the 8th American Joint Committee on Cancer classification. RESULTS: Of 1199 patients, 73 (6.1%) had positive paratracheal LNs at diagnosis. The median overall survival (OS) of 73 patients with initial paratracheal LN involvement was 2.10 years (range 0.01-10.1, 5-yrs OS 24.2%). Of 1071 patients who were eligible for recurrence evaluation, 70 patients (6.5%) developed paratracheal LN metastases as the first recurrence. The median time to recurrence was 1.28 years (range 0.28-5.96 yrs) and the median OS following recurrence was only 0.95 year (range 0.03-7.88). OS in 35 patients who had only paratracheal LN recurrence was significantly longer than in patients who had other recurrences (median OS 2.26 vs 0.51 yrs, 5-yrs OS; 26.8% vs 0%, P < 0.0001). Higher T stage (T3/T4) was an independently risk factor for paratracheal LN recurrence (odds ratio 5.10, 95% confidence interval 1.46-17.89). We segregated patients in 3 groups based on the distance of tumor's proximal edge to esophagogastric junction (low; ≤2 cm, medium; 2.0-7.0 cm, and high; >7.0 cm). Paratracheal LN metastases were more frequent with the proximal tumors (low, 4.2%; medium, 12.0%; high, 30.3%; Cochran-Armitage Trend test, P < 0.001). CONCLUSION: Paratracheal LN metastases were associated with a shorter survival in resectable EAC patients. Alternate approaches to prolong survival of this group of patients are warranted.

Outcomes of Advanced Gastroesophageal Cancer Patients with Equivocal HER2 Expression with or without ERBB2 Gene Amplification.

BACKGROUND: Prior studies have shown that patients whose tumor overexpresses Her2 at 3+ level by immunohistochemistry (IHC) fare better than those whose tumor overexpresses Her2 at 2+ level (with ERBB2 amplified). Therefore, it would be important to compare the outcome of patients whose tumor expresses Her2 at 2+ level but further classify by gene amplification studies as positive or negative. METHODS: We retrospectively identified patients with advanced gastroesophageal adenocarcinoma with low Her2 protein expression (2+ by IHC) whose tumors were evaluated for gene amplification of ERBB2 by fluorescence in situ hybridization (FISH). All patients received first-line therapy, and trastuzu-mab was added according to Her2 status. We compared overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) of the entire cohort and compared Her2-positive tumor patients' outcomes with Her2-negative tumor patients' outcomes. All patients had treatment response assessments and follow-ups at our institution. RESULTS: We identified 87 patients whose tumors expressed Her2 at 2+ level. 51 (58.6%) were Her2-negative and 36 (41.4%) were Her2-positive by FISH. For the entire cohort, the median OS was 26 months (95% confidence interval 16.6-37.6), and the median PFS was 12.2 months (95% confidence interval 9.7-19.3). Median OS, median PFS, and ORR did not differ between Her2-positive and Her2-negative patients (p = 0.70, p = 0.60, p = 0.91, respectively). CONCLUSIONS: Our data suggest that patients with Her2 positivity or negativity when tumors have lower Her2 protein expression (2 + by IHC) have similar clinical outcomes. Further research is warranted in this cohort.

A Gastric Cancer Peptide GX1-Modified Nano-Lipid Carriers Encapsulating Paclitaxel: Design and Evaluation of Anti-Tumor Activity.

AIM: The aim of this study was to develop a GX1-modified nanostructured lipid carrier (NLCs) and to evaluate its ability to improve the anti-gastric cancer tumor effects of paclitaxel (PTX). MAIN METHODS: The GX1-modified NLCs were synthesized and loaded with PTX (GX1-PTX-NLCs) by emulsion solvent evaporation technique. The anti-tumor activity and pharmacodynamics were then evaluated by in vitro cell studies and animal experiments. KEY FINDINGS: The GX1-modified NLCs were successfully synthesized and confirmed by 1H NMR and MALDI-TOF-MS. PTX-loaded NLCs produced particles with average size distribution less than or equal to 222 nm and good drug loading and entrapment efficiency. In vitro studies demonstrated that GX1-PTX-NLCs had a more obvious inhibitory effect on Co-HUVEC cells than PTX and unmodified PTX-NLCs. The cellular uptake results also showed that GX1-PTX-NLCs were largely concentrated in Co-HUVEC cells, and the uptake rates of GX1-PTX-NLCs in Co-HUVEC were higher than those of the free drug and the PTX-NLC. In vivo studies demonstrated that GX1-PTX-NLCs possess strong anti-tumor effect and showed higher tumor growth inhibition and lower toxicity in nude mice. SIGNIFICANCE: These results suggest that GX1-modified NLCs enhanced the anti-tumor activity of PTX and reduced its toxicity effectively. GX1-PTX-NLCs may be considered as a potent drug delivery system for therapy of gastric cancer.

Palliative care for advanced gastric cancer.

INTRODUCTION: Proactive palliative care can effectively relieve symptoms early and effectively as well as improve the quality of life of patients with gastric adenocarcinoma (GAC). AREAS COVERED: The review summarizes palliative care for GAC. GAC caused specific symptoms, such as malignant gastric outlet obstruction (GOO), bleeding, weight loss, and/or ascites, therefore, these symptoms must be addressed specifically. EXPERT OPINION: Palliative care should start early to control general symptoms, thus may improve the patient's condition to make the patient eligible for anti-cancer treatment. As some stage IV GAC patients can now live longer, palliative interventions become more important. A multimodality interdisciplinary approach is strongly encouraged.

Low metabolic activity in primary gastric adenocarcinoma is associated with resistance to chemoradiation and the presence of signet ring cells.

PURPOSES: Preoperative chemoradiation is a potential treatment option for localized gastric adenocarcinoma (GAC). Currently, the response to chemoradiation cannot be predicted. We analyzed the pretreatment maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) on positron emission tomography/computed tomography as potential predictors of the response to chemoradiation. METHODS: We analyzed the SUVmax and TLG data from 59 GAC patients who received preoperative chemoradiation. We used logistic regression models to predict a pathologic complete response (pCR) and Kaplan-Meier curves to determine overall survival among patients with high and low SUVmax or TLG. RESULTS: Twenty-nine patients (49%) had Siewert type III adenocarcinoma and 30 (51%) had tumors located in the lower stomach. Forty-one patients had poorly differentiated GAC, and 26 had signet ring cells. The median SUVmax was 7.3 (0-28.2) and the median TLG was 56.6 (0-1881.5). Patients with signet ring cells had a low pCR rate, as well as a low SUVmax and TLG. In the multivariable logistic regression model, high SUVmax was a predictor of pCR (odds ratio = 11.1, 95% confidence interval = 2.12-50.0, p = 0.004). Overall survival was not associated with the SUVmax (log-rank p = 0.69) or TLG (log-rank p = 0.85) CONCLUSION: A high SUVmax was associated with sensitivity to chemoradiation and pCR in GAC, and signet ring cells seemed to confer resistance.

Brain metastases in patients with upper gastrointestinal cancer is associated with proximally located adenocarcinoma and lymph node metastases.

BACKGROUND: As cancer patients are surviving longer, more patients manifest brain metastases (BRMs). However, the rate of BRMs from upper gastrointestinal cancer is unclear. We therefore evaluated the frequency and prognostic effect of BRMs in this setting. METHODS: We analyzed records of 2348 patients who were treated between January 2002 and December 2016 for upper gastrointestinal cancer, including esophageal and gastroesophageal junction adenocarcinoma (EAC; proximal EAC, Siewert types I and II), esophageal squamous cell carcinoma (ESCC), and gastric adenocarcinoma (GAC; Siewert type III and stomach cancer) in our Gastrointestinal Medical Oncology Database. Frequency, risk factors, and survival after BRMs were evaluated. RESULTS: Of 2348 patients, 68 (2.9%) had BRMs upon follow-up. The BRM rates were as follows: proximal EAC, 4.8%; Siewert type I, 5.9%; Siewert type II, 2.2%; Siewert type III, 0.7%; ESCC: 1.2%; and stomach cancer, 0%. Among EAC patients, Siewert type I and lymph node metastases were independent the risk factors for BRMs in the multivariable analysis. The median overall survival (OS) in the 68 patients with BRMs was only 1.16 years (95% CI 0.78-1.61). However, OS for patients who had a solitary BRM, who had BRM but no other distant metastasis, or who underwent surgery or stereotactic radiosurgery favorable. CONCLUSION: Patients with proximally located adenocarcinoma, or with lymph node metastases are at a higher risk for BRMs and patients fare better after treatment of isolated BRM.

Taxane-based or platinum-based combination chemotherapy given concurrently with radiation followed by surgery resulting in high cure rates in esophageal cancer patients.

BACKGROUND: Preoperative chemoradiotherapy (CRT) is one standard option for localized esophageal or gastroesophageal junction (GEJ) cancer patients but an optimal concurrent chemotherapy combination is not established. METHODS: 412 patients with resectable (cT1N1M0 or cT2-4N0-3M0) esophageal or GEJ cancer treated at the MDACC between October 2002 and June 2016 were analyzed. Exposures: CRT with DF or FOX followed by surgery (trimodality; TMT). Main outcomes and measures: Primary endpoints were overall survival (OS) and disease-free survival (DFS). Univariate and multivariate Cox analyses were performed. RESULTS: Of the 412 patients analyzed, 264 (64%) received DF and 148 (36%) FOX. The median age was 60 years, and 95% had adenocarcinoma. The clinical complete response, positron-emission tomography response, and pathologic complete response rates were 73%, 73%, and 30%, respectively. Median follow-up was 60.4 months. Median OS for the entire cohort was 81.6 months (95% confidence interval [CI], 56.3-122.0); 81.6 months (95% CI, 55.9-not estimable) for the DF group and 67.7 months (95% CI, 41.6-not estimable) for the FOX group (P = .24). The median DFS was 45.6 months (95% CI, 33.1-61.7) for the entire cohort; 49.5 months (95% CI, 38.6-70.3) for DF and 33.0 months (95% CI, 18.1-70.4; P = .38) for FOX. Higher tumor location (unfavorable) and clinical complete response (favorable) were prognostic for both OS and DFS in the multivariate analysis. CONCLUSION: At our high-volume center, the outcome of 412 TMT esophageal cancer patients was excellent. Taxane-based chemotherapy produces nonsignificant favorable trend.

Immunotherapy for esophageal cancer: a 2019 update.

Esophageal cancer remains a global health concern with a dismal prognosis and an estimated 5-year survival rate of approximately 10-15%. Immunotherapy is a novel treatment approach representing an effective and promising option against several types of cancer. The development of new and efficacious immunotherapeutic strategies, such as adoptive cell therapy-based, antibody-based and vaccine-based therapies, aims to prevent immunological escape and modify immunological responses. In this review, we discuss the theoretical background and current status of immunotherapy for patients with esophageal cancer. We also present ongoing clinical trials and summarize key findings concerning survival and safety analyses.

κ-opioid receptor activation promotes mitochondrial fusion and enhances myocardial resistance to ischemia and reperfusion injury via STAT3-OPA1 pathway.

Mitochondrial dynamics, determining mitochondrial morphology, quality and abundance, have recently been implicated in myocardial ischemia and reperfusion (MI/R) injury. The roles of κ-opioid receptor activation in cardioprotection have been confirmed in our previous studies, while the underlying mechanism associated with mitochondrial dynamics remains unclear. This study aims to investigate the effect of κ-opioid receptor activation on the pathogenesis of MI/R and its underlying mechanisms. MI/R mouse model and hypoxia-reoxygenation cardiomyocyte model were established in this study. Mitochondrial dynamics were analyzed with transmission electron microscopy in vivo and confocal microscopy in vitro. STAT3 phosphorylation and OPA1 expression were detected by Western blotting. We show here that κ-opioid receptor activation with its selective receptor agonist U50,488H promoted mitochondrial fusion and enhanced myocardial resistance to MI/R injury, while these protective effects were blockaded by nor-BNI, a selective κ-opioid receptor antagonist. In addition, κ-opioid receptor activation increased STAT3 phosphorylation and OPA1 expression, which were blockaded by nor-BNI. Furthermore, inhibition of STAT3 phosphorylation by stattic, a specific STAT3 inhibitor, repressed the effects of κ-opioid receptor activation on promoting OPA1 expression and mitochondrial fusion, as well as inhibiting cell apoptosis and oxidative stress both in vivo and in vitro during MI/R injury. Overall, our data for the first time provide evidence that κ-opioid receptor activation promotes mitochondrial fusion and enhances myocardial resistance to MI/R injury via STAT3-OPA1 pathway. Targeting the pathway regulated by κ-opioid receptor activation may be a potential therapeutic strategy for MI/R injury.

Salvianolic acid B regulates macrophage polarization in ischemic/reperfused hearts by inhibiting mTORC1-induced glycolysis.

Macrophages play important roles in the healing and remodeling of cardiac tissues after myocardial ischemia/reperfusion (MI/R) injury. Here we investigated the potential effects of salvianolic acid B (SalB), one of the abundant and bioactive compounds extracted from Chinese herb Salvia Miltiorrhiza (Danshen), on macrophage-mediated inflammation after MI/R and the underlying mechanisms. In primary cultured bone marrow-derived macrophages (BMDMs), SalB attenuated lipopolysaccharide (LPS)-induced M1 biomarkers (IL-6, iNOS, CCL2 and TNF-α) mRNA expression in a concentration-dependent manner. In contrast, M2 biomarkers (Arg1, Clec10a and Mrc) mRNA levels following interleukinin-4 (IL-4) stimulation were significantly upregulated by SalB. In addition, LPS stimulation potently induced transcriptional upregulation of RagD, an important activation factor of mammalian target of rapamycin complex 1 (mTORC1). Interestingly, SalB inhibited RagD upregulation and mTORC1 activation, decreased glycolysis, and reduced inflammatory cytokine production in LPS-stimulated macrophages, all of which were blunted in RagD knockdown macrophages. In mice subjected to MI/R, SalB treatment decreased cardiac M1-macrophages and increased M2-macrophages at 3 days post-MI/R, followed by decreased collagen deposition and ameliorated cardiac dysfunction at 7 days post-MI/R. Collectively, our data have shown that SalB decreases M1-polarized macrophages in MI/R hearts via inhibiting mTORC1-dependent glycolysis, which might contribute to alleviated inflammation and improved cardiac dysfunction afforded by SalB after MI/R.

A network pharmacology approach to reveal the protective mechanism of Salvia miltiorrhiza-Dalbergia odorifera coupled-herbs on coronary heart disease.

Salvia miltiorrhiza-Dalbergia odorifera coupled-herbs (SMDOCH) has been used to treat coronary heart disease (CHD) for thousands of years, but its unclear bioactive components and mechanisms greatly limit its clinical application. In this study, for the first time, we used network pharmacology to elucidate the mechanisms of action of SMDOCH on CHD. We collected 270 SMDOCH-related targets from 74 bioactive components and 375 CHD-related targets, with 58 overlapping common targets. Next, we performed enrichment analysis for common-target network and protein-protein interaction (PPI) network. The results showed that SMDOCH affected CHD mainly through 10 significant signaling pathways in three biological processes: 'vascular endothelial function regulation', 'inflammatory response', and 'lipid metabolism'. Six pathways belonged to the 'vascular endothelial function regulation' model, which primarily regulated hormone (renin, angiotensin, oestrogen) activity, and included three key upstream pathways that influence vascular endothelial function, namely KEGG:04933, KEGG:05418, and KEGG:04066. Three pathways, namely KEGG:04668, KEGG:04064, and KEGG:04620, belonged to the 'inflammatory response' model. One pathway (KEGG:04920) belonged to the 'lipid metabolism' model. To some extent, this study revealed the potential bioactive components and pharmacological mechanisms of SMDOCH on CHD, and provided a new direction for the development of new drugs for the treatment of CHD.