Gastric cancer (GC) is the fourth most lethal cancer. Effective treatments are lacking, and our knowledge of the pathogenic mechanisms in play is poor. Oridonin from the Chinese herb Rabdosia rubescens exerts various anticancer activities. However, the dose-dependent effects of oridonin on human GC remain unclear. Here, we found that oridonin inhibited GC cell growth in a time- and dose-dependent manner. Low-dose oridonin induced GC cell cycle arrest at G0/G1 and cell senescence by suppressing the c-Myc-AP4 pathway and enhancing p53-p21 signaling. AP4 overexpression partly abrogated the oridonin-induced senescence of GC cells. High-dose oridonin induced apoptosis and autophagy, with the autophagy inhibitor BafA1 attenuating oridonin-induced apoptosis. Together, the findings indicate that oridonin at different doses modulates GC cell senescence and apoptosis; oridonin may thus usefully treat GC.
PURPOSE: Resistin is produced by adipose tissue in rats, and is a negative regulator of the whole-body insulin action in glucose disposal. In humans, resistin is produced mainly from macrophages and thus might involve with the interplay between inflammation and metabolic syndromes. The purpose of this study was to determine the effect of detraining on resistin level, body composition, and insulin sensitivity for elite swimmers. METHODS: Intensive swimming training program was stopped for 6 months in 20 elite swimmers. Oral glucose tolerance test (OGTT), insulin response of OGTT, resistin, total cholesterol, LDL-C, LDL-C to HDL-C ratio, and triglyceride levels were measured at baseline (training) and after detraining. Body composition measures including BMI and waist circumference were also determined. RESULTS: Waist circumference (72.69±1.11 vs.76.12±1.59 cm, p<0.05) and area under curve of insulin were significantly elevated with detraining. Blood resistin level was significantly decreased (2.27±0.25 vs. 1.23±0.13 mg/dL, p<0.05). CONCLUSIONS: Long-term detraining significantly increased body fatness in the elite swimmers. However, the serum resistin level was significantly reduced with detraining, suggesting that resistin in humans is not playing the same role in insulin action as in rats.
In recent years, extensive research into novel forms of drug delivery has suggested that mucosal approaches offer a promising therapeutic alternative, especially for systemically acting drugs. Transmucosal drug delivery offers many benefits, including noninvasive administration, convenience, rapid onset, as well as elimination of hepatic first-pass metabolism. The investigated absorptive surfaces consist of the nasal, buccal, ocular, vaginal, and rectal mucosae. Among these, the nasal and buccal routes have proved the most promising to date. The bioavailability achieved mainly depends upon the pathophysiological state of the mucosa and the properties of both the drug and delivery systems. Various agents can increase the efficacy of transmucosal drug delivery. These include cyclodextrins, bile salts, surfactants, fusidic acid derivatives, microspheres, liposomes, and bioadhesive agents.The mechanisms of action, effectiveness, and toxicity profiles of these enhancers have been investigated extensively in both animal and human models.
Serum HBeAg status and liver cirrhosis severity at the time of diagnosis of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV)-related cirrhosis remain inconclusive. The aim was to investigate the status of HBeAg and cirrhosis severity at the time of HCC development in the natural history of HBV-related cirrhosis in mainland China.In a retrospective cross-sectional hospital-based setting, HBeAg status and severity of underlying cirrhosis, estimated by MELD (model for end-stage liver disease) scores and aspartate aminotransferase (AST)--to-platelet ratio index (APRI), were comprehensively compared in 377 HBsAg-positive compensated and decompensated liver cirrhosis and 434 with HCC patients to clarify the independent and joint effects of the factors.The majority (80.6%) of the HCC patients was negative for serum HBeAg. More than two-thirds of the patients with HCC had MELD scores <10. Severity of underlying liver cirrhosis and loss of serum HBeAg independently correlated with the risk of HCC development. Compared with the contrast group of HBeAg-positive patients with MELD scores > or =20, the odds ratio of HCC development in the patients with HBeAg negativity and MELD score <10 was 26.51 (95%CI: 8.98-78.28).A large proportion of HBV-related cirrhotic patients had negative serum HBeAg and mild cirrhosis severity at the time of diagnosis of HCC.
Gastric cancer (GC) is the third leading cause of cancer-related death. Although the therapeutic approaches have improved, the 5-year survival rate of GC patients after surgical resection remains low due to the high rates of metastasis and recurrence. Patients with schizophrenia have significantly lower incidences of cancer after long-term drug treatment, suggesting the potential or partially ameliorate the risk of cancer development of antipsychotic drugs. The goal of this study was to explore antipsychotic drugs with an optional effective therapy against gastric cellular carcinoma. We found that sertindole, an atypical antipsychotic, exhibited anti-tumor efficacy on human GC cells in vitro and in vivo. Moreover, sertindole in combination with cisplatin dramatically enhanced apoptosis-induction in GC cells. In addition, the pro-apoptotic effect of sertindole on GC might in part, involved in inhibition of STAT3 activation and downstream signals, including Mcl1, surviving, c-Myc, cyclin D1. Collectively, these results suggested that sertindole could be a potential anticancer reagent and be an attractive therapeutic adjuvant for the treatment of human GC.
Abstract Non-small cell lung cancers (NSCLCs) harboring deletions or inactivating mutations in STK11 (encoding LKB1) are associated with treatment-resistance, including to immune checkpoint blockade, and poor survival, yet the underlying mechanisms are poorly understood. Here, we combined multi-modal single-cell transcriptomics, whole-genome sequencing (WGS), and analysis of public data bases totaling >10,000 NSCLC whole-exome sequencing (WES) and when available RNA (RNA-seq) profiles of AACR GENIE, MSK IMPACT, TCGA and CPTAC, high-content imaging, and functional assays, to determine genomic and mechanistic features of STK11-mutant NSCLC. Across human WES/RNA-seq data, we find that STK11-mutant NSCLC have a significantly higher fraction of genome altered (FGA) and score strongly for the mRNA-based CIN70 signature compared to other NSCLC genotypes, overall indicating that these tumors have a higher degree of chromosomal instability (CIN). Using high-content imaging, we show that both human and murine STK11-mutant models have a higher rate of micronuclei and chromosome-mis-segregation events, confirming their CINhigh status in dynamic assays. Next, we show that tonic CIN-induced activation of cGAS-STING signaling, whose activation is typically thought of inducing type I interferon expression, results in strong suppression of anti-tumor immune signaling. Remarkably, genetic or pharmacologic suppression of cGAS, and thus depletion of the STING ligand cGAMP, results in reprogramming and re-sensitization of STK11-mutant models to cGAS-STING mediated type I interferon responses. Furthermore, we show that CIN promotes excessive production cGAMP in STK11-mutant models. We find upregulation of two ectonucleotidases (ENPP1 and CD73/NT5E) that hydrolyze exported cGAMP to adenosine, which may further contribute to the highly dysfunctional tumor-microenvironment observed in STK11-mutant tumors. Lastly, suppression of CIN through overexpression of mitotic-centromere associated kinesin (MCAK) in murine STK11-mutant models results in decreased tumor growth and sensitization to anti-PD1 therapy. In summary, we define STK11-mutant as archetypical chromosomally form of NSCLC, provide mechanistic basis that corelates with poor clinical outcomes, and demonstrate how relief of tonic CIN-induced changes may be therapeutically leveraged. Citation Format: Lindsay A. Caprio, Christy Hong, Amit Dipak Amin, Somnath Tagore, Johannes Melms, Luke Cai, Yiping Wang, Patricia Ho, Michael Mu, Hanina Hibshoosh, Brian Henick, Kwok K. Wong, Samuel F. Bakhoum, Benjamin Izar. Relief of chromosomal instability-induced cGAS-STING signaling sensitizes STK11-mutant non-small cell lung cancer to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5944.
Tumors affecting the head, neck, and brain account for significant morbidity and mortality. The curative efficacy of radiotherapy for these tumors is well established, but radiation carries a significant risk of neurologic injury. So far, neuroprotective therapies for radiation-induced brain injury are still limited. In this study we demonstrate that Stichodactyla helianthus (ShK)–170, a specific inhibitor of the voltage-gated potassium (Kv)1.3 channel, protected mice from radiation-induced brain injury. Mice were treated with ShK-170 for 3 days immediately after brain irradiation. Radiation-induced brain injury was assessed by MRI scans and a Morris water maze. Pathophysiological change of the brain was measured by immunofluorescence. Gene and protein expressions of Kv1.3 and inflammatory factors were measured by quantitative real-time PCR, reverse transcription PCR, ELISA assay, and western blot analyses. Kv currents were recorded in the whole-cell configuration of the patch-clamp technique. Radiation increased Kv1.3 mRNA and protein expression in microglia. Genetic silencing of Kv1.3 by specific short interference RNAs or pharmacological blockade with ShK-170 suppressed radiation-induced production of the proinflammatory factors interleukin-6, cyclooxygenase-2, and tumor necrosis factor–α by microglia. ShK-170 also inhibited neurotoxicity mediated by radiation-activated microglia and promoted neurogenesis by increasing the proliferation of neural progenitor cells. The therapeutic effect of ShK-170 is mediated by suppression of microglial activation and microglia-mediated neurotoxicity and enhanced neurorestoration by promoting proliferation of neural progenitor cells.
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