ABSTRACT
Type 2 diabetes mellitus is a prevalent metabolic disease, posing a considerable threat to public health. Oligonucleotide drugs have proven to be a promising field of therapy for the diseases. In this study, we reported that a herbal small RNA (sRNA), JGL-sRNA-h7 (B34735529, F1439.L002444.A11), could exhibit potent hypoglycemic effects by targeting glucose-6-phosphatase. Oral administration of sphingosine (d18:1)-JGL-sRNA-h7 bencaosomes ameliorated hyperglycemia and diabetic kidney injury better than metformin in db/db mice. Furthermore, glucose tolerance was also improved in sphingosine (d18:1)-JGL-sRNA-h7 bencaosomes-treated beagle dogs. Our study indicates that JGL-sRNA-h7 could be a promising hypoglycemic oligonucleotide drug.
ABSTRACT
Immune checkpoint blockade (ICB) therapies function by alleviating immunosuppression on tumor-infiltrating lymphocytes (TILs) but are often insufficient to fully reactivate these dysfunctional TILs. Although interleukin 12 (IL-12) has been used in combination with ICB to improve efficacy, this remains limited by severe toxicity associated with systemic administration of this cytokine. Here, we engineer a fusion protein composed of an anti-PD-1 antibody and a mouse low-affinity IL-12 mutant-2 (αPD1-mIL12mut2). Systemic administration of αPD1-mIL12mut2 displays robust antitumor activities with undetectable toxicity. Mechanistically, αPD1-mIL12mut2 preferentially activates tumor-infiltrating PD-1+CD8+T cells via high-affinity αPD-1 mediated cis-binding of low-affinity IL-12. Additionally, αPD1-mIL12mut2 treatment exerts an abscopal effect to suppress distal tumors, as well as metastasis. Collectively, αPD1-mIL12mut2 treatment induces robust systemic antitumor responses with reduced side effects.
Subject(s)
CD8-Positive T-Lymphocytes , Interleukin-12 , Lymphocytes, Tumor-Infiltrating , Programmed Cell Death 1 Receptor , Animals , Interleukin-12/metabolism , Interleukin-12/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , Programmed Cell Death 1 Receptor/metabolism , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Mice , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/drug effects , Mice, Inbred C57BL , Cell Line, Tumor , Female , Immune Checkpoint Inhibitors/pharmacology , Humans , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/geneticsABSTRACT
Coronavirus disease 2019, a newly emerging serious infectious disease, has spread worldwide. To date, effective drugs against the disease are limited. Traditional Chinese medicine was commonly used in treating COVID-19 patients in China. Here we tried to identify herbal effective lipid compounds from the lipid library of 92 heat-clearing and detoxication Chinese herbs. Through virtual screening, enzymatic activity and inhibition assays, and surface plasmon resonance tests, we identified lipid compounds targeting the main protease (Mpro ) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and verified their functions. Here, we found that natural lipid compounds LPC (14:0/0:0) and LPC (16:0/0:0) could target SARS-CoV-2 Mpro , recover cell death induced by SARS-CoV-2, and ameliorate acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) induced by bacterial lipopolysaccharides and virus poly (I:C) mimics in vivo and in vitro. Our results suggest that LPC (14:0/0:0) and LPC (16:0/0:0) might be potential pan remedy against ARDS.
Subject(s)
Acute Lung Injury , COVID-19 Drug Treatment , Respiratory Distress Syndrome , Acute Lung Injury/drug therapy , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Humans , Lipids , Mice , Molecular Docking Simulation , SARS-CoV-2ABSTRACT
In order to understand the status of Salmonella contamination of feed production chain in Karst rural areas, southwest of China, a total of 1077 feed samples including animal feed materials and feed products were randomly collected from different sectors of feed chain covering feed mills, farms, and feed sales in nine regions of Karst rural areas between 2009 and 2012, to conduct Salmonella test. The different positive rates with Salmonella contamination were detected, the highest was 4.7 % in 2009, the lowest was 0.66 % in 2011, while 4.3 % in 2010, 2.8 % in 2012, respectively. Twelve types of feed including concentrate, complete, self-made, and feed ingredients were inspected. Salmonella contamination mainly concentrated on animal protein material such as meat meal, meat and bone meal, feather meal, blood meal, and fish meal. No Salmonella contamination was detected in feed yeast, microbial protein, rapeseed, and soybean meal. Salmonella contamination existed in each sector of feed production chain. This investigation provided a basic reference for feed production management and quality control in feed production chain in Karst rural areas of China.