ABSTRACT
Background: Cerebral ischemic stroke is a serious condition with high incidence, mortality, and associated disability. Currently, effective therapeutic options are available for ischemic stroke are limited. Accumulating evidence indicates that sodium Danshensu, mono sodium compound derived from Salvia miltiorrhiza, plays protective roles in ischemic stroke. However, the underlying protective mechanism of sodium Danshensu in cerebral ischemic stroke remains unknown. Methods: In the current study, we explored the role and mechanism of sodium Danshensu on astrocytes exposed to oxygen-glucose deprivation/reoxygenation (OGD/R), which mimics the process of ischemia-reperfusion. The impact of sodium Danshensu on cell viability and apoptosis after OGD/R were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-dophenyl tetrazolium bromide (MTT) assay and flow cytometry. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot were used to detect the expression of target messenger RNA (mRNA) and proteins associated with apoptosis and autophagy. The release of lactate dehydrogenase (LDH) was determined, and the production of proinflammatory cytokines were detected using enzyme-linked immunosorbent assay (ELISA) kits. Results: It was found that sodium Danshensu could significantly increase cell viability and decrease LDH release and apoptosis. Besides, it inhibited the production of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6. Sodium Danshensu also dose-dependently decreased protein and mRNA levels of nucleotide binding oligomerization NOD-like receptor pyrin domain containing 3 (NLRP3) and high mobility group box 1 (HMGB1), which play a crucial role in promoting ischemic stroke-induced cell injury. Moreover, sodium Danshensu dose-dependently upregulated Beclin 1 expression, downregulated P62 protein expression, and further increased LC3B-II/LC3B-I ratio through inducing autophagy in astrocytes. Additionally, we noticed that sodium Danshensu dose-dependently increased tuberous sclerosis complex-2 (TSC2) protein expression, while significantly reduced the levels of mammalian target of rapamycin (mTOR) in the presence of OGD/R insult. Conclusions: These findings suggest that sodium Danshensu protects against OGD/R-induced injury by modulating the NLRP3 inflammasome and TSC2/mTOR pathways.
ABSTRACT
Background: Maturity-onset diabetes of the young (MODY) is one type of monogenic diabetes that is often misdiagnosed. The case refers to a case of maturity-onset diabetes of the young 12 (MODY12) who was misdiagnosed with type 1 diabetes (T1DM), and this was the first case of MODY12 induced by a large deletion of the ATP-binding cassette transporter C8 gene (ABCC8). Additionally, a literature review was conducted regarding the pathological mechanisms, clinical manifestations, diagnosis, and treatment of ABCC8-mutated diabetes. Case Description: A 22 years old, male patient had been misdiagnosed with T1DM for 4 years and had experienced poor glucose control with multiple daily insulin injections. Their glycated hemoglobin (HbA1c) was 12.9% at the time of admission and they had been experiencing frequent hypoglycemia. Next-generation sequencing found that the chr11p15.1 region had large fragment heterozygous deletion of exon 17 of the ABCC8 gene. According to the genetic test results, the patient was diagnosed as MODY12, insulin treatment was gradually stopped and converted to glimepiride for oral administration, and HbA1c decreased to 6.1%. After oral treatment for 8 months, the glimepride was stopped; however, HbA1c was 5.9% after 6 months of drug withdrawal and C-peptide level became elevated [fasting C-peptide (FCP) increase from 0.8 to 7.5 ng/mL, and 2 h postprandial C-peptide increase from 0.7 to. 4.1 ng/mL]. Conclusions: It is easy for underweight MODY patients to be misdiagnosed with T1DM. For T1DM patients with poor insulin treatment effects, repeated hypoglycemia, and persistent insulin secretion level, ABCC8 or other genes related to monogenic diabetes should be screened. An early diagnosis and transition of treatment can help improve prognosis.
ABSTRACT
Macrophage phagocytosis plays essential roles in antitumor immunity. CD47/SIRPα phagocytosis checkpoint blockade has demonstrated therapeutic potential in several hematopoietic cancers, but recent clinical studies reported very limited efficacy against solid malignancies. Here, we show that polyinosinic-polycytidylic acid (Poly(I:C)), a synthetic analog of double-stranded RNA, enhances the antitumor activity of CD47 blockade in colorectal cancer in vitro and in vivo. Poly(I:C) activation leads to a potent immune response characterized by the production of proinflammatory cytokines, especially IL-6. Stimulation with IL-6 promotes the PI3K signaling and cytoskeletal reorganization required for macrophage phagocytosis mediated by CD47 blockade. Our findings demonstrate the potential of Poly(I:C) to synergize the efficacy of CD47 blockade therapy and a novel role for IL-6 in macrophage phagocytosis, which provide new strategy for combinational cancer immunotherapy.
