Mesenchymal Stem Cells and Begacestat Mitigate Amyloid-ß 25-35-Induced Cognitive Decline in Rat Dams and Hippocampal Deteriorations in Offspring.

Alzheimer's disease (AD) is the most common cause of age-related neurodegeneration and cognitive decline. AD more commonly occurs in females than in males, so it is necessary to consider new treatments specifically targeting this population. The present study investigated the protective effects of Begacestat (γ-secretase inhibitor-953, GSI-953) and bone marrow-derived mesenchymal stem cells (BM-MSCs) during pregnancy on cognitive impairment in rat dams and neurodegeneration in offspring caused by the intracerebroventricular injection of Aß 25-35 before pregnancy. The performances of dams injected with amyloid-ß 25-35 (Aß 25-35) during behavioral tests were significantly impaired. The offspring of Aß 25-35-injected dams treated with BM-MSCs or GSI-953 showed a dramatically reduced number and size of activated microglial cells, enhancement in the processes length, and a decrease in the proinflammatory cytokine levels. Additionally, BM-MSC or GSI-953 therapy reduced Aß 25-35-induced increases in tau phosphorylation and amyloid precursor protein levels in the neonates' hippocampus and elevated the lower levels of glycogen synthase kinase-3 and brain-derived neurotrophic factor; moreover, reversed Aß 25-35-induced alterations in gene expression in the neonatal hippocampus. Finally, the treatments with BM-MSC or GSI-953 are globally beneficial against Aß 25-35-induced brain alterations, particularly by suppressing neural inflammation, inhibiting microglial cell activation, restoring developmental plasticity, and increasing neurotrophic signaling.

Bone Marrow-Derived Mesenchymal Stem Cells and γ-Secretase Inhibitor Treatments Suppress Amyloid-ß25-35-Induced Cognitive Impairment in Rat Dams and Cortical Degeneration in Offspring.

Alzheimer's disease (AD) is the most frequent cause of age-related neurodegeneration and ensuing cognitive impairment. Progressive deposition of extracellular amyloid beta (Aß) aggregates (plaques) and intracellular hyperphosphorylated Tau protein (p-Tau) are the core pathological markers of AD but may precede clinical symptoms by many years, presenting a therapeutic window of opportunity. Females are more frequently afflicted by AD than males, necessitating evaluation of novel treatments for the female population. The current study examined the protective efficacies of intravenous bone marrow-derived mesenchymal stem cells (BM-MSCs) and oral gamma-secretase inhibitor-953 (GSI-953) during pregnancy on cognitive impairment in rat dams and neurodegeneration in offspring induced by intracerebroventricular injection of Aß25-35 prior to pregnancy. The Aß25-35 (AD) group exhibited significant (P < 0.001) impairments in the Y-maze and novel object recognition test performance prior to conception. Histological analysis of the offspring cortex revealed substantial dendritic shrinkage and activation of microglial cells, while neurochemical analysis demonstrated significant increases in the proinflammatory cytokine interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). In contrast, BM-MSC or GSI-953 treatment of dams following Aß25-35 injection significantly (P < 0.001) reduced the number and size of activated microglial cells, markedly increased dendrite length, and reversed proinflammatory cytokine elevations in offspring. Moreover, BM-MSC or GSI-953 treatment reversed the Aß25-35-induced amyloid precursor protein and p-Tau elevations in the offspring brain; these changes were accompanied by upregulation of the brain-derived neurotrophic factor and downregulation of glycogen synthase kinase-3ß in the serum and brain. Treatment with BM-MSCs or GSI-953 also reversed Aß25-35-induced elevations in different gene expressions in the neonatal cortex. Finally, treatment of dams with BM-MSCs or GSI-953 prevented the Aß25-35-induced disruption of newborn brain development. Thus, BM-MSC and GSI-953 treatments have broad-spectrum effects against Aß25-35-induced brain pathology, including the suppression of neural inflammation, restoration of developmental plasticity, and promotion of neurotrophic signaling.

New typhoid vaccine using sponge-like reduced protocol: development and evaluation.

Purpose: Typhoid remains a major health problem, especially in the developing world. Furthermore, the emergence of multidrug-resistant and extensively drug-resistant strains of Salmonella typhi added a sense of urgency to develop more effective typhoid vaccines, one of which is bacterial ghosts (BGs), prepared by both genetic and chemical means. The chemical method includes incubation with numerous agents for a short time at their minimum inhibitory or minimum growth concentrations. This study included the preparation of BGs by a sponge-like reduced protocol (SLRP). Materials and Methods: Critical concentrations of sodium dodecyl sulfate, NaOH, and H2O2 were used. Moreover, high-quality BGs were visualized by scanning electron microscope (SEM). Subculturing was used to confirm the absence of vital cells. Besides, the concentrations of the released DNA and protein were estimated spectrophotometrically. In addition, the integrity of cells was proved by visualizing Gram-stained cells using a light microscope. Furthermore, a comparison between the immunogenicity and safety of the prepared vaccine and the available whole-cell killed vaccine was established. Results: Improved preparation of high-quality BGs of S. typhi, visualized by SEM, revealed punctured cells with intact outer shells. Moreover, the absence of vital cells was confirmed by subculturing. At the same time, the release of respective amounts of proteins and DNA is another evidence of BGs' production. Additionally, the challenge test provided evidence that the prepared BGs are immunogenic and have the same efficacy as the whole cell vaccine. Conclusion: The SLRP provided a simple, economical, and feasible method for BGs preparation.

Relationship of thyroid dysfunction with cardiovascular diseases: updated review on heart failure progression.

Heart disease remains the leading cause of death globally. Heart failure (HF) is a clinical syndrome that results from impairment of the ability of the ventricle to fill with or eject blood. Over the past two decades, accumulated evidence has revealed the contribution of thyroid hormones to cardiovascular (CV) events, exerting their action through genomic and non-genomic pathways within the cardiomyocytes. The pivotal role of thyroid hormones in maintaining cardiac homeostasis has been observed in previous investigations which suggest that the CV system is adversely impacted by fluctuations in thyroid hormone levels, such as those that occur in hypothyroidism, hyperthyroidism, and low triiodothyronine syndrome (LT3S). Thyroid dysfunction has direct effects on myocardial contractility, systolic and diastolic blood pressure, heart mass, heart rate, ejection fraction, and heart output, which may ultimately lead to HF. Recent clinical data have shown that thyroid hormone replacement therapy for hypothyroid patients appears to provide the potential for reducing CV events. Therefore, this review aims to address the impact of thyroid hormone dysfunction on pathophysiological mechanisms contributing to the development and progression of HF.

The potential role of interleukin-37 in infectious diseases.

Interleukin-37 (IL-37) is a newly introduced cytokine to interleukin-1 family. Many studies have demonstrated that IL-37 owns immunosuppressive effects against both innate and acquired immune responses via inhibition of several inflammatory mediators. Thence, IL-37 has anti-inflammatory action in some diseases including cancer, autoimmune diseases, cardiovascular diseases and infectious diseases. Recent investigations have reported the important role of IL-37 in immunity against viral, bacterial and fungal infections as they prevent inappropriate immune activation and suppress the inflammation induced by these infectious agents. Thus, IL-37 could play a crucial role in protecting host tissues from injury during infections by damping excessive inflammatory reactions. However, the precise roles of IL-37 in infectious diseases remain largely unknown. The current review shed light on the pivotal role of IL-37 in infectious diseases such as the human immunodeficiency virus-1 (HIV-1), viral myocarditis, hepatitis C virus (HCV), hepatitis B virus (HBV), tuberculosis, leprosy, pneumococcal pneumonia, listeria infection, aspergillosis, candidiasis and eumycetoma. In conclusion, this review reported that IL-37 has a crucial role in reducing infection-associated inflammation and has a good impact on inflammation-induced pathology. However, tight regulation that achieved balance between effector immune responses that required for pathogen elimination and limited tissue damage that resulted from excessive inflammation should be existed in the potential IL-37 therapy to prevent clinical complications of a disease.

The pleiotropic role of interleukin-17 in atherosclerosis.

Atherosclerosis is the main cause of cardiovascular diseases (CVDs), which considers the leading cause of mortality worldwide. Atherosclerosis is a chronic inflammatory condition of arterials' wall in which the development and the destabilization of plaque occur. Both innate and adaptive immunity play a significant role in modifying lipoproteins in arterials' wall. Recent investigations have demonstrated the opposing roles of CD4+ T cells subtypes in atherosclerosis. T helper-1 (Th1) response and pro-inflammatory cytokines possess proatherogenic effects, whereas T regulatory (Treg) cells have an atheroprotective role. Th17 cells have emerged as a new CD4+ T-cell subtype, which produce IL-17 that plays a crucial role in numerous inflammatory and autoimmune diseases. Recently, several studies have investigated the potential role of IL-17 in atherosclerosis. Some investigations have suggested a proatherogenic effect, however the others proposed an atheroprotective role. Hence, the exact role of IL-17 in the disease development and plaque stability is still debatable. In this review, we summarize the current knowledge on both atherogenesis and atheroprotective roles of IL-17. In addition, the synergistic and antagonistic effects of IL-17 with other cytokines in atherosclerosis will be discussed. On the basis of the current understanding of these roles, the possibility of developing novel therapeutic strategies against atherosclerosis may be evolved.