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Based on the structural and signaling roles of cholesterol, which are necessary for immune cell activity, high concentrations of cholesterol and its metabolites not only trigger malignant cell activities but also impede immune responses against cancer cells. To proliferate and evade immune responses, tumor cells overcome environmental restrictions by changing their metabolic and signaling pathways. Overexpression of mevalonate pathway enzymes and low-density lipoprotein receptor cause elevated cholesterol synthesis and uptake, respectively. Accordingly, cholesterol can be considered as both a cause and an effect of cancer. Variations in the effects of blood cholesterol levels on the outcome of different types of cancer may depend on the stage of cancer. However, positive effects of cholesterol-lowering drugs have been reported in the treatment of patients with some malignancies.

Acute myeloid leukemia (AML) comprises a multifarious and heterogeneous array of illnesses characterized by the anomalous proliferation of myeloid cells in the bone marrow microenvironment (BMM). The BMM plays a pivotal role in promoting AML progression, angiogenesis, and metastasis. The immune checkpoints (ICs) and metabolic processes are the key players in this process. In this review, we delineate the metabolic and immune checkpoint characteristics of the AML BMM, with a focus on the roles of BMM cells e.g. tumor-associated macrophages, natural killer cells, dendritic cells, metabolic profiles and related signaling pathways. We also discuss the signaling pathways stimulated in AML cells by BMM factors that lead to AML progression. We then delve into the roles of immune checkpoints in AML angiogenesis, metastasis, and cell proliferation, including co-stimulatory and inhibitory ICs. Lastly, we discuss the potential therapeutic approaches and future directions for AML treatment, emphasizing the potential of targeting metabolic and immune checkpoints in AML BMM as prognostic and therapeutic targets. In conclusion, the modulation of these processes through the use of directed drugs opens up new promising avenues in combating AML. Thereby, a comprehensive elucidation of the significance of these AML BMM cells' metabolic and immune checkpoints and signaling pathways on leukemic cells can be undertaken in the future investigations. Additionally, these checkpoints and cells should be considered plausible multi-targeted therapies for AML in combination with other conventional treatments in AML. 4fLEX7tLHnLn8Cp1swJnhp Video Abstract

Acute myeloid leukemia (AML) is one of the most prevalent leukemia in adults. Among the various NK receptors, killer immunoglobulin-like receptors (KIRs) carry out indispensable roles in NK cell development and function through engaging with class I human leukocyte antigens (HLA-I) as their ligands. Besides divergent KIR and HLA loci, KIR / HLA-I combinations have a significant effect on NK cell response. In this case–control study, we aimed to verify the association of KIR / HLA-I combinations with susceptibility to AML in the Southwestern Iranian population. KIR and HLA genotyping was performed with PCR-SSP by some novel primers for 181 patients with AML and 181 healthy controls. According to our results, the frequencies of KIR3DS1 ( p  = 0.0001, OR = 2.32, 95% CI 1.51–3.58), KIR2DS4fl ( p  = 0.02, OR = 1.53, 95% CI 1.05–2.21), CxT4 genotypes ( p  = 0.03, OR = 2.0, 95% CI 1.05–3.82), and T4 gene cluster ( p  = 0.01, OR = 1.99, 95% CI 1.17–3.41) were significantly higher in patients than controls, while C1/C2 genotype ( p  = 0.00002, OR = 0.39, 95% CI 0.25–0.61), HLA-A Bw4 ( p  = 0.02, OR = 0.6, 95% CI 0.38–0.94), and HLA-A*11 ( p  = 0.03, OR = 0.57, 95% CI 0.34–0.95) alleles were more frequent in controls. In addition, inhibitory (i)KIR / HLA-I combinations analysis revealed higher frequencies of KIR2DL1( +) / HLA-C2( +), KIR2DL2/3( +) / HLA-C1( +), KIR3DL1( +) / HLA-A Bw4( +), and KIR3DL2( +) / HLA-A*03/11( +) in the control group ( p  = 0.002, OR = 0.49, 95% CI 0.3–0.78; p  = 0.04, OR = 0.62, 95% CI 0.39–0.99; p  = 0.04, OR = 0.63, 95% CI 0.4–0.99; and p  = 0.03, OR = 0.62, 95% CI 0.4–0.95, respectively). Overall, the number of iKIR / HLA-I combinations was more in the control group. Moreover, KIR3DS1( +) / HLA-B Bw4 Ile80 ( +) and the sum of HLA-B Bw4/A Bw4 combined with KIR3DS1 as activating KIR / HLA-I combinations were more frequent among patients than controls ( p  = 0.01, OR = 1.99, 95% CI 1.14–3.49 and p  = 0.005, OR = 1.97, 95% CI 1.22–3.19, respectively). In conclusion, our results postulate that inhibitory combinations play a protective role against AML by developing potent NK cells during education. It is noteworthy that KIR / HLA-I combination studies can be applicable in donor selection for allogeneic NK cell therapy in hematological malignancies.

Background Adherent-invasive Escherichia coli (AIEC) is linked to intestinal inflammation in inflammatory bowel disease (IBD). Arthrospira platensis and Lactobacillus helveticus exhibit anti-inflammatory properties individually, yet their effects remain underexplored in IBD-associated inflammation. We aimed to investigate the anti-inflammatory potential of L. helveticus and the hydroalcoholic extract of A. platensis (HA- A. platensis ) in Caco-2 cells inflamed by IBD-associated E. coli . Methods Caco-2 cells inflamed by a Crohn’s disease (CD)-associated E. coli strain (MOI 10) were treated with HA-A. platensis (2 mg/mL) and/or L. helveticus (MOI 50) in live (LBC), heat-killed (HKC), or cell-free supernatant (CFS) forms. The anti-invasion/adhesion properties of L. helveticus and/or HA- A. platensis were investigated by assessing the CD-associated E. coli invasion/adhesion rate (%). Signaling molecules (NF-κB, STAT3, NOD2) were analyzed via qPCR to capture pathway activation dynamics, while cytokines (TNF-α, IL-1β, IL-8, IL-10) were quantified by ELISA to assess secreted functional proteins. Results HA- A. platensis reduced E. coli adhesion by 68% ( P  < 0.001) and completely inhibited invasion. L. helveticus (live form) decreased adhesion by 88% and invasion by 90%. Combined treatment showed synergistic effects, reducing adhesion by 89% and fully blocking invasion. HA- A. platensis downregulated STAT3 expression by 0.4-fold ( P  < 0.01), while L. helveticus (heat-killed form) reduced NF-κB by 0.51-fold ( P  < 0.05) and increased NOD2 by 1.8-fold ( P  < 0.01). Cytokine analysis revealed that HA- A. platensis decreased IL-1β by 0.61-fold ( P  < 0.001), and L. helveticus (heat-killed) reduced TNF-α (0.51-fold) and IL-8 (0.23-fold) while elevating anti-inflammatory IL-10 (4.39-fold; P  < 0.001). Conclusions L. helveticus and HA- A. platensis synergistically inhibit CD-associated E. coli pathogenicity and modulate inflammatory responses in vitro. These findings highlight their potential as adjunctive therapies for CD, warranting further preclinical validation.

The thoughts and ideas of artists and craftsmen, according to the way they perceive the manifestations of the world, are preserved in the form of works of visual arts, architecture and decorative crafts which are exhibited, as souvenirs of culture human. Aesthetics and art sciences introduce these works according to the change and transformation of human experiences, thus the precision and elegance “creativity” of artists throughout history, cultural value, dignity and validity of works of art are measured and determined. Today, given the new dimensions that have changed with technological progress and the production of new technical tools, the way of seeing the world and material effects has transformed and led to the creation of works of art more detailed and more complete. Paying more attention to (space) and creating new precise and comprehensive artistic dimensions is considered one of the modern achievements. The characteristics of design and creation of forms, which occupied the artist’s mind throughout the ages to see the world better and create better especially when he used “geometry”, he went through the exact terms of the world of senses and reason. Recently, some artists have paid special attention to the new common branch between mathematics, geometry and art called fractal geometry, which provides information about the common secret and harmony of the universe. Among them, modern architects and visual arts have created significant works in this regard.

Hepatopancreatobiliary (HPB) diseases, encompassing hepatobiliary and pancreatic disorders, pose substantial global health challenges due to their high morbidity and mortality rates. Recent research highlights the crucial role of the biliary microbiome in the development of these diseases. This study provides a comprehensive systematic review of the biliary microbiome's characteristics across various HPB disorders, including cholangiocarcinoma (CCA), pancreatic cancer (PC), primary sclerosing cholangitis (PSC), and gallstone disease (GSD). Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we screened articles from multiple databases, focusing on original research utilizing 16 S rRNA gene sequencing or metagenomics. Our review included 24 studies that met stringent inclusion criteria. The results indicate distinct alterations in bacterial diversity and composition associated with different HPB conditions, highlighting potential pathogenic mechanisms and candidate taxa as potential microbial indicators. In lithiasis conditions, elevated levels of Pyramidobacter and Citrobacter were associated with recurrent and giant common bile duct (CBD) stones. Proteobacteria were prevalent in PSC and CCA, potentially contributing to these diseases by promoting chronic inflammation. Sphingomonas was associated with both CCA and PSC, with potential implications for lymph node metastasis in PC. These findings suggest the potential of the biliary microbiome as a diagnostic tool, offering insights into the pathophysiology and possible therapeutic targets for HPB diseases. However, given the heterogeneity in methodologies and the limited number of studies including healthy controls, these observations remain preliminary; further prospective validation is required before clinical translation.

In this work, a novel series of N -phenylacetamide-1,2,3-triazole-indole-2-carboxamide derivatives 5a–n were designed by consideration of the potent α-glucosidase inhibitors containing indole and carboxamide-1,2,3-triazole- N -phenylacetamide moieties. These compounds were synthesized by click reaction and evaluated against yeast α-glucosidase. All the newly title compounds demonstrated superior potency when compared with acarbose as a standard inhibitor. Particularly, compound 5k possessed the best inhibitory activity against α-glucosidase with around a 28-fold improvement in the inhibition effect in comparison standard inhibitor. This compound showed a competitive type of inhibition in the kinetics. The molecular docking and dynamics demonstrated that compound 5k with a favorable binding energy well occupied the active site of α-glucosidase.

Background As the population ages, the incidence of falls and related injuries has become increasingly prominent, posing significant challenges to healthcare systems and negatively affecting the quality of life of the elderly. This study investigated the trend and spatiotemporal analysis of the age-standardized incidence and mortality rates of falls in Iran, specifically from 2010 to 2019. Methods An ecological study was conducted based on data from the IHME site for ten years, from 2010 to 2019. The annual age-standardized incidence and mortality rates per 100,000 individuals due to falls were calculated. A spatiotemporal statistical analysis was used to determine the geographical and temporal distribution. Findings Age-standardized incidence and mortality rates have decreased over ten years. Chahar Mahaal and Bakhtiari, Semnan, and Qazvin have reported the highest prevalence in both sexes, men and women. The death rate in Qazvin province for both sexes and men and Alborz province for women ranks first. According to the hotspot analysis results, Fars province has the highest incidence rate, and Kermanshah province has the highest death rate. Conclusion Population aging in Iran is a health-treatment challenge. Falling is one of the consequences of this challenge. The southern and western provinces allocate the highest age-standardized incidence and mortality rates. Ensuring equitable access to health care services for the target population is recommended to be a priority for politicians.

In this work, a novel series of quinoline-thiosemicarbazone-1,2,3-triazole-aceamide derivatives 10a-n as new potent α-glucosidase inhibitors was designed, synthesized, and evaluated. All the synthesized derivatives 10a-n were more potent than acarbose (positive control). Representatively, (E)-2-(4-(((3-((2-Carbamothioylhydrazineylidene)methyl)quinolin-2-yl)thio)methyl)-1H-1,2,3-triazol-1-yl)-N-phenethylacetamide ( 10n ), as the most potent entry, with IC 50  = 48.4 µM was 15.5-times more potent than acarbose. According to kinetic study, compound 10n was a competitive inhibitor against α-glucosidase. This compound formed the desired interactions with important residues of the binding pocket of α-glucosidase with favorable binding energy in the molecular docking and molecular dynamics. Compounds 10n , 10e , and 10 g as the most potent compounds among the synthesized compounds were evaluated in term of pharmacokinetics and toxicity via online servers. These evaluations predicted that compounds 10n , 10e , and 10 g had good pharmacokinetic properties and toxicity profile.

Background Leukemia, a type of blood cell cancer, is categorized by the type of white blood cells affected (lymphocytes or myeloid cells) and disease progression (acute or chronic). In 2020, it ranked 15th among the most diagnosed cancers and 11th in cancer-related deaths globally, with 474,519 new cases and 311,594 deaths (GLOBOCAN2020). Research into leukemia’s development mechanisms may lead to new treatments. Ubiquitin-specific proteases (USPs), a family of deubiquitinating enzymes, play critical roles in various biological processes, with both tumor-suppressive and oncogenic functions, though a comprehensive understanding is still needed. Aim This systematic review aimed to provide a comprehensive review of how Ubiquitin-specific proteases are involved in pathogenesis of different types of leukemia. Methods We systematically searched the MEDLINE (via PubMed), Scopus, and Web of Science databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) to identify relevant studies focusing on the role of USPs in leukemia. Data from selected articles were extracted, synthesized, and organized to present a coherent overview of the subject matter. Results The review highlights the crucial roles of USPs in chromosomal aberrations, cell proliferation, differentiation, apoptosis, cell cycle regulation, DNA repair, and drug resistance. USP activity significantly impacts leukemia progression, inhibition, and chemotherapy sensitivity, suggesting personalized diagnostic and therapeutic approaches. Ubiquitin-specific proteases also regulate gene expression, protein stability, complex formation, histone deubiquitination, and protein repositioning in specific leukemia cell types. Conclusion The diagnostic, prognostic, and therapeutic implications associated with ubiquitin-specific proteases (USPs) hold significant promise and the potential to transform leukemia management, ultimately improving patient outcomes.