Ameliorative impacts of interleukin 35 or thymoquinone nanoparticles on lipopolysaccharide-induced renal injury in rats.

Interleukin-35 (IL-35) is a novel anti-inflammatory component, and its role in protecting against acute kidney disease (AKD) has not been explored. Thymoquinone (TQ) has been widely used for many therapeutic targets. Inflammation/oxidative signaling plays essential roles in the pathogenesis of diverse disorders, such as AKD, cancer, cardiac disease, aging, and metabolic and neurodegenerative disorders. The objective of the investigation was to evaluate how IL-35 prevents inflammation and oxidative stress indicators in the kidneys of rats caused by lipopolysaccharide (LPS). The experimental rats were allocated into six groups: control (0.5 mL saline); TQ (0.5 mg/kg, b.w. IP), IL-35 (100 µg of IL-35 /kg, b.w. IP), LPS (500 µg/kg b.w. IP), LPS + IL-35, and LPS + TQ. Results indicate that the hematological and blood biochemical parameters were substantially restored by TQ or IL-35 therapy. The elevation of kidney function (uric acid, creatinine, and cystatin C) and oxidative related biomarkers (MDA, PC, and MYO) in rat kidneys was significantly restored by the TQ and IL-35 therapies after LPS administration (P < 0.05). Serum immunological variables IgM and IgG were significantly restored by TQ and IL-35 in LPS-treated rats. Both IL-35 and TQ markedly mitigated the decrease antioxidant related biomarkers (SOD, GSH, CAT and TAC) triggered by LPS. The IL-35 and TQ treatments significantly diminished serum levels of inflammatory responses such as TNF-α, NF-κB, IL-6 and IFN-γ, and significantly increased IL-10 in LPS-treated rats. Additionally, serum levels of MCP, Caspase-3, andBcl-2 were significantly diminished by TQ or IL-35 therapy. The histopathology and immunohistochemistry for NF-kB, PCNA and TNF-α cytokines revealedremodeling when treated with TQ and IL-35. In summary, administration of IL-35 or TQ can attenuateLPS-induced renal damage by extenuatingoxidative stress, tissue impairment, apoptosis, and inflammation, implicating IL-35 as a promising therapeutic agent in acute-related renal injury.

Gramine Exerts Cytoprotective Effects and Antioxidant Properties Against H2O2-Induced Oxidative Stress in HEK 293 Cells.

Oxidative stress caused due to the perturbations in the oxidant-antioxidant system can damage molecules and cause cellular alteration leading to the pathogenesis of multiple diseases. This study was designed and performed to investigate the antioxidant and anti-inflammatory effects of an alkaloid, gramine on H2O2-induced oxidative stress on HEK 293 cells. Cell viability and morphometric analysis of cells treated with H2O2 and gramine were studied. Oxidative stress and inflammatory and antioxidant enzymes such as ROS, LPO, NO, SOD, GSH, and CAT were analyzed. Furthermore, mRNA expression of SOD, CAT, and COX-2 was also evaluated. H2O2 at concentration > 0.3 mM and gramine at concentration > 80 µg/mL affect the proliferation. Viability and morphometric analysis showed that gramine has protective effects. Treating cells with gramine suppressed oxidative stress and inflammatory enzymes, whereas antioxidant enzymes were enhanced. SOD and CAT mRNA levels were overexpressed and COX-2 mRNA levels were decreased in the treated groups. Gramine possesses effective antioxidant potential and can regulate oxidative stress and damages associated with it.

Targeting Microglia in Alzheimer's Disease: From Molecular Mechanisms to Potential Therapeutic Targets for Small Molecules.

Alzheimer's disease (AD) is a common, progressive, and devastating neurodegenerative disorder that mainly affects the elderly. Microglial dysregulation, amyloid-beta (Aß) plaques, and intracellular neurofibrillary tangles play crucial roles in the pathogenesis of AD. In the brain, microglia play roles as immune cells to provide protection against virus injuries and diseases. They have significant contributions in the development of the brain, cognition, homeostasis of the brain, and plasticity. Multiple studies have confirmed that uncontrolled microglial function can result in impaired microglial mitophagy, induced Aß accumulation and tau pathology, and a chronic neuroinflammatory environment. In the brain, most of the genes that are associated with AD risk are highly expressed by microglia. Although it was initially regarded that microglia reaction is incidental and induced by dystrophic neurites and Aß plaques. Nonetheless, it has been reported by genome-wide association studies that most of the risk loci for AD are located in genes that are occasionally uniquely and highly expressed in microglia. This finding further suggests that microglia play significant roles in early AD stages and they be targeted for the development of novel therapeutics. In this review, we have summarized the molecular pathogenesis of AD, microglial activities in the adult brain, the role of microglia in the aging brain, and the role of microglia in AD. We have also particularly focused on the significance of targeting microglia for the treatment of AD.

Exploring the Role of Ubiquitin-Proteasome System in Parkinson's Disease.

Over the last decade, researchers have discovered that a group of apparently unrelated neurodegenerative disorders, such as Parkinson's disease, have remarkable cellular and molecular biology similarities. Protein misfolding and aggregation are involved in all of the neurodegenerative conditions; as a result, inclusion bodies aggregation starts in the cells. Chaperone proteins and ubiquitin (26S proteasome's proteolysis signal), which aid in refolding misfolded proteins, are frequently found in these aggregates. The discovery of disease-causing gene alterations that code for multiple ubiquitin-proteasome pathway proteins in Parkinson's disease has strengthened the relationship between the ubiquitin-proteasome system and neurodegeneration. The specific molecular linkages between these systems and pathogenesis, on the other hand, are unknown and controversial. We outline the current level of knowledge in this article, focusing on important unanswered problems.

Elucidating the role of hypoxia-inducible factor in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic multifactorial disease, provocative, and degenerative autoimmune condition that impacts millions of individuals around the globe. As a result of this understanding, anti-inflammatory drugs have been created, perhaps widely effective (like steroids) and highly specialized methods (including anti-TNF antibody) using biological therapies (including TNF inhibitors). Despite this, the connections between inflammatory response, articular development, and intracellular responsiveness to changes in oxygen concentration are undervalued in rheumatoid arthritis. Hypoxia, or a lack of oxygen, is thought to cause enhanced synovial angiogenesis in RA, which is mediated by some of the hypoxia-inducible factors like vascular endothelial growth factor (VEGF). Substantial genetic alterations occur when the HIF regulatory factors signaling cycle is activated, allowing organelles, tissues, and species to acclimatize to decreasing oxygen saturation. The most well-characterized hypoxia-responsive transcripts are the angiogenic stimulant VEGF, whose production is greatly elevated by hypoxia in several types of cells, especially RA synovium fibroblasts. Blocking vascular endothelial growth factors has been demonstrated to be helpful in murine models of rheumatism, indicating how hypoxia could trigger the angiogenesis process, resulting in the progression of RA. These mechanisms highlight the intimate affiliation amongst hypoxia, angiogenesis, and inflammation in rheumatoid arthritis. This review will look at how hypoxia activates molecular pathways and how other pathways involving inflammatory signals develop and sustain synovitis in rheumatoid arthritis.

10-Dehydrogingerdione Attenuates Tramadol-Induced Nephrotoxicity by Modulating Renal Oxidative Stress, Inflammation and Apoptosis in Experimental Rats: Role of HO-1 Activation and TLR4/NF-κB/ERK Inhibition.

Tramadol represents a synthetic opioid analgesic especially for mild to severe pain. Its dose must be commonly monitored according to pain status and to alleviate the appearance of any adverse effects such as renal cellular damage during its excretion. Present work aimed mainly to study the effects of tramadol intake on renal tissues and 10-dehydrogingerdione (10-DHGD) potential as a protective agent. Tramadol administration induced an increase in serum levels of urea, creatinine, uric acid, the renal immune expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and caspase-3 which turned out to be decreased by 10-DHGD intake. Our results also recorded a significant increase in renal malondialdehyde (MDA), toll-like receptor 4 (TLR4), and extracellular signal-regulated protein kinase-1 (ERK1) along with glutathione (GSH), superoxide dismutase (SOD), and heme oxygenase-1 (HO-1) decrease due to tramadol intake, which were counteracted by 10-DHGD administration as illustrated and supported by the histopathological findings. Our conclusion refers to renoprotective potential of 10-DHGD against tramadol adverse effects.

Preliminary Study of Gastroprotective Effect of Aloe perryi and Date Palm Extracts on Pyloric Ligation-Induced Gastric Ulcer in Experimental Rats.

OBJECTIVE: The present study was aimed at investigating the possible antiulcer activities of some natural phytochemicals Aloe perryi leaf extract (APLE) and flower extract (APFE) in addition to the date palm seed extract (DPSE) and the oily samples of DPSE in a pylorus ligation-induced ulcer model using ranitidine as a standard antiulcer drug. BACKGROUND: Peptic ulcer is a prevalent gastrointestinal disorder due to hypersecretion of gastric acid. It affects four million people worldwide, and 2-10% of these ulcers are perforated and cause bleeding. This increases the risk of morbidity and mortality. So we aimed to introduce a primary study alternatively safe method for treating peptic ulcer. MATERIALS AND METHODS: Forty-two Wistar Albino rats of either sex were randomly divided into seven groups (6/each). The pylorus ligation was done to induce ulcer in pretreated albino rats. The antiulcer activities of extracts were estimated at different dose levels (250 and 500 mg/kg) using ranitidine as a standard drug (50 mg/kg). Gastric volume, pH, and total and free acidity as well as ulcer index and percentage of ulcer inhibition were measured to elucidate the antiulcerogenic effects. Histological examination of gastric ulcer was also performed. Statistical analysis for the results was done where P < 0.05 was considered statistically significant. RESULTS: Pylorus ligation for 6 h in control rats resulted in gastric ulcer which was indicated by the accumulation of gastric secretion and increased total acidity and decreased pH. The pretreatment of rats with APLE, APFE, and DPSE in addition to the oily samples of DPSE significantly inhibited the ulcers induced by pylorus ligation. These effects were attributed to significant reductions in total and free acidity, ulcer index, and gastric volume while there is a marked decrease in gastric pH (the antisecretory) as well as mucosal strengthening properties of these phytochemicals. CONCLUSION: These findings give these extracts the potential to be a promising tool for the management of gastric ulcer after performing further clinical and experimental studies. Our study demonstrated the promising antiulcer activity of extracts and oils in pyloric ligation-induced gastric ulcer. To the best of our knowledge, this is the first study to explore the antiulcer activity of these extracts; however, further investigations may be recommended for full details about this antiulcerogenic capacity.