Effect of a high dose atorvastatin as added-on therapy on symptoms and serum AMPK/NLRP3 inflammasome and IL-6/STAT3 axes in patients with major depressive disorder: randomized controlled clinical study.

Background: Neuroinflammation pathways have been associated with the development of major depressive disorders (MDD). The anti-inflammatory characteristics of statins have been demonstrated to have significance in the pathophysiology of depression. Aim: To investigate the mechanistic pathways of high dose atorvastatin in MDD. Patients and methods: This trial included 60 patients with MDD who met the eligibility requirements. Two groups of patients (n = 30) were recruited by selecting patients from the Psychiatry Department. Group 1 received 20 mg of fluoxetine plus a placebo once daily. Group 2 received fluoxetine and atorvastatin (80 mg) once daily. All patients were assessed by a psychiatrist using the Hamilton Depression Rating Scale (HDRS). A HDRS score of ≤7 indicates remission or partial remission [HDRS<17 and>7]. Response was defined as ≥ 50% drop in the HDRS score. The serum concentrations of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP-3), interleukin-6 (IL-6), adenosine monophosphate activated protein kinase (AMPK), and signal transducer and activator of transcription factor-3 (STAT-3) were measured. Results: The atorvastatin group showed a significant reduction in the levels of all measured markers along with a statistical increase in the levels of AMPK when compared to the fluoxetine group. The atorvastatin group displayed a significant decrease in HDRS when compared to its baseline and the fluoxetine group. The response rate and partial remission were higher in the atorvastatin group than fluoxetine (p = 0.03, and p = 0.005), respectively. Conclusion: These results imply that atorvastatin at high doses may be a promising adjuvant therapy for MDD patients by altering the signaling pathways for AMPK/NLRP3 and IL-6/STAT-3. Clinical Trial Registration: clinicaltrials.gov, identifier NCT05792540.

Phytochemical investigation, antibacterial, and ameliorative potential effects of Tamarix nilotica on LPS-induced acute lung injury model in mice.

Acute lung injury (ALI) is a serious illness with a high mortality rate of 40-60%. It is characterised by systemic inflammatory processes and oxidative stress. Gram-negative bacterial infections are the major cause of ALI, and lipopolysaccharide (LPS) is the major stimulus for the release of inflammatory mediators. Hence, there is an urgent need to develop new therapies which ameliorate ALI and prevent its serious consequences. The Middle Eastern native plant Tamarix nilotica (Ehrenb) Bunge belongs to the family Tamaricaceae, which exhibits strong anti-inflammatory and antioxidant effects. Thus, the current work aimed to ensure the plausible beneficial effects of T. nilotica different fractions on LPS-induced acute lung injury after elucidating their phytochemical constituents using LC/MS analysis. Mice were randomly allocated into six groups: Control saline, LPS group, and four groups treated with total extract, DCM, EtOAc and n-butanol fractions, respectively, intraperitoneal at 100 mg/kg doses 30 min before LPS injection. The lung expression of iNOS, TGF-ß1, NOX-1, NOX-4 and GPX-1 levels were evaluated. Also, oxidative stress was assessed via measurements of MDA, SOD and Catalase activity, and histopathological and immunohistochemical investigation of TNF-α in lung tissues were performed. T. nilotica n-butanol fraction caused a significant downregulation in iNOS, TGF-ß1, TNF-α, NOX-1, NOX-4, and MDA levels (p ˂ 0.05), and significantly elevated GPX-1 expression levels, SOD, and catalase activity (p ˂ 0.05), and alleviated all histopathological abnormalities confirming its advantageous role in ALI. The antibacterial activities of T. nilotica and its different fractions were investigated by agar well diffusion method and broth microdilution method. Interestingly, the n-butanol fraction exhibited the best antibacterial activity against Klebsiella pneumoniae clinical isolates. It also significantly reduced exopolysaccharide quantity, cell surface hydrophobicity, and biofilm formation.

The Potential Neuroprotective Effect of Thymoquinone on Scopolamine-Induced In Vivo Alzheimer's Disease-like Condition: Mechanistic Insights.

BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disorder without effective treatment. Thymoquinone (TQ) has demonstrated potential in exhibiting anti-inflammatory, anti-cancer, and antioxidant characteristics. Despite TQ's neuroprotection effect, there is a scarcity of information regarding its application in AD research, and its molecular trajectories remain ambiguous. Thus, the objective of the current investigation was to examine the potential beneficial effects and underlying mechanisms of TQ in scopolamine (SCOP)-induced neuronal injury to mimic AD in vivo model. METHODS: Thirty mice were divided into normal, SCOP, and TQ groups. The Y-maze and pole climbing tests were performed to measure memory and motor performance. Afterwards, histopathological and immunohistochemical examinations were carried out. Furthermore, peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling pathway-related proteins and genes were detected with an emphasis on the role of miR-9. RESULTS: TQ has the potential to ameliorate cognitive deficits observed in SCOP-induced AD-like model, as evidenced by the improvement in behavioral outcomes, histopathological changes, modulation of the expression pattern of PPAR-γ downstream targets with a significant decrease in the deposition of amyloid beta (Aß). CONCLUSIONS: TQ provided meaningful multilevel neuroprotection through its anti-inflammatory and its PPAR-γ agonist activity. Consequently, TQ may possess a potential beneficial role against AD development.

Investigation of the phytochemical composition, antioxidant, antibacterial, anti-osteoarthritis, and wound healing activities of selected vegetable waste.

Agri-food wastes, produced following industrial food processing, are mostly discarded, leading to environmental hazards and losing the nutritional and medicinal values associated with their bioactive constituents. In this study, we performed a comprehensive analytical and biological evaluation of selected vegetable by-products (potato, onion, and garlic peels). The phytochemical analysis included UHPLC-ESI-qTOF-MS/MS in combination with molecular networking and determination of the total flavonoid and phenolic contents. Further, the antimicrobial, anti-osteoarthritis and wound healing potentials were also evaluated. In total, 47 compounds were identified, belonging to phenolic acids, flavonoids, saponins, and alkaloids as representative chemical classes. Onion peel extract (OPE) showed the higher polyphenolic contents, the promising antioxidant activity, the potential anti-osteoarthritis activity, and promising antimicrobial activity, especially against methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, OPE revealed to have promising in vivo wound healing activity, restoring tissue physiology and integrity, mainly through the activation of AP-1 signaling pathway. Lastly, when OPE was loaded with nanocapsule based hydrogel, the nano-formulation revealed enhanced cellular viability. The affinities of the OPE major metabolites were evaluated against both p65 and ATF-2 targets using two different molecular docking processes revealing quercetin-3,4'-O-diglucoside, alliospiroside C, and alliospiroside D as the most promising entities with superior binding scores. These results demonstrate that vegetable by-products, particularly, those derived from onion peels can be incorporated as natural by-product for future evaluation against wounds and osteoarthritis.

Chronotherapeutic neuroprotective effect of verapamil against lipopolysaccharide-induced neuroinflammation in mice through modulation of calcium-dependent genes.

BACKGROUND: Neuroinflammation is a major mechanism in neurodegenerative diseases such as Alzheimer's disease (AD), which is a major healthcare problem. Notwithstanding of ample researches figured out possible molecular mechanisms underlying the pathophysiology of AD, there is no definitive therapeutics that aid in neuroprotection. Therefore, searching for new agents and potential targets is a critical demand. We aimed to investigate the neuroprotective effect of verapamil (VRP) against lipopolysaccharide (LPS)-induced neuroinflammation in mice and whether the time of VRP administration could affect its efficacy. METHODS: Forty male albino mice were used and were divided into normal control, LPS only, morning VRP, and evening VRP. Y-maze and pole climbing test were performed as behavioral tests. Hematoxylin and eosin together with Bielschowsky silver staining were done to visualize neuroinflammation and phosphorylated tau protein (pTAU); respectively. Additionally, the state of mitochondria, the levels of microglia-activation markers, inflammatory cytokines, intracellular Ca2+, pTAU, and Ca2+-dependent genes involving Ca2+/ calmodulin dependent kinase II (CAMKII) isoforms, protein kinase A (PKA), cAMP response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF), with the level of VRP in the brain tissue were measured. RESULTS: LPS successfully induced neuroinflammation and hyperphosphorylation of tau protein, which was indicated by elevated levels of microglia markers, inflammatory cytokines, and intracellular Ca2+ with compromised mitochondria and downregulated CAMKII isoforms, PKA, CREB and BDNF. Pretreatment with VRP showed significant enhancement in the architecture of the brain and in the behavioral tests as indicated by the measured parameters. Moreover, morning VRP exhibited better neuroprotective profile compared to the evening therapy. CONCLUSIONS: VRP highlighted a multilevel of neuroprotection through anti-inflammatory activity, Ca2+ blockage, and regulation of Ca2+-dependent genes. Furthermore, chronotherapy of VRP administration should be consider to achieve best therapeutic efficacy.

DNA and eDNA-based tracking of the North African sharptooth catfish Clarias gariepinus.

The African sharptooth catfish, Clarias gariepinus, contributes much to the River Nile ecosystem by its high omnivorosity, sturdiness, growth rates, and fecundity. It was globally appreciated as a key fluvial aquaculture species. Yet, it is also one of the top world freshwater aliens. Monitoring the genetic diversity of different economically and ecologically important species as well as development of markers that aid their tracing and abundance are fundamental. This is chiefly due to the growing international threats of environmental pollution, reduction, and loss of biodiversity. Herein, the genetic diversity of C. gariepinus along the River Nile in Egypt was assessed through sequencing of the mitochondrial cytochrome oxidase subunit I (COI). Also, a qPCR assay based on C. gariepinus 16srDNA was developed to assess the species abundance through environmental water DNA samples (eDNA). The results showed low genetic diversity of that species in Egypt. Moreover, its populations exhibited high rates of fixation. Testing its eDNA-based marker resulted in an unambiguous quantitative trend in situ, in agreement with reports of local fishermen. These eDNA signals were strong at least 1 Km upstream to the initial sampling areas, even where no C. gariepinus fishing activities are carried out. This possibly indicated a degree of homogenous species-abundance in each of the studied areas. Finally, the results identified a need for better conservation strategies for C. gariepinus, since its low diversity in the Egyptian River Nile may represent a threat against its persistence under the continuously changing environmental conditions. Moreover, using non-invasive sampling methods, e.g. based on aquatic eDNA quantification, can aid much the detection of areas of abundance of C. gariepinus, especially for both the economic importance it contributes and the invasive power it possesses.