The bioengineered and multifunctional nanoparticles in pancreatic cancer therapy: Bioresponisive nanostructures, phototherapy and targeted drug delivery.

The multidisciplinary approaches in treatment of cancer appear to be essential in term of bringing benefits of several disciplines and their coordination in tumor elimination. Because of the biological and malignant features of cancer cells, they have ability of developing resistance to conventional therapies such as chemo- and radio-therapy. Pancreatic cancer (PC) is a malignant disease of gastrointestinal tract in which chemotherapy and radiotherapy are main tools in its treatment, and recently, nanocarriers have been emerged as promising structures in its therapy. The bioresponsive nanocarriers are able to respond to pH and redox, among others, in targeted delivery of cargo for specific treatment of PC. The loading drugs on the nanoparticles that can be synthetic or natural compounds, can help in more reduction in progression of PC through enhancing their intracellular accumulation in cancer cells. The encapsulation of genes in the nanoparticles can protect against degradation and promotes intracellular accumulation in tumor suppression. A new kind of therapy for cancer is phototherapy in which nanoparticles can stimulate both photothermal therapy and photodynamic therapy through hyperthermia and ROS overgeneration to trigger cell death in PC. Therefore, synergistic therapy of phototherapy with chemotherapy is performed in accelerating tumor suppression. One of the important functions of nanotechnology is selective targeting of PC cells in reducing side effects on normal cells. The nanostructures are capable of being surface functionalized with aptamers, proteins and antibodies to specifically target PC cells in suppressing their progression. Therefore, a specific therapy for PC is provided and future implications for diagnosis of PC is suggested.

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.

Advances in mesenchymal stem/stromal cell-based therapy and their extracellular vesicles for skin wound healing.

Wound healing is a dynamic and complicated process containing overlapping phases. Presently, definitive therapy is not available, and the investigation into optimal wound care is influenced by the efficacy and cost-effectiveness of developing therapies. Accumulating evidence demonstrated the potential role of mesenchymal stem/stromal cell (MSC) therapy in several tissue injuries and diseases due to their high proliferation and differentiation abilities along with an easy collection procedure, low tumorigenesis, and immuno-privileged status. MSCs have also accelerated wound repair in all phases through their advantageous properties, such as accelerating wound closure, improving re-epithelialization, elevating angiogenesis, suppressing inflammation, and modulating extracellular matrix (ECM) remodeling. In addition, the beneficial therapeutic impacts of MSCs are largely associated with their paracrine functions, including extracellular vesicles (EVs). Exosomes and microvesicles are the two main subgroups of EVs. These vesicles are heterogeneous bilayer membrane structures that contain several proteins, lipids, and nucleic acids. EVs have emerged as a promising alternative to stem cell-based therapies because of their lower immunogenicity, tumorigenicity, and ease of management. MSCs from various sources have been widely investigated in skin wound healing and regeneration. Considering these features, in this review, we highlighted recent studies that the investigated therapeutic potential of various MSCs and MSC-EVs in skin damages and wounds.

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.

Exosomal non-coding RNAs' role in immune regulation and potential therapeutic applications.

Exosomes are now significant players in both healthy and unhealthy cell-to-cell communication. Exosomes can mediate immune activation or immunosuppression, which can influence the growth of tumors. Exosomes affect the immune responses to malignancies in various ways by interacting with tumor cells and the environment around them. Exosomes made by immune cells can control the growth, metastasis, and even chemosensitivity of tumor cells. In contrast, exosomes produced by cancer cells can encourage immune responses that support the tumor. Exosomes carry circular RNAs, long non-coding RNAs, and microRNAs (miRNAs), all involved in cell-to-cell communication. In this review, we focus on the most recent findings concerning the role of exosomal miRNAs, lncRNAs, and circRNAs in immune modulation and the potential therapeutic implications of these discoveries.

A Mendelian Randomization Analysis Investigates Causal Associations between Inflammatory Bowel Diseases and Variable Risk Factors.

The question of whether variable risk factors and various nutrients are causally related to inflammatory bowel diseases (IBDs) has remained unanswered so far. Thus, this study investigated whether genetically predicted risk factors and nutrients play a function in the occurrence of inflammatory bowel diseases, including ulcerative colitis (UC), non-infective colitis (NIC), and Crohn's disease (CD), using Mendelian randomization (MR) analysis. Utilizing the data of genome-wide association studies (GWASs) with 37 exposure factors, we ran Mendelian randomization analyses based on up to 458,109 participants. Univariable and multivariable MR analyses were conducted to determine causal risk factors for IBD diseases. Genetic predisposition to smoking and appendectomy as well as vegetable and fruit intake, breastfeeding, n-3 PUFAs, n-6 PUFAs, vitamin D, total cholesterol, whole-body fat mass, and physical activity were related to the risk of UC (p < 0.05). The effect of lifestyle behaviors on UC was attenuated after correcting for appendectomy. Genetically driven smoking, alcohol consumption, appendectomy, tonsillectomy, blood calcium, tea intake, autoimmune diseases, type 2 diabetes, cesarean delivery, vitamin D deficiency, and antibiotic exposure increased the risk of CD (p < 0.05), while vegetable and fruit intake, breastfeeding, physical activity, blood zinc, and n-3 PUFAs decreased the risk of CD (p < 0.05). Appendectomy, antibiotics, physical activity, blood zinc, n-3 PUFAs, and vegetable fruit intake remained significant predictors in multivariable MR (p < 0.05). Besides smoking, breastfeeding, alcoholic drinks, vegetable and fruit intake, vitamin D, appendectomy, and n-3 PUFAs were associated with NIC (p < 0.05). Smoking, alcoholic drinks, vegetable and fruit intake, vitamin D, appendectomy, and n-3 PUFAs remained significant predictors in multivariable MR (p < 0.05). Our results provide new and comprehensive evidence demonstrating that there are approving causal effects of various risk factors on IBDs. These findings also supply some suggestions for the treatment and prevention of these diseases.

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.

Identification of novel candidate targets for suppressing ovarian cancer progression through IL-33/ST2 axis components using the system biology approach.

Background: Cancer-associated fibroblasts (CAFs) of ovarian cancer (OvC) are the most prevalent element of the tumor microenvironment (TM). By promoting angiogenesis, immunological suppression, and invasion, CAFs speed up the growth of tumors by changing the extracellular matrix's structure and composition and/or initiating the epithelial cells (EPT). IL-33/ST2 signaling has drawn a lot of attention since it acts as a pro-tumor alarmin and encourages spread by altering TM. Methods: Differentially expressed genes (DEGs) of the OvC tumor microenvironment were found in the GEO database, qRT-PCR, western blotting, and immunohistochemistry, and their presence and changes in healthy and tumor tissue content were examined. Primary cultures of healthy fibroblasts and CAFs obtained from healthy and tumor tissues retrieved from OvC samples were used for in vitro and in vivo investigations. Cultured primary human CAFs were utilized to investigate the regulation and the IL-33/ST2 axis role in the inflammation reactions. Results: Although ST2 and IL-33 expression was detected in both epithelial (EPT) and fibroblast cells of ovarian cancer, they are more abundant in CAFs. Lipopolysaccharides, serum amyloid A1, and IL-1ß, the inflammatory mediators, could all induce IL-33 expression through NF-κB activation in human CAFs. In turn, via the ST2 receptor, IL-33 affected the production of IL-6, IL-1ß, and PTGS2 in human CAFs via the MAPKs-NF-κB pathway. Conclusion: Our findings suggest that IL-33/ST2 is affected by the interaction of CAFs and epithelial cells inside the tumor microenvironment. Activation of this axis leads to increased expression of inflammatory factors in tumor CAFs and EPT cells. Therefore, targeting the IL-33/ST2 axis could have potential value in the prevention of OvC progression.

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.

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.

Designing Effective Multi-Target Drugs and Identifying Biomarkers in Recurrent Pregnancy Loss (RPL) Using In Vivo, In Vitro, and In Silico Approaches.

Recurrent pregnancy loss (RPL) occurs in approximately 5% of women. Despite an abundance of evidence, the molecular mechanism of RPL's pathology remains unclear. Here, we report the protective role of polo-like kinase 1 (PLK1) during RPL. We aimed to construct an RPL network utilizing GEO datasets and identified hub high-traffic genes. We also investigated whether the expressions of PLK1 were altered in the chorionic villi collected from women with RPL compared to those from healthy early pregnant women. Gene expression differences were evaluated using both pathway and gene ontology (GO) analyses. The identified genes were validated using in vivo and in vitro models. Mice with PLK1-overexpression and PLK1-knockdown in vitro models were produced by transfecting certain plasmids and si-RNA, respectively. The apoptosis in the chorionic villi, mitochondrial function, and NF-κB signaling activity was evaluated. To suppress the activation of PLK1, the PLK1 inhibitor BI2536 was administered. The HTR-8/SVneo and JEG-3 cell lines were chosen to establish an RPL model in vitro. The NF-κB signaling, Foxo signaling, PI3K/AKT, and endometrial cancer signaling pathways were identified via the RPL regulatory network. The following genes were identified: PLK1 as hub high-traffic gene and MMP2, MMP9, BAX, MFN1, MFN2, FOXO1, OPA1, COX15, BCL2, DRP1, FIS1, TRAF2, and TOP2A. Clinical samples were examined, and the results demonstrated that RPL patients had tissues with decreased PLK1 expression in comparison to women with normal pregnancies (p < 0.01). In vitro, PLK1 knockdown induced the NF-κB signaling pathway and apoptosis activation while decreasing cell invasion, migration, and proliferation (p < 0.05). Furthermore, the in vivo model proved that cell mitochondrial function and chorionic villi development are both hampered by PLK1 suppression. Our findings revealed that the PLK1/TRAF2/NF-κB axis plays a crucial role in RPL-induced chorionic villi dysfunction by regulating mitochondrial dynamics and apoptosis and might be a potential therapeutic target in the clinic.

A Feature Extraction Using Probabilistic Neural Network and BTFSC-Net Model with Deep Learning for Brain Tumor Classification.

BACKGROUND AND OBJECTIVES: Brain Tumor Fusion-based Segments and Classification-Non-enhancing tumor (BTFSC-Net) is a hybrid system for classifying brain tumors that combine medical image fusion, segmentation, feature extraction, and classification procedures. MATERIALS AND METHODS: to reduce noise from medical images, the hybrid probabilistic wiener filter (HPWF) is first applied as a preprocessing step. Then, to combine robust edge analysis (REA) properties in magnetic resonance imaging (MRI) and computed tomography (CT) medical images, a fusion network based on deep learning convolutional neural networks (DLCNN) is developed. Here, the brain images' slopes and borders are detected using REA. To separate the sick region from the color image, adaptive fuzzy c-means integrated k-means (HFCMIK) clustering is then implemented. To extract hybrid features from the fused image, low-level features based on the redundant discrete wavelet transform (RDWT), empirical color features, and texture characteristics based on the gray-level cooccurrence matrix (GLCM) are also used. Finally, to distinguish between benign and malignant tumors, a deep learning probabilistic neural network (DLPNN) is deployed. RESULTS: according to the findings, the suggested BTFSC-Net model performed better than more traditional preprocessing, fusion, segmentation, and classification techniques. Additionally, 99.21% segmentation accuracy and 99.46% classification accuracy were reached using the proposed BTFSC-Net model. CONCLUSIONS: earlier approaches have not performed as well as our presented method for image fusion, segmentation, feature extraction, classification operations, and brain tumor classification. These results illustrate that the designed approach performed more effectively in terms of enhanced quantitative evaluation with better accuracy as well as visual performance.