Nifuroxazide repurposing for protection from diabetes-induced retinal injury in rats: Implication of oxidative stress and JAK/STAT3 axis.

The prevalence of diabetes mellitus (DM) is alarmingly increasing worldwide. Diabetic retinopathy (DR) is a prevailing DM microvascular complication, representing the major cause of blindness in working-age population. Inflammation is a crucial player in DR pathogenesis. JAK/STAT3 axis is a pleotropic cascade that modulates diverse inflammatory events. Nifuroxazide (Nifu) is a commonly used oral antibiotic with reported JAK/STAT3 inhibition activity. The present study investigated the potential protective effect of Nifu against diabetes-induced retinal injury. Effect of Nifu on oxidative stress, JAK/STAT3 axis and downstream inflammatory mediators has been also studied. Diabetes was induced in Sprague Dawley rats by single intraperitoneal injection of streptozotocin (50 mg/kg). Animals were assigned into four groups: normal, Nifu control, DM, and DM + Nifu. Nifu was orally administrated at 25 mg/kg/day for 8 weeks. The effects of Nifu on oxidative stress, JAK/STAT3 axis proteins, inflammatory factors, tight junction proteins, histological, and ultrastructural alterations were evaluated using spectrophotometry, gene and protein analyses, and histological studies. Nifu administration to diabetic rats attenuated histopathological and signs of retinal injury. Additionally, Nifu attenuated retinal oxidative stress, inhibited JAK and STAT3 phosphorylation, augmented the expression of STAT3 signaling inhibitor SOCS3, dampened the expression of transcription factor of inflammation NF-κB, and inflammatory cytokine TNF-α. Collectively, the current study indicated that Nifu alleviated DR progression in diabetic rats, suggesting beneficial retino-protective effect. This can be attributed to blocking JAK/STAT3 axis in retinal tissues with subsequent amelioration of oxidative stress and inflammation.

Exosomes in COVID-19 infection: Focus on role in diagnosis, pathogenesis, immunity, and clinical trials.

Since the end of 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread as a new strain of coronavirus disease (COVID-19) and progressed as a global pandemic. Exosomes are membrane-bound vesicles released from almost all cells and are crucially involved in cell-cell communication. Interestingly, COVID-19 viral particles produce exosomes that moderate communication between infected and uninfected cells. Hence, there is growing evidence highlighting the crucial implications of exosomes in COVID-19 infection, transmission, intercellular spread, and reinfection. On the other hand, clinical trials have demonstrated mesenchymal stem cell-derived exosomes as a promising therapeutic strategy for severely affected COVID-19 patients. Also, convalescent plasma-derived exosomes have been proposed for multiple efficacies in COVID-19 patients. Furthermore, messenger RNAs (mRNA)-loaded exosomes were superior to mRNA-loaded lipid nanoparticles as a delivery system. Hence, exosomes can be used to safely induce SARS-CoV-2 immunity via their loading with mRNAs encoding immunogenic forms of SARS-CoV-2 spike and nucleocapsid proteins. Moreover, exosomes can be used as a nano-delivery system for microRNA to alleviate cytokine storm and prevent the progression of organ failure in COVID-19 patients. The present review summarizes state of the art concerning the role of exosomes in COVID-19 infection and accompanying organ complications as well as the potential use of exosomes in COVID-19 diagnosis, treatment, drug delivery, and vaccination. The review also sheds the light on the common biogenic pathway between the SARS-CoV-2 virus and exosomes. Additionally, the latest and current clinical trials using exosomes for COVID-19 infection are summarized.

Effect of Diacerein on HOTAIR/IL-6/STAT3, Wnt/ß-Catenin and TLR-4/NF-κB/TNF-α axes in colon carcinogenesis.

Colorectal cancer (CRC) is a common malignancy with high mortality and poor prognosis. Diacerein (DIA) is an anti-inflammatory used for treatment of osteoarthritis. We delineated some underlying molecular mechanisms of DIA's anti-carcinogenic effect in CRC using in vivo and in vitro models. Human Caco-2 cells were treated with DIA followed by MTT and Annexin V assays and CRC was experimentally induced using 1,2-dimethylhydrazine. DIA (50 mg/kg/day, orally) was administrated for 8 weeks. The MTT assay confirmed cytotoxic effect of DIA in vitro and Annexin V confirmed its apoptotic effect. DIA resulted in regression of tumour lesions with reduced colonic TLR4, NF-κB and TNF-α protein levels and down-regulated VEGF expression, confirming anti-angiogenic impact. DIA triggered caspase-3 expression and regulated Wnt/ß-Catenin pathway, by apparently interrupting the IL-6/STAT3/ lncRNA HOTAIR axis. In conclusion, DIA disrupted IL-6/STAT3/ lncRNA HOTAIR axis which could offer an effective therapeutic strategy for the management of CRC.