Diallyl Disulfide Mitigates Cadmium Hepatotoxicity by Attenuating Oxidative Stress and TLR-4/NF-κB Signaling and Upregulating PPARγ

Background: Heavy metals can cause serious health problems that affect different organs. Cadmium (Cd) is an environmental contaminant known for its toxicological consequences on different organs. Hepatotoxicity is a serious effect of exposure to Cd with oxidative stress (OS) and inflammation playing a central role. Diallyl disulfide (DADS), an organo-sulfur compound found in garlic, is known for its cytoprotective and antioxidant effects. In this study, the effect of DADS on Cd-induced inflammation, oxidative stress and liver injury was investigated. Methods: DADS was supplemented for 14 days via oral gavage, and a single intraperitoneal dose of Cd (1.2 mg/kg body weight) was administered to rats on day 7. Blood and liver samples were collected at the end of the experiment for analyses. Results: Cd administration resulted in remarkable hepatic dysfunction, degenerative changes, necrosis, infiltration of inflammatory cells, collagen deposition and other histopathological alterations. Cd increased liver malondialdehyde (MDA) and nitric oxide (NO) (p < 0.001), upregulated toll-like receptor (TLR)-4, nuclear factor-kappaB (NF-κB), pro-inflammatory mediators, and caspase-3 (p < 0.001) whereas decreased glutathione (GSH) and antioxidant enzymes (p < 0.001). Cd downregulated peroxisome proliferator activated receptor gamma (PPARγ), a transcription factor involved in inflammation and OS suppression (p < 0.001). DADS ameliorated liver injury and tissue alterations, attenuated OS and apoptosis, suppressed TLR-4/NF-κB signaling, and enhanced antioxidants. In addition, DADS upregulated PPARγ in the liver of Cd-administered rats. Conclusions: DADS is effective against Cd-induced hepatotoxicity and its beneficial effects are linked to suppression of inflammation, OS and apoptosis and upregulation of PPARγ. DADS could be valuable to protect the liver in individuals at risk of Cd exposure, pending further studies to elucidate other underlying mechanism(s)

Nano Methotrexate versus Methotrexate in Targeting Rheumatoid Arthritis

Nanomedicine has emerged as an important approach for targeting RA medication. Rheumatoid arthritis (RA) is a widespread autoimmune disorder marked by multiple inflamed joints. Gold nanoparticles (GNPs) have been demonstrated as efficacious nanocarriers due to their unique characteristics and the relative simplicity of their synthesis in varied sizes; moreover, they have the capability to alleviate several inflammatory markers. The current objective was to combine methotrexate (MTX) with GNPs to overcome MTX restrictions. GNPs were fabricated by a chemical reduction technique, utilizing sodium citrate and tween 20. The MTX-GNPs formulations were characterized in vitro by % entrapment efficiency (%EE), particle size, polydispersity index (PDI) zeta potential, and % release. The MTX-GNPs formulation was administrated as an intra-articular solution, and additionally, incorporated into a Carbopol gel to investigate its anti-arthritic effectiveness and bioavailability in vivo. The results indicated that a %EE of 87.53 ± 1.10%, and a particle size of 60.62 ± 2.41 nm with a PDI of 0.31 ± 0.03, and a zeta potential of −27.80 ± 0.36 mV were optimal. The in vitro release of MTX from the MTX-GNPs formulation demonstrated that the MTX-GNPs formulation’s release was 34.91 ± 1.96% and considerably (p p < 0.05). In vivo, MTX-GNPs formulations inhibited IL-6 by 36.52%, ACCP (63.25 %), COMP (28.16%), and RANKL (63.67%), as well as elevated IL-10 by 190.18%. Transdermal MTX-GNPs decreased IL-6 by 22.52%, ACCP (56.63%), COMP (52.64%), and RANKL (79.5%), as well as increased IL-10 by 168.37%. Histological investigation supported these recent findings. Conclusions: Marked improvements in MTX anti-arthritic effects are seen when it is conjugated to GNPs

Candesartan Attenuates Cisplatin-Induced Lung Injury by Modulating Oxidative Stress, Inflammation, and TLR-4/NF-&kappa;B, JAK1/STAT3, and Nrf2/HO-1 Signaling

Cisplatin (CIS) is an effective chemotherapeutic agent against different cancers. The use of CIS is associated with acute lung injury (ALI) and other adverse effects, and oxidative stress and inflammation were implicated in its toxic effects. Candesartan (CAN), an angiotensin II (Ang II) receptor blocker, showed beneficial effects against oxidative stress and inflammation. Therefore, this study investigated the potential of CAN to prevent CIS-induced oxidative stress, inflammation, and lung injury in rats, pointing to the involvement of TLR4/NF-&kappa;B, JAK1/STAT3, PPAR&gamma;, and Nrf2/HO-1 signaling. The rats received CAN (5 mg/kg) for 10 days and were challenged with a single dose of CIS (7 mg/kg) on day 7. CIS caused injury to the alveoli and the bronchial tree, increased lipid peroxidation, nitric oxide, myeloperoxidase, TLR-4, NF-&kappa;B p65, iNOS, TNF-&alpha;, IL-6, IL-1&beta;, and caspase-3, and decreased cellular antioxidants and IL-6 in the lungs of rats. CAN effectively prevented tissue injury, suppressed TLR-4/ NF-&kappa;B signaling, and ameliorated oxidative stress, inflammatory markers, and caspase-3 in CIS-administered rats. CAN enhanced antioxidants and IL-10, decreased Ang II, increased Ang (1&ndash;7), suppressed the phosphorylation of JAK1 and STAT3, and upregulated SOCS3 in CIS-administered rats. These effects were associated with the downregulation of Keap1 and enhanced Nrf2, GCLC, HO-1, and PPAR&gamma;. In conclusion, CAN prevented CIS-induced lung injury by attenuating oxidative stress, suppressing TLR-4/NF-&kappa;B and JAK1/STAT3 signaling, Ang II, and pro-inflammatory mediators, and upregulating PPAR&gamma;, and Nrf2/HO-1 signaling

Use of failure-to-rescue to identify international variation in postoperative care in low-, middle- and high-income countries: A 7-day cohort study of elective surgery

The incidence and impact of postoperative complications are poorly described. Failure-to-rescue, the rate of death following complications, is an important quality measure for perioperative care but has not been investigated across multiple health care systems. Methods. We analysed data collected during the International Surgical Outcomes Study, an international 7-day cohort study of adults undergoing elective inpatient surgery. Hospitals were ranked by quintiles according to surgical procedural volume (Q1 lowest to Q5 highest). For each quintile we assessed in-hospital complications rates, mortality, and failure-to-rescue. We repeated this analysis ranking hospitals by risk-adjusted complication rates (Q1 lowest to Q5 highest). Results. A total of 44 814 patients from 474 hospitals in 27 low-, middle-, and high-income countries were available for analysis. Of these, 7508 (17%) developed one or more postoperative complication, with 207 deaths in hospital (0.5%), giving an overall failure-to-rescue rate of 2.8%. When hospitals were ranked in quintiles by procedural volume, we identified a threefold variation in mortality (Q1: 0.6% vs Q5: 0.2%) and a two-fold variation in failure-to-rescue (Q1: 3.6% vs Q5: 1.7%). Ranking hospitals in quintiles by risk-adjusted complication rate further confirmed the presence of important variations in failureto- rescue, indicating differences between hospitals in the risk of death among patients after they develop complications. Conclusions. Comparison of failure-to-rescue rates across health care systems suggests the presence of preventable postoperative deaths. Using such metrics, developing nations could benefit from a data-driven approach to quality improvement, which has proved effective in high-income countries