Objective: The hyperinflammatory response, caused by severe acute respiratory syndrome-2 (SARS-CoV-2), is the most common cause of death in patients with coronavirus disease 2019 (COVID-19). The etiopathogenesis of this illness is not fully understood. Macrophages appear to play a key part in COVID-19’s pathogenic effects. Therefore, this study aims to examine serum inflammatory cytokines associated with the activation state of macrophages in COVID-19 patients and attempt to find accurate predictive markers for disease severity and mortality risk in hospital.Methods: 180 patients with COVID-19 and 90 healthy controls (HCs) participated in this study. Patients were divided into three different subgroups, mild (n=81), severe (n=60), and critical groups (n=39). Serum samples were collected and IL (Interleukin)-10, IL-23, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), IL-17, monocyte chemoattractant protein-1 (MCP-1) and chemokine ligand 3 (CCL3) were determined by ELISA. In parallel, myeloperoxidase (MPO) and C-reactive protein (CRP) were measured using colorimetric and electrochemiluminescence methods, respectively. Data were collected, and their associations with disease progression and mortality were assessed using regression models and receiver operating characteristic (ROC) curves.Results: Compared to HCs, a significant increase in IL-23, IL-10, TNF-α, IFN-γ and MCP-1, were observed in COVID-19 patients. Serum levels of IL-23, IL-10, and TNF-α were significantly higher in COVID-19 patients with critical cases compared to mild and severe cases, and correlated positively with CRP level. However, non-significant changes were found in serum MPO and CCL3 among the studied groups. Moreover, significant positive association has been observed among increased IL-10, IL-23 and TNF-α in serum of COVID-19 patients. Furthermore, a binary logistic regression model was applied to predict death’s independent factors. Results showed that IL-10 alone or in combination with IL23 and TNF-α are strongly linked with non-survivors in COVID-19 patients. Finally, ROC curve results uncovered that IL-10, IL-23 and TNF-α were excellent predictors for prognosing COVID-19.Conclusion: The elevations of IL-10, IL-23, and TNF-α levels were seen in severe and critical cases of COVID-19 patients and their elevations were linked to the in-hospital mortality of the disease. A prediction model shows that the determination of these cytokines upon admission is important and should be done on COVID-19 patients as a way of evaluating the prognosis of the disease. COVID-19 Patients with high IL-10, IL-23, and TNF-α on admission are more likely to experience a severe form of the disease; therefore, those patients should be cautionary monitored and treated.

Curcumin, the principal bioactive compound of Curcuma longa (turmeric), has received extensive scientific attention for its remarkable pharmacological and epigenetic activities, particularly in cancer prevention and therapy. This review provides a comprehensive overview of curcumin’s biochemical, pharmacological, and molecular actions. Curcumin exerts potent antioxidant, anti-inflammatory, and anticancer effects by modulating multiple signaling pathways, including NF-κB, PI3K/Akt, and Wnt/ β -catenin. Despite its broad therapeutic potential, curcumin’s clinical application is limited by poor solubility, rapid metabolism, and low systemic bioavailability. To address these challenges, advanced nanotechnology-based drug delivery systems such as nanoparticles, liposomes, micelles, and polymeric carriers have been developed to enhance its solubility, stability, and targeted bioavailability. Importantly, curcumin demonstrates a multifaceted epigenetic influence that encompasses the inhibition of DNA methyltransferases leading to DNA demethylation and reactivation of silenced tumor-suppressor genes, modulation of histone acetylation and methylation balance to restore normal chromatin accessibility, regulation of non-coding RNAs such as microRNAs, lncRNAs, and circRNAs that control gene expression, and alteration of RNA methylation (m ⁶ A modification) through modulation of METTL3, FTO, and YTHDF proteins, which influence mRNA stability and translation efficiency. Collectively, these molecular and epigenetic effects reinforce curcumin’s potential as a promising multi-target agent for cancer prevention and therapy. Further pharmacogenomic and clinical studies are essential to standardize curcumin formulations and translate these preclinical findings into effective therapeutic applications.

Purpose: Oxidative stress (OS) and inflammation are pivotal points in the pathophysiology of coronavirus disease-2019 (COVID-19). This study aims to use routine laboratory and oxidative stress/antioxidative biomarkers as predictors for the mortality of the disease. Patients and Methods: This prospective cohort study, made up of 120 COVID-19 patients from emergency units in Erbil, Duhok, Kirkuk, and Sulaymaniyah cities in Iraq, from May the 1^st to May the 30^th, 2021, and 60 healthy controls (HCs) (n = 60). The patients were re-categorized into mild (n = 54), severe (n = 40), and critical (n = 26) groups based on the clinical criteria. Following admission to the hospital, blood was directly collected for measuring routine laboratory biomarkers. Results: Neutrophils and neutrophil/lymphocyte ratio (NLR) were higher in the critical group, while lymphocytes were lower in the severe and critical groups compared to the mild group. The CRP, ferritin, and D-dimer values were more elevated in severe and critical cases than in mild COVID-19 cases. The levels of malondialdehyde (MDA), nitric oxide (NO), and copper were elevated, while the superoxide dismutase (SOD) activity level and total antioxidant capacity (TAC) level were lower. However, vitamin C, glutathione peroxidase (GPx), and catalase activity levels were not changed in the COVID-19 groups compared to the HCs. NO and ferritin were predictors of ICU hospitalization; D-dimer, MDA, and NLR were predictors of mortality. NO, and NLR were predictors of SpO₂ depression. Moreover, NO, and copper have both good diagnostic values, their cutoffs were 39.01 and 11.93, respectively. Conclusion: There is an association between immune dysregulation and oxidative imbalance. The biomarkers, that could be considered as predictors for the severity and mortality of COVID-19, are the NLR, NO, ferritin, and D-dimer. The age equal to and older than 50 has a poor prognosis in the Kurdish population. Graphical Abstract:

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a devastating pandemic that causes disease with a variability in susceptibility and mortality based on variants of various clinical and demographic factors, including particular genes among populations. OBJECTIVES: Determine associations of demographic, clinical, laboratory, and single nucleotide polymorphisms in the ACE2, TMPRSS2, TNF -α, and IFN -γ genes to the incidence of infection and mortality in COVID-19 patients. DESIGN: Prospective cohort study SETTINGS: Various cities in the Kurdistan Region of Iraq. PATIENTS AND METHODS: This prospective cohort study compared laboratory markers (D-dimer, tumor necrosis factor-alpha [TNF-α], interferon-gamma [IFN-γ], C-reactive protein [CRP], lymphocyte and neutrophil counts) between COVID-19 patients and healthy controls. DNA was extracted from blood, and genotypes were done by Sanger sequencing. MAIN OUTCOME MEASURES: Single nucleotide polymorphisms of the ACE2, TMPRSS2, TNF -α, and IFN -γ genes and demographic characteristics and laboratory markers for predicting mortality in COVID-19. SAMPLE SIZE: 203 (153 COVID-19 patients, 50 health control subjects). RESULTS: Forty-eight (31.4%) of the COVID-19 patients died. Age over 40 and comorbidities were risk factors for mortality, but the strongest associations were with serum IFN-γ, the neutrophil-to-lymphocyte ratio (NLR), and serum TNF-α. The AA genotype and A allele of TMPRSS2 rs2070788 decreased while the GA genotype and A allele of TNF -α increased susceptibility to COVID-19. Patients with the GA genotype of TNF-α rs1800629 had shorter survival times (9.9 days) than those carrying the GG genotype (18.3 days) ( P <.0001 by log-rank test). The GA genotype versus the GG genotype was associated with higher levels of serum TNF-α. The GA genotype increased mortality rates by up to 3.8 fold. The survival rate for COVID-19 patients carrying the IFN -γ rs2430561 TT genotype (58.5%) was lower than in patients with the TA and AA genotypes (80.3%). The TT genotype increased the risk of death (HR=3.664, P <.0001) and was linked to high serum IFN-γ production. Olfactory dysfunction was a predictor of survival among COVID-19 patients. CONCLUSIONS: Age older than 40, comorbidities, the NLR and particular genotypes for and the IFN -γ and TNF -α genes were risk factors for death. Larger studies in different populations must be conducted to validate the possible role of particular SNPs as genetic markers for disease severity and mortality in COVID-19 disease. LIMITATIONS: Small sample size. CONFLICT OF INTEREST: None.

Kenpaullone is known for its neuroprotective and anti-inflammatory properties. We explored the potential of a specific intervention to influence cognitive abilities and disease-related brain changes in a mice model replicating key aspects of Alzheimer's disease (AD). We employed 5XFAD transgenic mice, which develop Aβ plaques and cognitive impairments that mirror those observed in individuals with Alzheimer's disease (AD). The animals were treated with Kenpaullone (1 mg/kg, 3 mg/kg, and 5 mg/kg) or a vehicle (DMSO). The study evaluated memory using the Morris water maze (MWM) and the novel object recognition (NOR) task. This study employed immunohistochemistry, ELISA, and Western blot to analyze Aβ plaques and proinflammatory factors, investigating neurodegeneration. In contrast, the expression of genes related to neurodegeneration and apoptosis was evaluated using polymerase chain reaction (PCR). Administration of Kenpaullone yielded significant improvements in cognitive performance in the 5XFAD mice. Mice that received the 5 mg/kg treatment demonstrated the highest improvement in spatial learning and recognition memory. Furthermore, Kenpaullone decreased the burden of amyloid-beta plaques in key brain regions associated with memory (hippocampus and cortex), along with decreased levels of proinflammatory cytokines. Furthermore, Kenpaullone treatment resulted in a downregulation of genes related to neurodegeneration and apoptosis, suggesting a potential therapeutic benefit in mitigating neural apoptosis in AD. Our results suggest that Kenpaullone holds promise for improving cognitive function and mitigating neuropathological changes in AD, warranting further exploration as a potential medicinal substance.