One of the most prevalent cardiovascular problems linked with type 2 diabetes mellitus (T2DM) is diabetic cardiomyopathy (DCM). DCM is associated with myocardial oxidative stress, inflammation, apoptosis, suppressed autophagy, extracellular matrix remodeling, and fibrosis. The current study aims to investigate the protective effect of sodium-glucose transport 2 inhibitor (SGLT2i) dapagliflozin and/or exercise on DCM. Thirty adult male Sprague Dawley rats are used. T2DM is induced by a 6-week high-fat diet (HFD) followed by a single intraperitoneal (IP) injection of 35 mg/kg streptozotocin (STZ). Rats are divided into five groups, control, diabetic (DM), DM + swimming, DM + dapagliflozin, and DM + dapagliflozin and swimming. Serum glucose, insulin, insulin resistance (HOMA-IR), and cardiac enzymes (CK-MB and lactate dehydrogenase (LDH) are measured. Heart specimens are used for evaluation of cellular oxidative stress markers malondialdehyde (MDA), antioxidant enzymes, glutathione (GSH), and catalase (CAT), as well as mRNA expression of TGF-β, MMP9, IL-1β, and TNF-α. Stained sections with haematoxylin and eosin (H & E) and Masson trichrome are used for histopathological evaluation and detection of fibrosis, respectively. Immunohistochemical staining for apoptosis (caspase-3), and autophagy (LC3) are also carried out. The combinations of SGLT2i and exercise exhibited the most significant cardioprotective effect. It improved diabetic-induced histopathological alterations in the myocardium and attenuated the elevation of serum blood glucose, CK-MB, LDH, myocardial MDA, and mRNA expression of TNF-α, IL-1β, TGF-β, MMP9, and the immune expression of caspase-3. Moreover, this combination increased the serum insulin, myocardial antioxidants GSH and CAT, and increase the immune expression of the LC-3. In conclusion, a combination of SGLT2i and exercise exerted a better antioxidant, anti-inflammatory, and antifibrotic effect in DCM. Moreover, the combination enhances the autophagic capacity of the heart.

Malathion is one of the most used organophosphorus pesticides that is used for many reasons such as agriculture and industry. Human exposure to malathion may occur through various means, such as eating food that has been treated with it. Malathion not only increases oxidative stress but also decreases the antioxidant capacity. Curcumin is a powerful antioxidant with many pharmacological actions. Curcumin can act as a free radical scavenger and inhibit the activation and nuclear translocation of NF-κB. Curcumin could combat the lipid peroxidation and antioxidant depletion that trigger the apoptotic pathways. This study aims to examine the antioxidant, anti-inflammatory, and antiapoptotic effects of curcumin. Twenty-four Sprague Dawley rats were divided into four groups (six rats each): control, curcumin, malathion, and malathion + curcumin groups. At the assigned time, blood samples were used for the assessment of serum creatinine, and the kidneys were excised and washed; parts of them were used for the assessment of total oxidant status (TOS), oxidative stress index (OSI), the oxidative stress marker malondialdehyde (MDA), total antioxidant capacity (TAC), and glutathione (GSH) activity, other parts were fixed in formalin for further staining. Histopathological evaluation was performed for the fixed specimens after staining with H&E, sirus red, and the immunohistochemical staining for NF-κβ, TNF-α, Caspase-3, Nrf2, and HO-1. Curcumin significantly decreases the serum creatinine after malathion exposure and significantly restores the oxidant/antioxidant balance by increasing TAC and GSH and decreasing TOS, OSI, and MDA. Curcumin exerts its reno-protective effect and restores the histological architecture of the kidney by downregulating the immune expression of NF-κβ, TNF-α, and Caspase-3 and upregulating the expression of Nrf2 and HO-1. This study concluded that curcumin protects against nephrotoxicity caused by malathion by exerting its antioxidant, anti-inflammatory, and anti-apoptotic capabilities.

Introduction: Inhibiting cyclooxygenase-2 (COX-2) is a potential strategy in inflammation therapy. Thus, developing COX-2 inhibitors plays a pivotal role in efficient inflammation treatment. This study discloses the synthesis of new heterocyclic compounds incorporating pyridine, pyran, and/or pyrazole moieties as COX-2 inhibitors. Methods: In this study, the Claisen–Schmidt reaction of 1-(5-hydroxy-1,3-diphenyl-1H-pyrazol-4-yl)ethan-1-one 1 and p-methoxybenzaldehyde in ethanol containing aqueous sodium hydroxide (10%) led to the formation of 1-(5-hydroxy-1,3-diphenyl-1H-pyrazol-4-yl)-3-(4-methoxyphenyl)prop-2-en-1-one) 2. The latter compound was allowed to react as a key precursor with various nucleophiles such as ethyl cyanoacetate, malononitrile, cyclohexanone, ethyl acetoacetate, hydrazine, cyano acid hydrazide, hydrazide, and/or thiosemicarbazide to yield new heterocyclic derivatives comprising pyridine, pyran, and/or pyrazole moieties 3–15, according to the Michael addition reaction. The newly synthesized compounds were depicted using spectroscopic techniques such as IR, ¹H-NMR, ¹³C-NMR, and MS. Moreover, their anti-inflammatory efficiency was in vitro evaluated by means of protein denaturation inhibition and cell membrane protection assay. Results: The results of 2^−ΔΔct values of COX-2 expression for compounds 6, 11, 12, and 13 were 6.6, 2.9, 25.8, and 10.1, respectively. Therefore, compound 12, followed by 13, 11, and 6, showed potent anti-inflammatory properties by in vitro evaluation. Further, an in silico molecular docking study was performed on the best-docked compounds and reference drug (Diclofenac) to investigate their binding affinities against the active site of the target enzyme. The obtained results from the in silico study aligned with the biological evaluation. Conclusions: The studies open new doors for designing new heterocycles containing pyridine, pyran, and/or pyrazole moieties as potent anti-inflammatory agents.

Background: Ulcerative colitis (UC) is an idiopathic chronic inflammation of colonic and rectal mucosa. The peroxisome proliferator-activated receptor α (PPARα) has been identified as having protective effects in UC. Aim: The study aimed to investigate the efficacy of fenofibrate, a PPARα agonist, in UC. Methods: A total of 70 patients with mild to moderate UC were allocated randomly and assigned to two groups (n = 35 each) from Gastroenterology Department, Faculty of Medicine, Menoufia University. The mesalamine group received a placebo along with 1 g of mesalamine three times daily, while the fenofibrate group received 1 g of mesalamine three times and fenofibrate 160 mg once daily. The study duration was for six months. A gastroenterologist assessed patients by non-invasive Partial Mayo Score (PMS) and the Inflammatory Bowel Disease Questionnaire (IBDQ) to evaluate clinical response and remission. The serum levels of silent information regulator 1 (SIRT1), NOD-like receptor protein 3 (NLRP3), and adenosine monophosphate activated protein kinase (AMPK), as well as fecal calprotectin levels were examined to determine the biological effect of fenofibrate. Results: After treatment, the fenofibrate group showed statistically significant reductions in PMS (p = 0.044) and improved digestive domain of IBDQ (p = 0.023). Additionally, there were significant decreases in serum NLRP3 (p = 0.041) and fecal calprotectin (p = 0.035), along with significant increases in SIRT1 (p = 0.002) and AMPK (p = 0.0003). The fenofibrate group also had higher response and remission rates compared to the mesalamine group. Conclusion: Fenofibrate may be a promising adjunct for improving clinical outcomes, quality of life, and modulating inflammation in mild to moderate patients with UC. Trial Registration Identifier: NCT05781698.