Upregulation of the proinflammatory cytokine-induced neutrophil chemoattractant-1 and monocyte chemoattractant protein-1 in rats' intestinal anastomotic wound healing—Does it matter?

SummaryBackgroundThe proinflammatory cytokines and growth-promoting factor are essential components of the wound healing process. We hypothesized that under healthy conditions, faster healing of intestinal anastomotic wound is due to an early upregulation of proinflammatory cytokines, cytokine-induced neutrophil chemoattractant-1 (CINC-1) that is followed by a quicker upregulation of homeostatic chemokine, monocyte chemoattractant protein-1 (MCP-1) and late upregulation of transforming growth factor (TGF-β).MethodsWe characterized the time course of CINC-1, MCP-1 and TGF-β release at four wounds (skin, muscle, small bowel, and colonic anastomosis) after surgery on 38 juvenile male Sprague Dawley rats. The tissue samples of each site were harvested at 0 (control), 1, 3, 5, 7 and 14 days postoperatively (n = 6–8/group) and analyzed by ELISA kits for CINC-1, MCP-1 and TGF-β.ResultsCINC-1 expression peaked earlier in muscle and colonic wounds when compared to skin and small bowel. MCP-1 levels were elevated early in skin and muscle wounds, but later expression of MCP-1 was shown in colonic wounds. TGF-β levels were unchanged in all wound sites.ConclusionAn earlier peak in CINC-1 levels and later expression of MCP-1 were seen in colonic wounds, but no significant increase in TGF-β levels was observed. These findings support the early healing process in intestinal anastomotic wounds

Umbelliferone inhibits spermatogenic defects and testicular injury in lead-intoxicated rats by suppressing oxidative stress and inflammation, and improving Nrf2/HO-1 signaling

© 2020 Alotaibi et al. Introduction: Lead (Pb) is an environmental toxic metal that threatens human health. Umbelliferone (UMB) is a coumarin with known medicinal and protective properties against cytotoxicity. This study explored the ameliorative effect of UMB against Pb-induced testicular toxicity in rats, focusing on steroidogenesis, oxidative stress and inflammation. Materials and Methods: Rats received lead acetate (50 mg/kg) and UMB (25, 50 or 100 mg/kg) via oral gavage for 4 weeks. Results: Pb-intoxicated rats exhibited testicular tissue injury and decreased serum levels of LH, FSH and testosterone. The count, viability, motility and normal morphology of the sperms were decreased accompanied with downregulated steroidogenesis markers in Pbinduced group. UMB prevented testicular injury, increased serum levels of LH, FSH and testosterone, upregulated steroidogenesis markers and improved the semen quality. In addition, UMB attenuated oxidative stress and oxidative DNA damage, downregulated the expression of pro-inflammatory mediators and Bax, boosted antioxidant defenses and Bcl2, and upregulated Nrf2/HO-1 signaling in Pb-intoxicated rats. Conclusion: UMB prevents Pb-induced testicular injury by suppressing oxidative damage, inflammation and cell death, and boosting antioxidant defenses, Nrf2/HO-1 signaling and pituitary-gonadal axis. Thus, UMB may represent a protective and cost-effective agent against Pb testicular toxicity, pending further investigations to elucidate other underlying mechanisms.Open Access funding provided by the Qatar National Library

Farnesol attenuates cadmium-induced kidney injury by mitigating oxidative stress, inflammation and necroptosis and upregulating cytoglobin and PPARγ in rats

Heavy metals are environmental pollutants that can harm animals and humans even at low concentrations. Cadmium (Cd) is known for its serious health effects on different organs and its toxicity is associated with oxidative stress (OS) and inflammation. Farnesol (FAR), a sesquiterpene alcohol found in many vegetables and fruits, possesses promising anti-inflammatory and antioxidant activities. This study evaluated the effect of FAR on Cd-induced kidney injury, pinpointing its effect of the redox status, inflammation, fibrosis and necroptosis. Rats in this study received FAR for 14 days and Cd on day 7. Elevated serum creatinine, urea and uric acid, and several kidney histopathological alterations were observed in Cd-administered rats. Cd increased MDA, decreased antioxidants, downregulated PPARγ and upregulated NF-κB p65, IL-6, TNF-α, and IL-1β. Necroptosis mediators (RIP1, RIP3, MLKL, and caspase-8) and α-SMA were upregulated, and collagen deposition was increased in Cd-administered rats. FAR ameliorated kidney injury markers and tissue damage, attenuated OS, suppressed NF-κB and inflammatory mediators, and enhanced antioxidants. In addition, FAR suppressed RIP1, RIP3, MLKL, caspase-8, and α-SMA, and enhanced kidney cytoglobin and PPARγ. In conclusion, FAR protects against Cd nephrotoxicity by suppressing OS, inflammatory response and necroptosis, effects associated with enhanced antioxidants, cytoglobin, and PPARγ

Mechanistic insights into carbonic anhydrase IX inhibition by coumarins from Calendula officinalis: in vitro and in silico approaches †

Given the critical role of carbonic anhydrase IX (CA IX) in various pathological conditions, there is a significant demand for new inhibitors to enhance patient outcomes and clinical management. In this study, we examined the inhibitory effectiveness of five coumarins derived from Calendula officinalis against CA IX using in vitro assays and computational modeling. Among the coumarins tested, xeroboside and isobaisseoside were identified as the most potent inhibitors. Kinetic studies indicated that xeroboside and isobaisseoside exhibit a mixed inhibition mode. Molecular docking analysis showed that the tested coumarins exhibit binding affinities and extensive polar interactions with CA IX. These coumarins demonstrated significant hydrophobic interactions and occupied the same binding site as acetazolamide (AAZ). Molecular dynamics (MD) indicated that xeroboside and isobaisseoside exhibited consistent trajectories and notable energy stabilization during their interaction with CA IX. MM/PBSA calculations showed that xeroboside displayed the lowest binding free energy (−27.26 ± 2.48 kJ mol−1). Potential Energy Landscape (PEL) analysis revealed distinct and stable conformational states for the CA IX–ligand complexes, with xeroboside exhibiting the most stable and lowest energy configuration. These computational findings are consistent with the experimental results, highlighting the potential efficacy of xeroboside and isobaisseoside as CA IX inhibitors. In conclusion, Calendula officinalis-derived coumarins are promising candidates as effective CA IX inhibitors

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)

Factors regulating the renal circulation in spontaneously hypertensive rats

Hypertension is one of the leading causes of health morbidity and mortality which are linked to many life threatening diseases such as stroke heart problems and renal dysfunction. The integrity of renal microcirculation is crucial to maintaining the clearance and the excretory function in the normotensive and hypertensive conditions. Furthermore, any alteration in the renal function is involved in the pathophysiology of hypertension. The aim of this review is to provide a brief discussion of some factors that regulate renal haemodynamics in spontaneously hypertensive rats, an animal model of hypertension, and how these factors are linked to the disease

Upregulation of the proinflammatory cytokine-induced neutrophil chemoattractant-1 and monocyte chemoattractant protein-1 in rats' intestinal anastomotic wound healing—Does it matter?

The proinflammatory cytokines and growth-promoting factor are essential components of the wound healing process. We hypothesized that under healthy conditions, faster healing of intestinal anastomotic wound is due to an early upregulation of proinflammatory cytokines, cytokine-induced neutrophil chemoattractant-1 (CINC-1) that is followed by a quicker upregulation of homeostatic chemokine, monocyte chemoattractant protein-1 (MCP-1) and late upregulation of transforming growth factor (TGF-β). We characterized the time course of CINC-1, MCP-1 and TGF-β release at four wounds (skin, muscle, small bowel, and colonic anastomosis) after surgery on 38 juvenile male Sprague Dawley rats. The tissue samples of each site were harvested at 0 (control), 1, 3, 5, 7 and 14 days postoperatively (n = 6–8/group) and analyzed by ELISA kits for CINC-1, MCP-1 and TGF-β. CINC-1 expression peaked earlier in muscle and colonic wounds when compared to skin and small bowel. MCP-1 levels were elevated early in skin and muscle wounds, but later expression of MCP-1 was shown in colonic wounds. TGF-β levels were unchanged in all wound sites. An earlier peak in CINC-1 levels and later expression of MCP-1 were seen in colonic wounds, but no significant increase in TGF-β levels was observed. These findings support the early healing process in intestinal anastomotic wounds