Summary 1. Our previous study has shown that leptin induces cardiomyocyte hypertrophy; however, the mechanisms are poorly understood. Recent studies have shown that peroxisome proliferator‐activated receptor α (PPARα) activation might be responsible for pathological remodeling and severe cardiomyopathy. Leptin, as an endogenous activator of PPARα, regulates energy metabolism through activating PPARα in many cells. Therefore, we hypothesized that leptin induces cardiomyocyte hypertrophy through activating the cardiac PPARα pathway. 2. Cultured neonatal rat cardiomyocytes were used to evaluate the effects of PPARα on hypertrophy. The selective PPARα antagonist GW6471 concentration‐dependently decreased atrial natriuretic factor mRNA expression by 23%, 36%, 44% and 59%, and significantly decreased total RNA levels, protein synthesis and cell surface areas, all of which were elevated by 72 h of leptin treatment. The augmentation of reactive oxygen species levels in leptin treated cardiomyocytes was reversed by 0.1–10 μmol/L GW6471 (40%, 52% and 58%). After 24 h of treatment, leptin concentration‐dependently enhanced mRNA expression by 7%, 93%, 100% and 256%, and protein expression by 31.2%, 64.2%, 143% and 199%, and the activity of PPARα. Meanwhile, cardiomycytes receiving 72 h of treatment with the PPARα agonist, fenofibrate, concentration‐dependently increased total RNA levels, atrial natriuretic factor mRNA expression, protein synthesis and cell surface area. Treatment of fenofibrate for 4 h also elevated oxygen species levels in a concentration‐dependent manner. 3. In conclusion, these findings show that leptin induces hypertrophy through the activation of the PPARα pathway in cultured neonatal rat cardiomyocytes.
Foot-and-mouth disease virus (FMDV) O/CHN/Mya98/33-P strain was isolated from the esophageal-pharyngeal fluid sample of cattle, and was shown to cause persistent infection. Its leader protein contains 200 amino acids with one amino acid deletion, which is upstream and next to the second initiation codon compared with the majority of FMDV Mya98 strains. The FMDV genome includes two initiation codons that can produce two different leader proteins, Lab (from the first AUG) and Lb (from the second AUG). For convenience, the inter-AUG region was named as La. Previously, it was found that a recombinant virus with Lab of FMDV O/CHN/Mya98/33-P strain had higher proliferation efficiency, and better ability to inhibit the host innate immune response. Three full-length infectious cDNA clones—rHN33-Lb, rHN33-La, and rHNGSLX-Lb—containing the FMDV O/CHN/Mya98/33-P strain leader proteins Lb, La, or the FMDV O/GSLX/2010 strain leader protein Lb, respectively, were constructed based on an established infectious clone r-HN rescued from FMDV O/HN/CHN/93 strain. After infecting pig kidney primary cells, rHN33-La showed higher replication efficiency than r-HN, and rHN33-Lb displayed better ability to resist host innate immunity than rHNGSLX-Lb. These results demonstrated that the inter-AUG region of FMDV strain O/CHN/Mya98/33-P leader protein must be involved in increasing viral replication efficiency. Additionally, the Lb of FMDV O/CHN/Mya98/33-P must be involve in increasing its ability to inhibit host innate immune response, and the distinctive amino acids G56 and/or R118 of FMDV leader protein may play essential roles in it.
Background The phosphatidylinositol 3-kinase (PI3K) is frequently hyperactivated in cancer and plays important roles in both malignant and immune cells. The effect of PI3Kα inhibitors on the tumor microenvironment (TME) remains largely unknown. Here, we investigated the modulation of the TME by a clinical PI3Kα-specific inhibitor CYH33. Methods The activity of CYH33 against a panel of murine tumors in the immune-competent context or athymic mice was detected. Single-cell RNA sequencing and multi-parameter flow cytometry were performed to determine the immune profiling of TME. The effect of CYH33 on immune cells was conducted with primary murine cells. Results CYH33 exhibited more potent antitumor activity in immune-competent context. CYH33 enhanced the infiltration and activation of CD8 + T and CD4 + T cells, while attenuating M2-like macrophages and regulatory CD4 + T cells. Increase in memory T cells was confirmed by the induction of long-term immune memory on CYH33 treatment. Mechanistically, CYH33 relieved the suppressed expansion of CD8 + T cells via preferential polarization of the macrophages to the M1 phenotype. CYH33 promoted fatty acid (FA) metabolism in the TME, while FA enhanced the activity of CD8 + T cells in vitro. The combination of CYH33 with the FA synthase (FASN) inhibitor C75 synergistically inhibited tumor growth with enhanced host immunity. Conclusions CYH33 induces immune activation and synergizes with FASN inhibitor to further promote the antitumor immunity, which gains novel insights into how PI3K inhibitors exert their activity by modulating TME and provides a rationale for the concurrent targeting of PI3K and FASN in breast cancer treatment.
There is great interest in developing small molecules agents capable of reversing tumor immune escape to restore the body's immune system. As an immunosuppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO-1) is considered a promising target for oncology immunotherapy. Currently, none of IDO-1 inhibitors have been launched for clinical practice yet. Thus, the discovery of new IDO-1 inhibitors is still in great demand. Herein, a series of diverse ortho-naphthaquinone containing natural product derivatives were synthesized as novel IDO-1 inhibitors. Among them, 1-ene-3-ketone-17-hydroxyl derivative 12 exhibited significantly improved enzymatic and cellular inhibitory activity against IDO-1 when compared to initial lead compounds. Besides, the molecular docking study disclosed that the two most potent compounds 11 and 12 have more interactions within the binding pocket of IDO-1 via hydrogen-bonding, which may account for their higher IDO-1 inhibitory activity.
Based on the reactive oxygen species (ROS) regulatory properties of diphenyleneiodonium (DPI), we investigated the effects of DPI on host-infected T. gondii proliferation and determined specific concentration that inhibit the intracellular parasite growth but without severe toxic effect on human retinal pigment epithelial (ARPE-19) cells. As a result, it is observed that host superoxide, mitochondria superoxide and H2O2 levels can be increased by DPI, significantly, followed by suppression of T. gondii infection and proliferation. The involvement of ROS in anti-parasitic effect of DPI was confirmed by finding that DPI effect on T. gondii can be reversed by ROS scavengers, N-acetyl-L-cysteine and ascorbic acid. These results suggest that, in ARPE-19 cell, DPI can enhance host ROS generation to prevent T. gondii growth. Our study showed DPI is capable of suppressing T. gondii growth in host cells while minimizing the un-favorite side-effect to host cell. These results imply that DPI as a promising candidate material for novel drug development that can ameliorate toxoplasmosis based on ROS regulation. Key words: T. gondii, reactive oxygen species, diphenyleneiodonium, N-acetyl-L-cysteine, ARPE-19 cell
Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in hematopoietic cells and is a negative regulator of T cell receptor (TCR) signaling. Recent studies have demonstrated that HPK1 is a promising therapeutic target for cancer immunotherapy. In despite of great progress in the development of HPK1 inhibitors, none of them has been approved for cancer therapy. Developing HPK1 inhibitors with structurally distinct scaffold is still needed. Herein, we describe the design and synthesis of a series of HPK1 inhibitors with 7H-pyrrolo[2,3-d]pyrimidine scaffold, exemplified by 31. Compound 31 showed potent inhibitory activity against HPK1 with an IC50 value of 3.5 nM and favorable selectivity within a panel of kinases. It also potently inhibited the phosphorylation level of SLP76, a substrate of HPK1, and enhanced the IL-2 secretion in human T cell leukemia Jurkat cells. Our finds provide new clues for further optimization and development to generate HPK1 inhibitors with improved efficacy and pharmaceutical properties for cancer immunotherapy.
Abstract St. Louis encephalitis virus infection was detected in summer 2015 in southern California after an 11-year absence, concomitant with an Arizona outbreak. Sequence comparisons showed close identity of California and Arizona isolates with 2005 Argentine isolates, suggesting introduction from South America and underscoring the value of continued arbovirus surveillance.
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