Neuroprotective Effect of Ponicidin Alleviating the Diabetic Cognitive Impairment: Regulation of Gut Microbiota.

Cognitive impairment is a major complication of diabetes mellitus, which is caused by constitutive hyperglycaemia. Ponicidin is a diterpenoid isolated from a Chinese traditional herb (Rabdosia rubescens) and demonstrates the various pharmacological effects. The goal of this study was to scrutinise the neuroprotective effect of ponicidin against diabetic nephropathy (DN) induced by streptozotocin (STZ). Intraperitoneal administration of STZ (55 mg/kg) was used for the induction of diabetes and rats were received oral administration of ponicidin (5, 10 and 15 mg/kg) until 28 days. The body weight, food intake, water intake and blood glucose level were assessed at regular time interval. Plasma insulin level, antioxidant, inflammatory cytokines, apoptosis marker and faecal gut microbiota compositions were estimated. DN-induced group rats revealed the augmented glucose level, water intake, food intake and reduced body weight. Ponicidin significantly (P < 0.001) repressed the glucose level and water food intake and improved the body weight and plasma insulin. Ponicidin significantly (P < 0.001) repressed the malonaldehyde (MDA) level and boosted the level of glutathione (GSH), glutathione reductase (GR) and superoxide dismutase (SOD) in the brain and serum level. Ponicidin significantly (P < 0.001) repressed the level of interleukin-1ß (IL-1ß), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and enhanced the level of interleukin-4 (IL-4), interleukin-10 (IL-10) in the brain and serum level. DN group rats exhibited the enhanced relative abundance of Firmicutes, along with enhancing the Firmicutes/Bacteroidetes ratio and repressing the Bacteroidetes relative abundance. Ponicidin effectually restored the relative abundance of Allobaculum, Lactobacillus and Ruminococcus genera. Our findings clearly demonstrated that ponicidin has a neuroprotective effect against diabetic cognitive impairment through modulating the gut microbiome.

Oral Endothelium Corneum Gigeriae Galli Therapy for Pancreatic Duct Stones: A Prospective Cohort Study.

BACKGROUND: Pancreatic duct stones obstruct the pancreatic ducts and aggravate clinical symptoms of chronic pancreatitis. Only isolated case reports have shown that some drugs may be useful in dissolving pancreatic duct stones. Endothelium corneum gigeriae galli is a Chinese medicine widely used to cure multifarious lithiasis and maldigestion. This study aimed to evaluate the efficacy of endothelium corneum gigeriae galli oral therapy in the dissolution of stones and evaluate the improvement of clinical symptoms in patients with pancreatic duct stones. METHODS: Sixty-eight patients with pancreatic duct stones were randomly divided into the endothelium corneum gigeriae galli and control groups. Endothelium corneum gigeriae galli was given orally to the endothelium corneum gigeriae galli group, and the placebo was given to the control group. Both groups were reviewed by computed tomography and magnetic resonance imaging; abdominal pain, exocrine and endocrine pancreatic function, and the nutritional status of patients were measured after the study. RESULTS: The dissolution rate of the endothelium corneum gigeriae galli group was significantly higher than that of the control group (P = .002). The abdominal pain of the endothelium corneum gigeriae galli group was relieved more significantly compared to that of the control group (P < .001). The exocrine and endocrine pancreatic function of the endothelium corneum gigeriae galli group improved more significantly than that of the control group (P < .001). The nutritional status of the endothelium corneum gigeriae galli group was significantly higher than that of the control group (P = .003). CONCLUSION: Overall, oral endothelium corneum gigeriae galli treatment could dissolve pancreatic duct stones, relieve abdominal pain, improve exocrine and endocrine pancreatic functions, and control the deterioration of nutritional status. Endothelium corneum gigeriae galli treatment should be useful in pancreatic duct stones therapy.

Redirecting anti-Vaccinia virus T cell immunity for cancer treatment by AAV-mediated delivery of the VV B8R gene.

Immunotherapies, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor-T (CAR-T) cells, are only efficient in a small proportion of tumor patients. One of the major reasons for this is the lack of immune cell infiltration and activation in the tumor microenvironment (TME). Recent research reported that abundant bystander CD8+ T cells targeting viral antigens exist in tumor infiltrates and that virus-specific memory T cells could be recalled to kill tumor cells. Therefore, virus-specific memory T cells may be effective candidates for tumor immunotherapy. In this study, we established subcutaneous tumor mice models that were pre-immunized with Vaccinia virus (VV) and confirmed that tumor cells with ectopic expression of the viral B8R protein could be recognized and killed by memory T cells. To create a therapeutic delivery system, we designed a recombinant adeno-associated virus (rAAV) with a modified tumor-specific promoter and used it to deliver VV B8R to tumor cells. We observed that rAAV gene therapy can retard tumor growth in VV pre-immunized mice. In summary, our study demonstrates that rAAV containing a tumor-specific promoter to restrict VV B8R gene expression to tumor cells is a potential therapeutic agent for cancer treatment in VV pre-immunized or VV-treated mice bearing tumors.

Opportunities and challenges in targeted therapy and immunotherapy for pancreatic cancer.

Pancreatic cancer is one of the most malignant tumours with a poor prognosis. In recent years, the incidence of pancreatic cancer is on the rise. Traditional chemotherapy and radiotherapy for pancreatic cancer have been improved, first-line and second-line palliative treatments have been developed, and adjuvant treatments have also been used in clinical. However, the 5-year survival rate is still less than 10% and new treatment methods such as targeted therapy and immunotherapy need to be investigated. In the past decades, many clinical trials of targeted therapies and immunotherapies for pancreatic cancer were launched and some of them showed an ideal prospect in a subgroup of pancreatic cancer patients. The experience of both success and failure of these clinical trials will be helpful to improve these therapies in the future. Therefore, the current research progress and challenges of selected targeted therapies and immunotherapies for pancreatic cancer are reviewed.

Chaperone-mediated autophagy affects tumor cell proliferation and cisplatin resistance in esophageal squamous cell carcinoma.

BACKGROUND: Chaperone-mediated autophagy (CMA) is a lysosomal degradation pathway of selective soluble proteins. Lysosomal membrane associated protein 2a (LAMP2a) is the lysosomal membrane receptor of CMA and influences CMA activity. Although it has been suggested that higher expression of LAMP2a is associated with more advanced tumor node metastasis (TNM) stages and shorter survival time in patients with esophageal squamous cell carcinoma (ESCC), the underlying mechanism has not been known yet. METHODS: In this study, we modulated the activity of CMA through LAMP2a or small molecular compounds in human ESCC cells to investigate its role in ESCC. RESULTS: We found that down-regulating the activity of CMA could inhibit the proliferation and colony formation of ESCC cells as well as increase their sensitivity to cisplatin. CONCLUSIONS: Our results promote better understanding of how CMA affects human ESCC and provide a new therapeutic target against ESCC through down-regulating LAMP2a.

CNOT7 depletion reverses natural killer cell resistance by modulating the tumor immune microenvironment of hepatocellular carcinoma.

A major obstacle to effective cancer immunotherapy is the tumor immune microenvironment. Natural killer (NK) cell resistance has been suggested as a primary cause of poor prognosis in hepatocellular carcinoma (HCC), which seemingly correlates with CNOT7 overexpression. CNOT7, a cytoplasmic mRNA deadenylase that is highly expressed in HCC, may regulate cytokine transforming growth factor-ß1 (TGF-ß1) secretion by controlling nuclear factor-κB subunit p65 trafficking. CNOT7 depletion suppresses TGF-ß1 secretion in HCC and promotes interferon-γ (IFN-γ) secretion by NK cells, and we previously demonstrated that CNOT7 depletion reversed IFN-γ resistance in HCC cells. Therefore, we hypothesized that CNOT7 depletion might reverse NK cell resistance by influencing the tumor immune microenvironment of HCC. To test this hypothesis, we examined the correlation between CNOT7, STAT1, TGF-ß1 and IFN-γ expression with hepatitis B virus-related cirrhosis and HCC with hepatitis B virus-related cirrhosis. We found that modulation of CNOT7 expression alters TGF-ß1 secretion in HCC and IFN-γ secretion in NK cells. We also examined the effects of NK cells in HepG2 cells with CNOT7 knockdown, which showed that NK cell surface CD107a expression is up-regulated and caspase-3 expression is significantly enhanced in CNOT7-deficient HepG2 cells. Overall, our results show that knockdown of CNOT7 expression reverses NK cell resistance in HCC cells. Therefore, CNOT7 depletion has potential as a new adjuvant therapy in immunotherapy for HCC.