Targeting Caspases 3/6 and Cathepsins L/B May Decrease Laminopathy-Induced Apoptosis in Alzheimer's Disease.

Background: Laminopathy is a pathological manifestation observed in Alzheimer's disease (AD), leading to neuronal apoptosis. Objective: Our objective was to assess inhibitors of enzymes involved in laminopathy. Methods: The mRNA expression of the cathepsins L and B, caspases 3 and 6, lamins b1 and b2, granzymes A and B, and lamins A and C were extracted and analyzed from GSE5281 and GSE28146 datasets. A total of 145 ligands were selected for molecular docking. Subsequently, 10 ns and 100 ns atomistic molecular dynamics (MD) and Martini 3 were performed with NAMD for two selected ligands (PubChem id: 608841 and ChEMBL id: 550872). Results: The mRNA expression level highlighted caspase 6 and lamin A/C upregulation in the hippocampus of the AD samples, in contrast to cathepsin B, lamin b2, and caspase 3. Moreover, there was a strong correlation between the expression level of cathepsin B, lamin A/C, and caspase 6 in the AD group. The MD results suggested molecule with ChEMBL id of 550872 had higher free binding energy, while in longer simulation the molecule with PubChem id of 608841 was suggested to be more stable in complex with the receptor. Conclusions: Our findings suggest that lamins A/C, cathepsins B/L, caspase 6, and lamin B2 are associated with laminopathy as potential factors contributing to apoptosis in AD. We propose that simultaneous inhibition of caspases 6 and cathepsins L may decrease the rate of apoptosis triggered by lamin degradation. Nevertheless, further studies are required to confirm these observations due to the lack of in vivo findings.

Carvacrol Exerts Anti-Inflammatory, Anti-Oxidative Stress and Hepatoprotective Effects Against Diclofenac-Induced Liver Injury in Male Rats.

Background: Diclofenac (DIC) is an NSAID that can cause toxic effects in animals and humans and carvacrol (CAR) is a monoterpene compound that displays effective pharmacological and biological actions. The purpose of this work was to assess the influences of CAR on DIC-induced liver injury and oxidative stress in male rats. Methods: The male Wistar rats were segregated into four groups. Group 1, the control group; Group 2 received DIC-only (10 mg/kg BW, p.o); Group 3, received CAR-only (10 mg/kg BW, p.o), and group 4 received DIC plus CAR. The serum levels as well as the activity of several liver-associated markers, and oxidative and anti-oxidant compounds were tested. The expression of pro-inflammatory mediators was also studied using the qRT-PCR analysis. Results: Our results showed that DIC treatment was associated with the elevation in the serum levels of liver-related markers together with the increase in the serum and the hepatic levels of malondialdehyde (MDA) and protein carbonyl (PC). Moreover, DIC reduced the activity of the antioxidant system in the rats and increased lymphocyte infiltration into the hepatocytes. CAR; however, protected the hepatocytes from the toxic effects of DIC by enhancing the activity of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and Glutathione (GSH). By diminishing the expression of tumor necrosis factor (TNF)-α, CAR was also capable of preventing the inflammatory effects of DIC on liver cells. Conclusions: The findings of this study indicated that the administration of CAR could alleviate the noxious effects of DIC on the antioxidant defense system and liver tissue.

In Silico Interactions of Natural and Synthetic Compounds with Key Proteins Involved in Alzheimer's Disease: Prospects for Designing New Therapeutics Compound.

Memory impairment is a result of multiple factors including amyloid-beta (Aß) accumulation. Several receptors are mediated for Aß transport and signaling. Moreover, blood lipids are involved in Aß signaling pathway through these receptors. Mediated blood lipid level by statins aims to regulate Aß signaling cascade. First, the structure of receptors was taken from the RCSB PDB database and prepared with MGLTools and AutoDock tool 4. Second, the ligand was prepared for docking through AutoDock Vina. The binding affinity was calculated, and the binding sites were determined through LigPlot+ software. Besides, pharmacokinetic properties were calculated through multiple software. Finally, a molecular dynamics (MD) simulation was conducted to evaluate ligands stability along with clustering analysis to evaluate proteins connection. Our molecular docking and dynamic analyses revealed silymarin as a potential inhibitor of acetylcholinesterase (AChE), P-glycoprotein, and angiotensin-converting enzyme 2 (ACE2) with 0.704, 0.85, and 0.83 Å for RMSD along with -114.27, -107.44, and -122.51 kcal/mol for free binding energy, respectively. Moreover, rosuvastatin and quercetin have more stability compared to silymarin and donepezil in complex with P-glycoprotein and ACE2, respectively. Eventually, based on clustering and pharmacokinetics analysis, silymarin, rosuvastatin, and quercetin are suggested to be involved in peripheral clearance of Aß. The bioactivity effects of mentioned statins and antioxidants are predicted to be helpful in treating memory impairment in Alzheimer's disease (AD). Nevertheless, mentioned drug effect could be improved by nanoparticles to facilitate penetration of the blood-brain barrier (BBB).

Microbiota-Pain Association; Recent Discoveries and Research Progress.

The relationship between gut microbiota and pain, such as visceral pain, headaches (migraine), itching, prosthetic joint infection (PJI), chronic abdominal pain (CAP), joint pain, etc., has received increasing attention. Several parts of the evidence suggest that microbiota is one of the most important pain modulators and they can regulate pain in the central and peripheral nervous systems. Any alteration in microbiota by diet or antibiotics mediation may characterize a novel therapeutic strategy for pain management. The present study includes the most up-to-date and influential scientific findings on the association of microbiota with pain, despite the fact that the underlying mechanism is not identified in most cases. According to recent research, identifying the molecular mechanisms of the microbiota-pain pathway can have a unique perspective in treating many diseases, even though there is a long way to reach the ideal point. This study will stress the influence of microbiota on the common diseases that can stimulate the pain with a focus on underlying mechanisms.