Mesenchymal stem-cells' exosomes are renoprotective in postmenopausal chronic kidney injury via reducing inflammation and degeneration.

Chronic kidney disease (CKD) is an important global disease its rates are increasing worldwide. CKD is caused by injuries to kidney tissue that exceeds the rate of regeneration, which with time lead to irreversible renal damage and CKD become evident. In females, diminished estrogen supply in the postmenopausal period is associated with greater risk for developing CKD. In this study we isolated exosomes from bone marrow mesenchymal stem/stromal cells (BM-MSCs) and tested their therapeutic effects on post-menopause CKD (PM-CKD) and compared their effects with BM-MSCs. The menopause model was achieved by bilateral ovariectomy in 8-months-old female albino rats, then no treatment, 2 million BM-MSCs or 100 µg of exosomes (Exo) was given intravenously in tail vein to ovariectomized rats and the study continued for 8 weeks post-ovariectomy. Changes in weight, urine volume, urine protein content, kidney function biochemical parameters (creatinine and BUN), Kidney oxidative stress (MDA), kidney antioxidant parameters (SOD, GPx and CAT), histopathological changes, immunohistochemical expression of KIM-1 and, finally, genes related to renal damage (peroxiredoxin-3, KIM-1 and ICAM-1) and inflammation (TNF-α, Cox2 and IL-6) were recorded for all study groups. Post-ovariectomy there was an increased body weight, drastic reduction of estrogen and progesterone levels, reduced urine output, increased urinary protein excretion, elevated serum creatinine and BUN, increased MDA and reduced GPx SOD, and CAT in kidney tissue, chronic inflammation, degenerative and fibrotic lesions in histopathological examination, high expression of KIM-1 immunohistochemically and changes in gene expression analyses all pointing to the development of CKD in the study rats. In the PM-CKD groups receiving BM-MSCs or Exo, the whole chronic inflammatory picture was completely reversed towards a much normal kidney structure and function. The improvements were more observable with Exo compared to BM-MSCs. Overall, our results show for the first time that exosomes isolated from BM-MSCs are more potent in reducing chronic inflammatory changes in the kidney of postmenopausal females compared to the cell-based approach using BM-MSCs. Therefore, MSCs-derived exosomes are a promising therapeutic approach for preserving postmenopausal kidney structure and function and, subsequently, should improve the quality of life of postmenopausal females.

SGLT2 inhibitor empagliflozin monotherapy alleviates renal oxidative stress in albino Wistar diabetic rats after myocardial infarction induction.

Acute kidney injury (AKI) is a sudden insult of the kidney that happens within a short period of time, which is associated with poor prognosis in diabetic patients with myocardial infarction (MI). Subclinical AKI is a condition in which tubular damage biomarkers [Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1(KIM-1)] are positive even in the absence of elevated serum creatinine. Recent studies reported that SGLT-2 inhibitors could protect against subclinical AKI in diabetic patients by elevating the level of ß-Hydroxybutyric acid (ßOHB). This study aims to examine the reno-protective potential of empagliflozin (EMPA) against MI associated AKI in diabetic rats. Eighty Albino Wistar rats were divided into: (1) nondiabetic sham group (CS), (2) nondiabetic + myocardial infarction group (CM), (3) diabetic + myocardial infarction group (DM) and (4) diabetic + myocardial infarction + empagliflozin group (DME). At the end of the experiment, blood samples and kidneys were collected for biochemical analysis, histopathological, and immunohistochemical studies. After induction of myocardial infarction, there was a significant decrease in serum creatinine and NGAL levels in DME. After EMPA administration, mesangial matrix index and glomerular area were lowered in DME if compared to DM group. As a marker for tubular injury, we used anti-NGAL and anti-KIM-1 immunohistochemistry. Strong positive reaction was noticed in DM group if compared to DME group which showed weak positive reaction. Levels of renal mRNAs [NGAL; KIM-1; Nox-2,4; TLR-2,4; MyD88; TNF- α and IL-1 ß, 18] in DME group were reduced significantly compared to DM group. In conclusion, empagliflozin can protect against subclinical acute kidney injury in diabetic albino Wistar rats after myocardial infarction induction, which could improve the clinical outcome of SGLT-2 inhibitors in diabetic patients.

Effect of colibacillosis on the immune response to a rabbit viral haemorrhagic disease vaccine.

Viral haemorrhagic disease (VHD) and colibacillosis are common diseases in rabbits that cause economic losses worldwide. The effect of colibacillosis on the immune response of vaccinated rabbits against rabbit haemorrhagic disease virus (RHDV) was studied. Four groups (G1-G4) were included. G1 was the negative control group; G2 was the RHDV vaccine group; G3 was the E. coli-infected group; and G4 was the E. coli-infected + RHDV vaccine group. The E. coli infection and RHDV vaccination were simultaneously performed, with another previous infection, 3 days before vaccination. At 28 days post-vaccination (PV), the rabbits (G2-G4) were challenged intramuscularly with 0.5 ml of RHDV at a dose of 103 50% median lethal dose (LD50)/rabbit. The rabbits were observed for clinical signs, body weight gain and mortality rates. Tissue, blood, serum, and faecal samples and rectal swabs were collected at 3, 5, 7, 14, 21 and 28 days PV. Significant clinical signs and mortality and a decrease in BW were observed in the infected + RHDV vaccine group. On the 3rd day post-infection (PI), compared with all the other groups, the vaccinated group (G2) had significantly upregulated hepatic tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels; however, the infected + RHDV vaccine group had significantly higher intestinal levels of TNF-α and IL-6 than the other groups. Furthermore, E. coli infection in vaccinated rabbits led to immunosuppression, as shown by significant decreases (P < 0.05) in heterophil phagocytic activity, the CD4+/CD8+ ratio, and HI antibody responses to RHDV and a significant increase in the heterophil to lymphocyte (H/L) ratio. In conclusion, colibacillosis leads to immunosuppression involving a shift in the equilibrium of cytokines and reduced weight gain and mortality in vaccinated rabbits and could be a contributing factor in RHDV vaccination failure in rabbit farming.

Immunogenic FEAT protein circulates in the bloodstream of cancer patients.

BACKGROUND: FEAT is an intracellular protein that potently drives tumorigenesis in vivo. It is only weakly expressed in normal human tissues, including the testis. In contrast, FEAT is aberrantly upregulated in most human cancers. The present study was designed to investigate whether FEAT is applicable to tumor immunotherapy and whether FEAT is discernible in the bloodstream as a molecular biomarker of human cancers. METHODS: Two mouse FEAT peptides with predicted affinities for major histocompatibility complex H-2Kb and H-2Db were injected subcutaneously into C57BL/6 mice before subcutaneous transplantation of isogenic B16-F10 melanoma cells. Intracellular localization of FEAT was determined by immunogold electron microscopy. Immunoprecipitation was performed to determine whether FEAT was present in blood from cancer patients. A sandwich enzyme-linked immunosorbent assay was used to measure FEAT concentrations in plasma from 30 cancer patients and eight healthy volunteers. RESULTS: The vaccination experiments demonstrated that FEAT was immunogenic, and that immune responses against FEAT were induced without deleterious side effects in mice. Electron microscopy revealed localization of FEAT in the cytoplasm, mitochondria, and nucleus. Immunoprecipitation identified FEAT in the blood plasma from cancer patients, while FEAT was not detected in plasma exosomes. Plasma FEAT levels were significantly higher in the presence of cancers. CONCLUSIONS: These findings suggest that FEAT is a candidate for applications in early diagnosis and prevention of some cancers.