Discovery of common molecular signatures and drug repurposing for COVID-19/Asthma comorbidity: ACE2 and multi-partite networks.

Angiotensin-converting enzyme 2 (ACE2) is identified as the functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the ongoing global coronavirus disease-2019 (COVID-19) pandemic. This study aimed to elucidate potential therapeutic avenues by scrutinizing approved drugs through the identification of the genetic signature associated with SARS-CoV-2 infection in individuals with asthma. This exploration was conducted through an integrated analysis, encompassing interaction networks between the ACE2 receptor and common host (co-host) factors implicated in COVID-19/asthma comorbidity. The comprehensive analysis involved the identification of common differentially expressed genes (cDEGs) and hub-cDEGs, functional annotations, interaction networks, gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and module construction. Interaction networks were used to identify overlapping disease modules and potential drug targets. Computational biology and molecular docking analyzes were utilized to discern functional drug modules. Subsequently, the impact of the identified drugs on the expression of hub-cDEGs was experimentally validated using a mouse model. A total of 153 cDEGs or co-host factors associated with ACE2 were identified in the COVID-19 and asthma comorbidity. Among these, seven significant cDEGs and proteins - namely, HRAS, IFNG, JUN, CDH1, TLR4, ICAM1, and SCD-were recognized as pivotal host factors linked to ACE2. Regulatory network analysis of hub-cDEGs revealed eight top-ranked transcription factors (TFs) proteins and nine microRNAs as key regulatory factors operating at the transcriptional and post-transcriptional levels, respectively. Molecular docking simulations led to the proposal of 10 top-ranked repurposable drug molecules (Rapamycin, Ivermectin, Everolimus, Quercetin, Estradiol, Entrectinib, Nilotinib, Conivaptan, Radotinib, and Venetoclax) as potential treatment options for COVID-19 in individuals with comorbid asthma. Validation analysis demonstrated that Rapamycin effectively inhibited ICAM1 expression in the HDM-stimulated mice group (p < 0.01). This study unveils the common pathogenesis and genetic signature underlying asthma and SARS-CoV-2 infection, delineated by the interaction networks of ACE2-related host factors. These findings provide valuable insights for the design and discovery of drugs aimed at more effective therapeutics within the context of lung disease comorbidities.

Mixed-Grade Urothelial Carcinoma: Insights Into Clinical Behavior and Prognostic Implications Compared to Pure Low-Grade and High-Grade Urothelial Carcinomas.

CONTEXT.­: Low-grade urothelial carcinoma (LGUC) and high-grade urothelial carcinoma (HGUC) are distinguished based on architectural and cytological features, with the anticipation that HGUC exhibits more aggressive behavior and a worse prognosis compared to LGUC. The current World Health Organization classification recognizes mixed-grade urothelial carcinoma (MGUC, for the purposes of this study) as a separate category that behaves like LGUC if the high-grade component is <5% and states that any tumor with ≥5% high-grade component should be graded as HGUC. OBJECTIVE.­: To evaluate the risk of tumor recurrence, grade, and stage progression of MGUC compared to LGUC and HGUC. DESIGN.­: A total of 150 de novo noninvasive polypoid urothelial carcinomas (41 cases of MGUC, 59 of LGUC, and 50 of HGUC) were included. Tumor recurrence, grade, and stage progression were compared among the MGUC, LGUC, and HGUC cases. RESULTS.­: Tumor recurrence was observed in 14 of 41 (34.2%) of MGUC, 33 of 59 (55.9%) of LGUC, and 28 of 50 (56%) of HGUC. Grade progression occurred in 5 of 41 (12.2%) of MGUC cases and 5 of 59 (8.5%) of LGUC cases. No stage progression was observed in LGUC or MGUC cases, while 7 of 50 (14%) of HGUC cases showed stage progression. MGUC was associated with lower odds and hazard of recurrence compared to LGUC. The rate of grade progression was higher in MGUC and occurred after a shorter interval compared to LGUC. CONCLUSIONS.­: MGUC showed a prognosis closer to LGUC. Our study supports the current recommendation to classify tumors with <5% high-grade component as MGUC, as these tumors display clinical characteristics and outcomes close to that of pure LGUC.

Dual role of mesenchymal stem/stromal cells and their cell-free extracellular vesicles in colorectal cancer.

Colorectal cancer (CRC) is one of the main causes of cancer-related deaths. However, the surgical control of the CRC progression is difficult, and in most cases, the metastasis leads to cancer-related mortality. Mesenchymal stem/stromal cells (MSCs) with potential translational applications in regenerative medicine have been widely researched for several years. MSCs could affect tumor development through secreting exosomes. The beneficial properties of stem cells are attributed to their cell-cell interactions as well as the secretion of paracrine factors in the tissue microenvironment. For several years, exosomes have been used as a cell-free therapy to regulate the fate of tumor cells in a tumor microenvironment. This review discusses the recent advances and current understanding of assessing MSC-derived exosomes for possible cell-free therapy in CRC.

Ductal, intraductal, and cribriform carcinoma of the prostate: Molecular characteristics and clinical management.

Prostatic acinar adenocarcinoma accounts for approximately 95% of prostate cancer (CaP) cases. The remaining 5% of histologic subtypes of CaP are known to be more aggressive and have recently garnered substantial attention. These histologic subtypes - namely, prostatic ductal adenocarcinoma (PDA), intraductal carcinoma of the prostate (IDC-P), and cribriform carcinoma of the prostate (CC-P) - typically exhibit distinct growth characteristics, genomic features, and unique oncologic outcomes. For example, PTEN mutations, which cause uncontrolled cell growth, are frequently present in IDC-P and CC-P. Germline mutations in homologous DNA recombination repair (HRR) genes (e.g., BRCA1, BRCA2, ATM, PALB2, and CHEK2) are discovered in 40% of patients with IDC-P, while only 9% of patients without ductal involvement had a germline mutation. CC-P is associated with deletions in common tumor suppressor genes, including PTEN, TP53, NKX3-1, MAP3K7, RB1, and CHD1. Evidence suggests abiraterone may be superior to docetaxel as a first-line treatment for patients with IDC-P. To address these and other critical pathological attributes, this review examines the molecular pathology, genetics, treatments, and oncologic outcomes associated with CC-P, PDA, and IDC-P with the objective of creating a comprehensive resource with a centralized repository of information on PDA, IDC-P, and CC-P.

Quercetin modulates expression of serum exosomal long noncoding RNA NEAT1 to regulate the miR-129-5p/BDNF axis and attenuate cognitive impairment in diabetic mice.

AIMS: Cognitive impairment poses a considerable health challenge in the context of type 2 diabetes mellitus (T2DM), emphasizing the need for effective interventions. This study delves into the therapeutic efficacy of quercetin, a natural flavonoid, in mitigating cognitive impairment induced by T2DM in murine models. MATERIALS AND METHODS: Serum exosome samples were obtained from both T2DM-related and healthy mice for transcriptome sequencing, enabling the identification of differentially expressed mRNAs and long noncoding RNAs (lncRNAs). Subsequent experiments were conducted to ascertain the binding affinity between mmu-miR-129-5p, NEAT1 and BDNF. The structural characteristics and dimensions of isolated exosomes were scrutinized, and the expression levels of exosome-associated proteins were quantified. Primary mouse hippocampal neurons were cultured for in vitro validation, assessing the expression of pertinent genes as well as neuronal vitality, proliferation, and apoptosis capabilities. For in vivo validation, a T2DM mouse model was established, and quercetin treatment was administered. Changes in various parameters, cognitive ability, and the expression of insulin-related proteins, along with pivotal signaling pathways, were monitored. KEY FINDINGS: Analysis of serum exosomes from T2DM mice revealed dysregulation of NEAT1, mmu-miR-129-5p, and BDNF. In vitro investigations demonstrated that NEAT1 upregulated BDNF expression by inhibiting mmu-miR-129-5p. Overexpression of mmu-miR-129-5p or silencing NEAT1 resulted in the downregulation of insulin-related protein expression, enhanced apoptosis, and suppressed neuronal proliferation. In vivo studies validated that quercetin treatment significantly ameliorated T2DM-related cognitive impairment in mice. SIGNIFICANCE: These findings suggest that quercetin holds promise in inhibiting hippocampal neuron apoptosis and improving T2DM-related cognitive impairment by modulating the NEAT1/miR-129-5p/BDNF pathway within serum exosomes.

Identification of Glandular (Acinar)/Tubule Formation in Invasive Carcinoma of the Breast: A Study to Determine Concordance Using the World Health Organization Definition.

CONTEXT.­: The Nottingham Grading System (NGS) developed by Elston and Ellis is used to grade invasive breast cancer (IBC). Glandular (acinar)/tubule formation is a component of NGS. OBJECTIVE.­: To investigate the ability of pathologists to identify individual structures that should be classified as glandular (acinar)/tubule formation. DESIGN.­: A total of 58 hematoxylin-eosin photographic images of IBC with 1 structure circled were classified as tubules (41 cases) or nontubules (17 cases) by Professor Ellis. Images were sent as a PowerPoint (Microsoft) file to breast pathologists, who were provided with the World Health Organization definition of a tubule and asked to determine if a circled structure represented a tubule. RESULTS.­: Among 35 pathologists, the κ statistic for assessing agreement in evaluating the 58 images was 0.324 (95% CI, 0.314-0.335). The median concordance rate between a participating pathologist and Professor Ellis was 94.1% for evaluating 17 nontubule cases and 53.7% for 41 tubule cases. A total of 41% of the tubule cases were classified correctly by less than 50% of pathologists. Structures classified as tubules by Professor Ellis but often not recognized as tubules by pathologists included glands with complex architecture, mucinous carcinoma, and the "inverted tubule" pattern of micropapillary carcinoma. A total of 80% of participants reported that they did not have clarity on what represented a tubule. CONCLUSIONS.­: We identified structures that should be included as tubules but that were not readily identified by pathologists. Greater concordance for identification of tubules might be obtained by providing more detailed images and descriptions of the types of structures included as tubules.

Translational research of new developments in targeted therapy of colorectal cancer.

A severe global health concern is the rising incidence and mortality rate of colorectal cancer (CRC). Chemotherapy, which is typically used to treat CRC, is known to have limited specificity and can have noticeable side effects. A paradigm shift in cancer treatment has been brought about by the development of targeted therapies, which has led to the appearance of pharmacological agents with improved efficacy and decreased toxicity. Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2), and BRAF are among the molecular targets covered in this review that are used in targeted therapy for CRC. The current discussion also covers advancements in targeted therapeutic approaches, such as antibody-drug conjugates, immune checkpoint inhibitors, and chimeric antigen receptor (CAR) T-cell therapy. A review of the clinical trials and application of these particular therapies in treating CRC is also done. Despite the improvements in targeted therapy for CRC, problems such as drug resistance and patient selection remain to be solved. Despite this, targeted therapies have offered fresh possibilities for identifying and treating CRC, paving the way for the development of personalized medicine and extending the life expectancy and general well-being of CRC patients.

Reduced expression of miR-221 is associated with the pro-apoptotic pathways in spermatozoa of oligospermia men.

Oligospermia and asthenozoospermia, both frequent, can lead to male infertility. Oligospermia might be viewed as a milder form of azoospermia because the same mutations that produce azoospermia in some individuals also create oligospermia in other individuals. In this, we looked at different characteristics of oligospermia men, counting the level of apoptosis and a few related apoptotic and oxidative stress components, and compared them to solid controls. In this study, semen samples from healthy fertile men (n = 35) and oligospermia (n = 35) were collected, and sperm death rates in both groups were examined using flow cytometry. Also, gene expression of apoptotic and anti-apoptotic markers and miR-221 were investigated (Real-Time PCR). Moreover, for the evaluation of catalase and SOD activity and anti-inflammatory cytokines, including IL-10 and TGF-ß, the specific ELISA kits and procedures were applied. As a result, higher gene and protein expression levels of PTEN, P27, and P57 were observed in patients with oligospermia. In contrast, lower mRNA expression of AKT and miR-221 was detected in this group. In addition, IL-10, TGF-ß, and catalase activity were suppressed in the oligospermia group compared with healthy men samples. Moreover, the frequency of apoptosis of sperm cells is induced in patients. In conclusion, apoptosis-related markers, PTEN, and the measurement of significant and efficient oxidative stress markers like SOD and catalase in semen plasma could be considered as the critical diagnostic markers for oligospermia. Future studies will be better able to treat oligospermia by showing whether these indicators are rising or falling.

miR-199a-3p suppresses neuroinflammation by directly targeting MyD88 in a mouse model of bone cancer pain.

AIMS: Pain is a profoundly debilitating symptom in cancer patients, leading to disability, immobility, and a marked decline in their quality of life. This study aimed to investigate the potential roles of miR-199a-3p in a murine model of bone cancer pain induced by tumor cell implantation in the medullary cavity of the femur. MATERIALS AND METHODS: We assessed pain-related behaviors, including the paw withdrawal mechanical threshold (PWMT) and the number of spontaneous flinches (NSF). To investigate miRNA expression and its targets in astrocytes, we employed a combination of RNA-seq analysis, qRT-PCR, Western blotting, EdU, TUNEL, ChIP, ELISA, and luciferase reporter assays in mice (C3H/HeJ) with bone cancer pain and control groups. KEY FINDINGS: On days 10, 14, 21, and 28 post-surgery, we observed significant differences in PWTL, PWMT, and NSF when compared to the sham group (P < 0.001). qRT-PCR assays and miRNA sequencing results confirmed reduced miR-199a-3p expression in astrocytes of mice with bone cancer pain. Gain- and loss-of-function experiments demonstrated that miR-199a-3p suppressed astrocyte activation and the expression of inflammatory cytokines. In vitro investigations revealed that miR-199a-3p mimics reduced the levels of inflammatory factors in astrocytes and MyD88/NF-κB proteins. Furthermore, treatment with a miR-199a-3p agonist resulted in reduced expression of MyD88, TAK1, p-p65, and inflammatory mediators, along with decreased astrocyte activation in the spinal cord. SIGNIFICANCE: Collectively, these findings demonstrate that upregulation of miR-199a-3p may offer a therapeutic avenue for mitigating bone cancer pain in mice by suppressing neuroinflammation and inhibiting the MyD88/NF-κB signaling pathway.

Evolution of the HIF targeted therapy in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, affecting hundreds of thousands of people worldwide and can affect people of any age. The pathogenesis of ccRCC is most commonly due to biallelic loss of the tumor suppressor gene VHL. VHL is the recognition subunit of an E3-ubiquitin-ligase-complex essential for degradation of the hypoxia-inducible factors (HIF) 1α and 2α. Dysfunctional degradation of HIF results in overaccumulation, which is particularly concerning with the HIF2α subunit. This leads to nuclear translocation, dimerization, and transactivation of numerous HIF-regulated genes responsible for cell survival and proliferation in ccRCC. FDA-approved therapies for RCC have primarily focused on targeting downstream effectors of HIF, then incorporated immunotherapeutics, and now, novel approaches are moving back to HIF with a focus on interfering with upstream targets. This review summarizes the role of HIF in the pathogenesis of ccRCC, novel HIF2α-focused therapeutic approaches, and opportunities for ccRCC treatment.

Progressing nanotechnology to improve targeted cancer treatment: overcoming hurdles in its clinical implementation.

The use of nanotechnology has the potential to revolutionize the detection and treatment of cancer. Developments in protein engineering and materials science have led to the emergence of new nanoscale targeting techniques, which offer renewed hope for cancer patients. While several nanocarriers for medicinal purposes have been approved for human trials, only a few have been authorized for clinical use in targeting cancer cells. In this review, we analyze some of the authorized formulations and discuss the challenges of translating findings from the lab to the clinic. This study highlights the various nanocarriers and compounds that can be used for selective tumor targeting and the inherent difficulties in cancer therapy. Nanotechnology provides a promising platform for improving cancer detection and treatment in the future, but further research is needed to overcome the current limitations in clinical translation.

Molecular mechanisms of long non-coding RNAs in differentiation of T Helper17 cells.

T helper (Th) 17 cells are one of the most important T cell subsets in a number of autoimmune and chronic inflammatory diseases. During infections, Th17 cells appear to play an important role in the clearance of extracellular pathogens. Th17 cells, on the other hand, are engaged in inflammation and have been linked to the pathophysiology of a number of autoimmune illnesses and human inflammatory disorders. A diverse group of RNA molecules known as lncRNAs serve critical functions in gene expression regulation. They may interact with a wide range of molecules, including DNA, RNA, and proteins, and have a complex structure. LncRNAs, which have restricted or no protein-coding activity, are implicated in a number of illnesses due to their regulatory impact on a variety of biological processes such as cell proliferation, apoptosis, and differentiation. Several lncRNAs have been associated with Th7 cell development in the context of immune cell differentiation. In this article, we cover new studies on the involvement of lncRNAs in Th17 cell differentiation in a variety of disorders, including auto-immune diseases, malignancies, asthma, heart disease, and infections.

Pathological role of inflammation in ocular disease progress and its targeting by mesenchymal stem cells (MSCs) and their exosome; current status and prospect.

Because of their unique capacity for differentiation to a diversity of cell lineages and immunosuppressive properties, mesenchymal stem cells (MSC) are being looked at as a potential new treatment option in ophthalmology. The MSCs derived from all tissue sources possess immunomodulatory attributes through cell-to-cell contact and releasing a myriad of immunomodulatory factors (IL-10, TGF-ß, growth-related oncogene (GRO), indoleamine 2,3 dioxygenase (IDO), nitric oxide (NO), interleukin 1 receptor antagonist (IL-1Ra), prostaglandin E2 (PGE2)). Such mediators, in turn, alter both the phenotype and action of all immune cells that serve a pathogenic role in the progression of inflammation in eye diseases. Exosomes from MSCs, as natural nano-particles, contain the majority of the bioactive components of parental MSCs and can easily by-pass all biological barriers to reach the target epithelial and immune cells in the eye without interfering with nearby parenchymal cells, thus having no serious side effects. We outlined the most recent research on the molecular mechanisms underlying the therapeutic benefits of MSC and MSC-exosome in the treatment of inflammatory eye diseases in the current article.

The protective role of sulforaphane and Homer1a in retinal ischemia-reperfusion injury: Unraveling the neuroprotective interplay.

AIMS: Retinal ischemia/reperfusion (I/R) injury is a common pathological basis for various ophthalmic diseases. This study aimed to investigate the potential of sulforaphane (SFN) and Homer1a in regulating cell apoptosis induced by retinal I/R injury and to explore the underlying regulatory mechanism between them. MATERIALS AND METHODS: In in vivo experiments, C57BL/6J mice and Homer1flox/-/Homer1a+/-/Nestin-Cre+/- mice were used to construct retinal I/R injury models. In vitro experiments utilized the oxygen-glucose deprivation-reperfusion (OGD/R) injury model with primary retinal ganglion cells (RGCs). The effects of Homer1a and SFN on cell apoptosis were observed through pathological analyses, flow cytometry, and visual electrophysiological assessments. KEY FINDINGS: We discovered that after OGD/R injury, apoptosis of RGCs and intracellular Ca2+ activity significantly increased. However, these changes were reversed upon the addition of SFN, and similar observations were reproduced in in vivo studies. Furthermore, both in vivo and in vitro studies confirmed the upregulation of Homer1a after I/R, which could be further enhanced by the administration of SFN. Moreover, upregulation of Homer1a resulted in a reduction in cell apoptosis and pro-apoptotic proteins, while downregulation of Homer1a had the opposite effect. Flash visual evoked potential, oscillatory potentials, and escape latency measurements in mice supported these findings. Furthermore, the addition of SFN strengthened the neuroprotective effects in the OGD/R + H+ group but weakened them in Homer1flox/-/Homer1a+/-/Nestin-Cre+/- mice. SIGNIFICANCE: These results indicate that Homer1a plays a significant role in the therapeutic potential of sulforaphane for retinal I/R injury, thereby providing a theoretical basis for clinical treatment.

The developing role of extracellular vesicles in autoimmune diseases: special attention to mesenchymal stem cell-derived extracellular vesicles.

Autoimmune diseases are complex, chronic inflammatory conditions initiated by the loss of immunological tolerance to self-antigens. Nowadays, there is no effective and useful therapy for autoimmune diseases, and the existing medications have some limitations due to their nonspecific targets and side effects. During the last few decades, it has been established that mesenchymal stem cells (MSCs) have immunomodulatory functions. It is proposed that MSCs can exert an important therapeutic effect on autoimmune disorders. In parallel with these findings, several investigations have shown that MSCs alleviate autoimmune diseases. Intriguingly, the results of studies have demonstrated that the effective roles of MSCs in autoimmune diseases do not depend on direct intercellular communication but on their ability to release a wide spectrum of paracrine mediators such as growth factors, cytokines and extracellular vehicles (EVs). EVs that range from 50 to 5,000 nm were produced by almost any cell type, and these nanoparticles participate in homeostasis and intercellular communication via the transfer of a broad range of biomolecules such as modulatory proteins, nucleic acids (DNA and RNA), lipids, cytokines, and metabolites. EVs derived from MSCs display the exact properties of MSCs and can be safer and more beneficial than their parent cells. In this review, we will discuss the features of MSCs and their EVs, EVs biogenesis, and their cargos, and then we will highlight the existing discoveries on the impacts of EVs from MSCs on autoimmune diseases such as multiple sclerosis, arthritis rheumatic, inflammatory bowel disease, Type 1 diabetes mellitus, systemic lupus erythematosus, autoimmune liver diseases, Sjögren syndrome, and osteoarthritis, suggesting a potential alternative for autoimmune conditions therapy.

A thorough understanding of the role of lncRNA in prostate cancer pathogenesis; Current knowledge and future research directions.

In the entire world, prostate cancer (PCa) is one of the most common and deadly cancers. Treatment failure is still common among patients, despite PCa diagnosis and treatment improvements. Inadequate early diagnostic markers and the emergence of resistance to conventional therapeutic approaches, particularly androgen-deprivation therapy, are the causes of this. Long non-coding RNAs (lncRNAs), as an essential group of regulatory molecules, have been reported to be dysregulated through prostate tumorigenesis and hold great promise as diagnostic targets. Besides, lncRNAs regulate the malignant features of PCa cells, such as proliferation, invasion, metastasis, and drug resistance. These multifunctional RNA molecules interact with other molecular effectors like miRNAs and transcription factors to modulate various signaling pathways, including AR signaling. This study aimed to compile new knowledge regarding the role of lncRNA through prostate tumorigenesis in terms of their effects on the various malignant characteristics of PCa cells; in light of these characteristics and the significant potential of lncRNAs as diagnostic and therapeutic targets for PCa. AVAILABILITY OF DATA AND MATERIALS: Not applicable.

UV and solar-based photocatalytic degradation of organic pollutants from ceramics industrial wastewater by Fe-doped ZnS nanoparticles.

UV and solar-based photocatalytic degradation of 2,4-dichlorophenol (2,4-DCP) as an organic contaminant in ceramics industry wastewater by ZnS and Fe-doped ZnS NPs was the focus of this research. Nanoparticles were prepared using a chemical precipitation process. The cubic, closed-packed structure of undoped ZnS and Fe-doped ZnS NPs was formed in spherical clusters, according to XRD and SEM investigations. According to optical studies, the optical band gaps of pure ZnS and Fe-doped ZnS nanoparticles are 3.35 and 2.51 eV, respectively, and Fe doping increased the number of carriers with high mobility, improved carrier separation and injection efficiency, and increased photocatalytic activity under UV or visible light. Doping of Fe increased the separation of photogenerated electrons and holes and facilitated charge transfer, according to electrochemical impedance spectroscopy investigations. Photocatalytic degradation studies revealed that in the present pure ZnS and Fe-doped ZnS nanoparticles, 100% treatment of 120 mL of 15 mg/L phenolic compound was obtained after 55- and 45-min UV-irradiation, respectively, and complete treatment was attained after 45 and 35-min solar light irradiation, respectively. Because of the synergistic effects of effective surface area, more effective photo-generated electron and hole separation efficiency, and enhanced electron transfer, Fe-doped ZnS demonstrated high photocatalytic degradation performance. The study of Fe-doped ZnS's practical photocatalytic treatment capability for removing 120 mL of 10 mg/L 2,4-DCP solution made from genuine ceramic industrial wastewater revealed Fe-doped ZnS's excellent photocatalytic destruction of 2,4-DCP from real industrial wastewater.