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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 (Aβ). 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.

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 Ca 2+ , pTAU, and Ca 2+ -dependent genes involving Ca 2+ / 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 Ca 2+ 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, Ca 2+ blockage, and regulation of Ca 2+ -dependent genes. Furthermore, chronotherapy of VRP administration should be consider to achieve best therapeutic efficacy. Graphical Abstract

The journal retracts the article \"The Potential Neuroprotective Effect of Thymoquinone on Scopolamine-Induced In Vivo Alzheimer's Disease-like Condition: Mechanistic Insights\" [...].The journal retracts the article \"The Potential Neuroprotective Effect of Thymoquinone on Scopolamine-Induced In Vivo Alzheimer's Disease-like Condition: Mechanistic Insights\" [...].

Background: Parkinson’s disease (PD) is a neurological condition that typically shows up with aging. It is characterized by generalized slowness of movement, resting tremor or stiffness, and bradykinesia. PD patients’ brains mostly exhibit an increase in inflammatory mediators and microglial response. Nevertheless, a variety of non-steroidal anti-inflammatory medications (NSAIDS) offered neuroprotection in animal models and preclinical trials. Aim: The current systematic review and meta-analysis were designed to try to resolve the debate over the association of NSAID use with the development of PD because the results of several studies were somehow contradictory. Methods: An intense search was performed on Scopus, PubMed, and Web of Science databases for articles relating the incidence of PD to the use of NSAIDs. Statistical analysis of the included studies was carried out using Review Manager version 5.4.1 by random effect model. The outcome was identified as the development of PD in patients who were on NSAIDs, ibuprofen only, aspirin only, and non-aspirin NSAIDs. This was analyzed using pooled analysis of odds ratio (OR) at a significance level of ≤0.05 and a confidence level of 95%. A statistically significant decreased risk of PD was observed in patients taking NSAIDs, Ibuprofen, and non-aspirin NSAIDs. Results: The ORs of PD occurrence in patients who took NSAIDs, Ibuprofen, and non-aspirin NSAIDs were 0.88 [95% CI (0.8–0.97), p = 0.01], 0.73 [95% CI (0.53–1), p = 0.05] and 0.85 [95% CI (0.75–0.97), p = 0.01]. Meanwhile, the risk of PD in patients who took aspirin was not statistically significant. Conclusion: In conclusion, Ibuprofen, non-aspirin NSAIDs, and other types of NSAIDs could be associated with a reduction in PD risk. However, there was no association between aspirin intake and the development of PD.

Objectives: Traumatic brain injury (TBI) is one of the top causes of morbidity and mortality worldwide. The review aimed to discuss and summarize the current evidence on the effectiveness of adjuvant neuroprotective treatments in terms of their effect on brain injury biomarkers in TBI patients. Methods: To identify relevant studies, four scholarly databases, including PubMed, Cochrane, Scopus, and Google Scholar, were systematically searched using predefined search terms. English-language randomized controlled clinical trials reporting changes in brain injury biomarkers, namely, neuron-specific enolase (NSE), glial fibrillary acid protein (GFAP), ubiquitin carboxyl-terminal esterase L1 (UCHL 1 ) and/or S100 beta (S100 ß), were included. The methodological quality of the included studies was assessed using the Cochrane risk-of-bias tool. Results: A total of eleven studies with eight different therapeutic options were investigated; of them, tetracyclines, metformin, and memantine were discovered to be promising choices that could improve neurological outcomes in TBI patients. The most utilized serum biomarkers were NSE and S100 ß followed by GFAP, while none of the included studies quantified UCHL 1 . The heterogeneity in injury severity categories and measurement timing may affect the overall evaluation of the clinical efficacy of potential therapies. Therefore, unified measurement protocols are highly warranted to inform clinical decisions. Conclusion: Few therapeutic options showed promising results as an adjuvant to standard care in patients with TBI. Several considerations for future work must be directed towards standardizing monitoring biomarkers. Investigating the pharmacotherapy effectiveness using a multimodal biomarker panel is needed. Finally, employing stratified randomization in future clinical trials concerning potential confounders, including age, trauma severity levels, and type, is crucial to inform clinical decisions. Clinical Trial Registration: [ https://www.crd.york.ac.uk/prospero/dis ], identifier [CRD42022316327].

Neurological injury is a crucial problem that interferes with the therapeutic use of vinca alkaloids as well as the quality of patient life. This study was conducted to assess the impact of using loratadine or diosmin/hesperidin on neuropathy induced by vinca alkaloids. Patients were randomized into one of three groups as follows: group 1 was the control group, group 2 received 450 mg diosmin and 50 mg hesperidin combination orally twice daily, and group 3 received loratadine 10 mg orally once daily. Subjective scores (numeric pain rating scale, douleur neuropathique 4, and functional assessment of cancer therapy/gynecologic oncology group–neurotoxicity (FACT/GOG-Ntx) scores), neuroinflammation biomarkers, adverse drug effects, quality of life, and response to chemotherapy were compared among the three groups. Both diosmin/hesperidin and loratadine improved the results of the neurotoxicity subscale in the FACT/GOG-Ntx score (p < 0.001, p < 0.01 respectively) and ameliorated the upsurge in neuroinflammation serum biomarkers. They also reduced the incidence and timing of paresthesia (p = 0.001 and p < 0.001, respectively) and dysuria occurrence (p = 0.042). Both loratadine and diosmin/hesperidin attenuated the intensity of acute neuropathy triggered by vinca alkaloids. Furthermore, they did not increase the frequency of adverse effects or interfere with the treatment response.

Background Hepatocellular carcinoma (HCC) remains a major health problem despite the emergence of several preventive and therapeutic modalities. HCC has heterogeneous and wide morpho-molecular patterns, resulting in unique clinical and prognostic criteria. Therefore, we aimed to study the clinical and pathological criteria of HCC to update the morpho-molecular classifications and provide a guide to the diagnosis of this disease. Methods Five hundred thirty pathologically analyzed HCC cases were included in this study. The clinical and survival data of these cases were collected. Results Hepatitis C virus is still the dominant cause of HCC in Egypt. Post-direct-acting antiviral agent HCC showed an aggressive course compared to interferon-related HCC. Old age, male gender, elevated alpha-fetoprotein level, tumor size, and background liver were important prognostic parameters. Special HCC variants have characteristic clinical, laboratory, radiological, prognostic, and survival data. Tumor-infiltrating lymphocytes rather than neutrophil-rich HCC have an excellent prognosis. Conclusions HCC is a heterogenous tumor with diverse clinical, pathological, and prognostic parameters. Incorporating the clinicopathological profile per specific subtype is essential in the treatment decision of patients with HCC. Trial registration This was a retrospective study that included 530 HCC cases eligible for analysis. The cases were obtained from the archives of the Pathology Department, during the period between January 2010 and December 2019. Clinical and survival data were collected from the patients’ medical records after approval by the institutional review board (IRB No. 246/2021) of Liver National Institute, Menoufia University. The research followed the guidelines outlined in the Declaration of Helsinki and registered on ClinicalTrials.gov (NCT05047146).

Understanding the molecular mechanism underlying the pathogenesis of knee osteoarthritis (KOA) may be beneficial in fetching new therapeutics. Our study aims to investigate the implication of Wnt/ β-catenin pathway in development of KOA by detection of the downstream target genes and their crosstalk with miR-214 in patients with KOA and to correlate that with the clinical findings. Sixty participants were involved in the study. The levels of miR-214, β-catenin, Wnt4, matrix metalloproteinase 3 (MMP3), Bax, caspase 3, and phosphorylated glycogen synthase kinase-3 beta (pGSK3β) were determined. All participants were assessed clinically and radiologically regarding knee joint pain, stiffness, range of motion, and knee medial cartilage thickness. Besides, a correlation between Western Ontario and McMaster Universities (WOMAC) score, clinical, and radiological data, and the measured parameters was conducted. Patients with KOA showed downregulated miR-214 with upregulated β-catenin, Wnt4, MMP3, Bax, caspase 3, and pGSK3β compared to healthy individuals. Statistically significant positive correlation between WOMAC score, knee joint pain regarding Visual Analogue Scale (VAS) with β-catenin, pGSK3β, Wnt4, MMP3, Bax, and caspase 3, and significant negative relationship between them and knee joint medial cartilage thickness; while there was a statistically significant negative correlation between WOMAC, and clinical findings of osteoarthritis and miR-214 and significant positive relationship between it and knee joint medial cartilage thickness. This study provides valuable insights into involvement of the Wnt/β-catenin and miR-214 in KOA pathogenesis. By targeting these molecular components, future therapeutics may modulate their activity and mitigate chondrocyte apoptosis and matrix degradation, potentially halting KOA progression.

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. To investigate the mechanistic pathways of high dose atorvastatin in MDD. 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. 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 ( = 0.03, and = 0.005), respectively. 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. clinicaltrials.gov, identifier NCT05792540.

Parkinson's disease (PD) is caused by the progressive loss of dopaminergic neurons in the substantia nigra. Neuroinflammation is considered a key factor contributing to the pathophysiology of PD. Current gold-standard therapies for PD provide only symptomatic relief without slowing disease progression, highlighting the need to develop new disease-modifying treatments. Metformin has been demonstrated to exert a neuroprotective role in several neurodegenerative disorders including PD. This study aimed to clarify the role of metformin as adjuvant therapy in patients with PD. Sixty patients with PD were divided into 2 groups (n = 30). Patients in group 1 received levodopa/carbidopa (250/25 mg) three times daily for 3 months plus placebo (Control group), while those in group 2 received levodopa/carbidopa (250/25 mg) three times daily and 500 mg metformin two times daily (Metformin group). Patients were assessed via Unified Parkinson's Disease Rating Scale (UPDRS). The serum concentrations of toll like receptor 4 (TLR-4), α-synuclein, brain derived neurotropic factor (BDNF), and high mobility group box 1 (HMGB-1) were measured before and after treatment. The improvement in UPDRS from baseline to 3 months. Change in the level of biological markers. The control group did not show significant difference in UPDRS when compared to their baseline value by Wilcoxon test ( > 0.05), meanwhile the metformin group showed significant difference when compared to before treatment by Wilcoxon test ( < 0.05). There were no significant differences between the two groups in UPDRS after treatment ( > 0.05) by Man Whitney test. However, the metformin group showed a significant decrease in TLR-4, HMGB-1, and α-synuclein along with a statistically significant increase in BDNF ( < 0.05) when compared to its baseline and control group. The control group did not show any significant changes in all markers when compared to their baseline. While no significant differences in UPDRS scores were observed between the metformin and control groups, trends in biomarker changes suggest a potential impact of adjunctive metformin use on the underlying pathophysiology of PD. Further studies are needed to assess its effects on motor symptoms over a longer duration. identifier NCT05781711.