Emicizumab as a Promising Form of Therapy for Type A Hemophilia - A Review of Current Knowledge from Clinical Trials.

Hemophilia is a plasma bleeding disorder characterized by a deficiency of certain blood clotting factors. The most common forms of this disease, i.e., type A and type B, affect approximately 400,000 people worldwide. Without appropriate treatment ensuring the proper coagulation cascade, this disease may lead to serious disability. Minimizing patient discomfort is possible via replacement therapy, consisting of the substitution of a missing coagulation factor via intravenous administration. Frequent medication and the risk related to factor inhibitors are significant disadvantages, necessitating the improvement of current therapies or the development of novel ones. This review examines the humanized bispecific antibody Emicizumab which ensures hemostasis by mimicking the action of the coagulation factor VIII, a deficiency of which causes type A hemophilia. The paper outlines the topic and then summarizes available clinical trials on Emicizumab in type A hemophilia. Several interventional clinical trials have found Emicizumab to be effective in decreasing bleeding episodes and raising patient satisfaction among various hemophilia A populations. Current Emicizumab-related trials are forecast to be completed between 2024 and 2030, and in addition to congenital hemophilia A, the trials cover acquired hemophilia A and patients playing sports. Providing a more comprehensive understanding of Emicizumab may revolutionize the management of hemophilia type A and improve quality of life. Conclusively, Emicizumab is a gentler therapy owing to subcutaneous delivery and fewer injections, which reduces injection-site reactions and makes therapy less burdensome, ultimately decreasing hospital visits and indirect costs.

Britanin - a beacon of hope against gastrointestinal tumors?

Britanin is a bioactive sesquiterpene lactone known for its potent anti-inflammatory and anti-oxidant properties. It also exhibits significant anti-tumor activity, suppressing tumor growth in vitro and in vivo. The current body of research on Britanin includes thirty papers predominantly related to neoplasms, the majority of which are gastrointestinal tumors that have not been summarized before. To drive academic debate, the present paper reviews the available research on Britanin in gastrointestinal tumors. It also outlines novel research directions using data not directly concerned with the digestive system, but which could be adopted in future gastrointestinal research. Britanin was found to counteract liver, colorectal, pancreatic, and gastric tumors, by regulating proliferation, apoptosis, autophagy, immune response, migration, and angiogenesis. As confirmed in pancreatic, gastric, and liver cancer, its most commonly noted molecular effects include nuclear factor kappa B and B-cell lymphoma 2 downregulation, as well as Bcl-2-associated X protein upregulation. Moreover, it has been found to induce the Akt kinase and Forkhead box O1 axis, activate the AMP-activated protein kinase pathway, elevate interleukin-2 and peroxisome proliferator-activated receptor-γ levels, reduce interleukin-10, as well as downregulate matrix metalloproteinase-9, Twist family bHLH transcription factor 1, and cyclooxygenase-2. It also inhibits Myc-HIF1α interaction and programmed death ligand 1 transcription by interrupting the Ras/ RAF/MEK/ERK pathway and mTOR/P70S6K/4EBP1 signaling. Future research should aim to unravel the link between Britanin and acetylcholinesterase, mast cells, osteolysis, and ischemia, as compelling data have been provided by studies outside the gastrointestinal context. Since the cytotoxicity of Britanin on noncancerous cells is significantly lower than that on tumor cells, while still being effective against the latter, further in-depth studies with the use of animal models are merited. The compound exhibits pleiotropic biological activity and offers considerable promise as an anti-cancer agent, which may address the current paucity of treatment options and high mortality rate among patients with gastrointestinal tumors.

Biomedical Trends in Stimuli-Responsive Hydrogels with Emphasis on Chitosan-Based Formulations.

Biomedicine is constantly evolving to ensure a significant and positive impact on healthcare, which has resulted in innovative and distinct requisites such as hydrogels. Chitosan-based formulations stand out for their versatile utilization in drug encapsulation, transport, and controlled release, which is complemented by their biocompatibility, biodegradability, and non-immunogenic nature. Stimuli-responsive hydrogels, also known as smart hydrogels, have strictly regulated release patterns since they respond and adapt based on various external stimuli. Moreover, they can imitate the intrinsic tissues' mechanical, biological, and physicochemical properties. These characteristics allow stimuli-responsive hydrogels to provide cutting-edge, effective, and safe treatment. Constant progress in the field necessitates an up-to-date summary of current trends and breakthroughs in the biomedical application of stimuli-responsive chitosan-based hydrogels, which was the aim of this review. General data about hydrogels sensitive to ions, pH, redox potential, light, electric field, temperature, and magnetic field are recapitulated. Additionally, formulations responsive to multiple stimuli are mentioned. Focusing on chitosan-based smart hydrogels, their multifaceted utilization was thoroughly described. The vast application spectrum encompasses neurological disorders, tumors, wound healing, and dermal infections. Available data on smart chitosan hydrogels strongly support the idea that current approaches and developing novel solutions are worth improving. The present paper constitutes a valuable resource for researchers and practitioners in the currently evolving field.

Senescent adipocytes and type 2 diabetes - current knowledge and perspective concepts.

Among civilization diseases, the number of individuals suffering from type 2 diabetes (T2DM) is expected to increase to more than a billion in less than 20 years, which is associated with, e.g., populational aging, poor diet, sedentary lifestyle, genetic predispositions, and immunological factors. T2DM affects many organs and is characterized by insulin resistance, high glucose levels, and adipocyte dysfunction, which are related to senescence. Although this type of cellular aging has beneficial biological functions, it can also act unfavorable since senescent adipocytes resist apoptosis, enhance cytokine secretion, downregulate cell identity genes, and acquire the senescence-associated secretory phenotype that renders a more oxidative environment. Opposing T2DM is possible via a wide variety of senotherapies, including senolytics and senomorphics; nevertheless, further research is advised to expand therapeutic possibilities and benefits. Consequences that ought to be deeply researched include secretory phenotype, chronic inflammation, increasing insulin resistance, as well as impairment of adipogenesis and functioning of adipocyte cells. Herein, despite reviewing T2DM and fat tissue senescence, we summarized the latest adipocyte-related anti-diabetes solutions and suggested further research directions.

Synthesis, Computational, and Anticancer In Vitro Investigations of Aminobenzylnaphthols Derived from 2-Naphtol, Benzaldehydes, and α-Aminoacids via the Betti Reaction.

Multicomponent reactions have emerged as an important approach for the synthesis of diverse and complicated chemical compounds. They have various advantages over two-component reactions, including the convenience of one-pot procedures and the ability to modify the structure of agents. Here, we employed in vitro and in silico studies to explore the anticancer potential of novel aminobenzylnaphthols derived from the Betti reaction (MMZ compounds). MTT assay was used to explore the cytotoxic activity of the compounds in pancreatic (BxPC-3 cells) and colorectal (HT-29) cancer cell lines or normal human lung fibroblasts (WI-38 cells). Proapoptotic properties of two derivatives MMZ-45AA and MMZ-140C were explored using AO/EB and annexin V-FITC/PI staining. In silico studies including ADMET profiling, molecular target prediction, docking, and dynamics were employed. The compounds exhibited cytotoxic properties and showed proapoptotic properties in respective IC50 concentrations. As indicated by in silico investigations, anticancer activity of MMZs can be attributed to the inhibition of ADORA1, CDK2, and TRIM24. Furthermore, compounds exhibited favorable ADMET properties. MMZs constitute an interesting scaffold for the potential development of new anticancer agents.

In Vitro and In Silico Investigation of BCI Anticancer Properties and Its Potential for Chemotherapy-Combined Treatments.

BACKGROUND: DUSP6 phosphatase serves as a negative regulator of MAPK kinases involved in numerous cellular processes. BCI has been identified as a potential allosteric inhibitor with anticancer activity. Our study was designed to test the anticancer properties of BCI in colon cancer cells, to characterize the effect of this compound on chemotherapeutics such as irinotecan and oxaliplatin activity, and to identify potential molecular targets for this inhibitor. METHODS: BCI cytotoxicity, proapoptotic activity, and cell cycle distribution were investigated in vitro on three colon cancer cell lines (DLD1, HT-29, and Caco-2). In silico investigation was prepared to assess BCI drug-likeness and identify potential molecular targets. RESULTS: The exposure of colorectal cancer cells with BCI resulted in antitumor effects associated with cell cycle arrest and induction of apoptosis. BCI exhibited strong cytotoxicity on DLD1, HT-29, and Caco-2 cells. BCI showed no significant interaction with irinotecan, but strongly attenuated the anticancer activity of oxaliplatin when administered together. Analysis of synergy potential further confirmed the antagonistic interaction between these two compounds. In silico investigation indicated CDK5 as a potential new target of BCI. CONCLUSIONS: Our studies point to the anticancer potential of BCI but note the need for a precise mechanism of action.

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides as an Important Scaffold for Anticancer Drug Discovery-In Vitro and In Silico Evaluation.

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides (MM-compounds) are a relatively new class of heterocyclic compounds that exhibit a wide variety of biological actions, including anticancer properties. Here, we used caspase enzyme activity assays, flow cytometry analysis of propidium iodide (PI)-stained cells, and a DNA laddering assay to investigate the mechanisms of cell death triggered by the MM-compounds (MM134, -6, -7, and -9). Due to inconsistent results in caspase activity assays, we have performed a bromodeoxyuridine (BrdU) incorporation assay, colony formation assay, and gene expression profiling. The compounds' cytotoxic and pro-oxidative properties were also assessed. Additionally, computational studies were performed to demonstrate the potential of the scaffold for future drug discovery endeavors. MM-compounds exhibited strong micromolar (0.06-0.35 µM) anti-proliferative and pro-oxidative activity in two cancer cell lines (BxPC-3 and PC-3). Activation of caspase 3/7 was observed following a 24-h treatment of BxPC-3 cells with IC50 concentrations of MM134, -6, and -9 compounds. However, no DNA fragmentation characteristics for apoptosis were observed in the flow cytometry and DNA laddering analysis. Gene expression data indicated up-regulation of BCL10, GADD45A, RIPK2, TNF, TNFRSF10B, and TNFRSF1A (TNF-R1) following treatment of cells with the MM134 compound. Moreover, in silico studies indicated AKT2 kinase as the primary target of compounds. MM-compounds exhibit strong cytotoxic activity with pro-oxidative, pro-apoptotic, and possibly pro-necroptotic properties that could be employed for further drug discovery approaches.

Insights into the Role of LncRNAs and miRNAs in Glioma Progression and Their Potential as Novel Therapeutic Targets.

Accumulating evidence supports that both long non-coding and micro RNAs (lncRNAs and miRNAs) are implicated in glioma tumorigenesis and progression. Poor outcome of gliomas has been linked to late-stage diagnosis and mostly ineffectiveness of conventional treatment due to low knowledge about the early stage of gliomas, which are not possible to observe with conventional diagnostic approaches. The past few years witnessed a revolutionary advance in biotechnology and neuroscience with the understanding of tumor-related molecules, including non-coding RNAs that are involved in the angiogenesis and progression of glioma cells and thus are used as prognostic biomarkers as well as novel therapeutic targets. The emerging research on lncRNAs and miRNAs highlights their crucial role in glioma progression, offering new insights into the disease. These non-coding RNAs hold significant potential as novel therapeutic targets, paving the way for innovative treatment approaches against glioma. This review encompasses a comprehensive discussion about the role of lncRNAs and miRNAs in gene regulation that is responsible for the promotion or the inhibition of glioma progression and collects the existing links between these key cancer-related molecules.

Epigallocatechin-3-Gallate Therapeutic Potential in Cancer: Mechanism of Action and Clinical Implications.

Cellular signaling pathways involved in the maintenance of the equilibrium between cell proliferation and apoptosis have emerged as rational targets that can be exploited in the prevention and treatment of cancer. Epigallocatechin-3-gallate (EGCG) is the most abundant phenolic compound found in green tea. It has been shown to regulate multiple crucial cellular signaling pathways, including those mediated by EGFR, JAK-STAT, MAPKs, NF-κB, PI3K-AKT-mTOR, and others. Deregulation of the abovementioned pathways is involved in the pathophysiology of cancer. It has been demonstrated that EGCG may exert anti-proliferative, anti-inflammatory, and apoptosis-inducing effects or induce epigenetic changes. Furthermore, preclinical and clinical studies suggest that EGCG may be used in the treatment of numerous disorders, including cancer. This review aims to summarize the existing knowledge regarding the biological properties of EGCG, especially in the context of cancer treatment and prophylaxis.

The artificial oxygen carrier erythrocruorin-characteristics and potential significance in medicine.

The diminishing supply and increasing costs of donated blood have motivated research into novel hemoglobin-based oxygen carriers (HBOCs) that can serve as red blood cell (RBC) substitutes. HBOCs are versatile agents that can be used in the treatment of hemorrhagic shock. However, many of the RBC substitutes that are based on mammalian hemoglobins have presented key limitations such as instability and toxicity. In contrast, erythrocruorins (Ecs) are other types of HBOCs that may not suffer these disadvantages. Ecs are giant metalloproteins found in annelids, crustaceans, and some other invertebrates. Thus far, the Ecs of Lumbricus terrestris (LtEc) and Arenicola marina (AmEc) are the most thoroughly studied. Based on data from preclinical transfusion studies, it was found that these compounds not only efficiently transport oxygen and have anti-inflammatory properties, but also can be modified to further increase their effectiveness. This literature review focuses on the structure, properties, and application of Ecs, as well as their advantages over other HBOCs. Development of methods for both the stabilization and purification of erythrocruorin could confer to enhanced access to artificial blood resources.

Recent Advances in Molecular Mechanisms of Cancer Immunotherapy.

Cancer is among the current leading causes of death worldwide, despite the novel advances that have been made toward its treatment, it is still considered a major public health concern. Considering both the serious impact of cancer on public health and the significant side effects and complications of conventional therapeutic options, the current strategies towards targeted cancer therapy must be enhanced to avoid undesired toxicity. Cancer immunotherapy has become preferable among researchers in recent years compared to conventional therapeutic options, such as chemotherapy, surgery, and radiotherapy. The understanding of how to control immune checkpoints, develop therapeutic cancer vaccines, genetically modify immune cells as well as enhance the activation of antitumor immune response led to the development of novel cancer treatments. In this review, we address recent advances in cancer immunotherapy molecular mechanisms. Different immunotherapeutic approaches are critically discussed, focusing on the challenges, potential risks, and prospects involving their use.

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides as Novel Potential Anticancer Agents: Apoptosis, Oxidative Stress, and Cell Cycle Analysis.

The current study continues the evaluation of the anticancer potential of three de novo synthesized pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides-MM129, MM130, and MM131-against human cancer cells of HeLa, HCT 116, PC-3, and BxPC-3 lines. The pro-apoptotic activity of the investigated sulfonamides was shown by observations of changes in the mitochondrial transmembrane potential of the tested cells, externalization of phosphatidylserine on the cellular membrane surface, and cell morphology in microscopic imaging. The computational studies have shown that MM129 exhibited the lowest binding energy values when docked against CDK enzymes. In addition, the highest stability was shown for complexes formed between MM129 and CDK5/8 enzymes. All examined compounds induced cell cycle arrest in the G0/G1 phase in the BxPC-3 and PC-3 cells and simultaneously caused the accumulation of cells in the S phase in the HCT 116 cells. In addition, the increase in the subG1 fraction was observed in PC-3 and HeLa cells. The application of a fluorescent H2DCFDA probe revealed the high pro-oxidative properties of the tested triazine derivatives, especially MM131. In conclusion, the obtained results suggest that MM129, MM130, and MM131 exhibited strong pro-apoptotic properties towards investigated cells, mainly against the HeLa and HCT 116 cell lines, and high pro-oxidative potential as well. Moreover, it is suggested that the anticancer activity of the tested compounds may be associated with their ability to inhibit CDK enzymes activities.

Substances of Natural Origin in Medicine: Plants vs. Cancer.

Continuous monitoring of the population's health is the main method of learning about disease prevalence. National and international data draw attention to the persistently high rates of cancer incidence. This necessitates the intensification of efforts aimed at developing new, more effective chemotherapeutic and chemopreventive drugs. Plants represent an invaluable source of natural substances with versatile medicinal properties. Multidirectional activities exhibited by natural substances and their ability to modulate key signaling pathways, mainly related to cancer cell death, make these substances an important research direction. This review summarizes the information regarding plant-derived chemotherapeutic drugs, including their mechanisms of action, with a special focus on selected anti-cancer drugs (paclitaxel, irinotecan) approved in clinical practice. It also presents promising plant-based drug candidates currently being tested in clinical and preclinical trials (betulinic acid, resveratrol, and roburic acid).

PD-1/PD-L1 and DNA Damage Response in Cancer.

The application of immunotherapy for cancer treatment is rapidly becoming more widespread. Immunotherapeutic agents are frequently combined with various types of treatments to obtain a more durable antitumor clinical response in patients who have developed resistance to monotherapy. Chemotherapeutic drugs that induce DNA damage and trigger DNA damage response (DDR) frequently induce an increase in the expression of the programmed death ligand-1 (PD-L1) that can be employed by cancer cells to avoid immune surveillance. PD-L1 exposed on cancer cells can in turn be targeted to re-establish the immune-reactive tumor microenvironment, which ultimately increases the tumor's susceptibility to combined therapies. Here we review the recent advances in how the DDR regulates PD-L1 expression and point out the effect of etoposide, irinotecan, and platinum compounds on the anti-tumor immune response.

Doxorubicin-An Agent with Multiple Mechanisms of Anticancer Activity.

Doxorubicin (DOX) constitutes the major constituent of anti-cancer treatment regimens currently in clinical use. However, the precise mechanisms of DOX's action are not fully understood. Emerging evidence points to the pleiotropic anticancer activity of DOX, including its contribution to DNA damage, reactive oxygen species (ROS) production, apoptosis, senescence, autophagy, ferroptosis, and pyroptosis induction, as well as its immunomodulatory role. This review aims to collect information on the anticancer mechanisms of DOX as well as its influence on anti-tumor immune response, providing a rationale behind the importance of DOX in modern cancer therapy.

Genotoxicity of Novel Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides in Normal and Cancer Cells In Vitro.

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides constitute a novel group of heterocyclic compounds with broad biological activities including anticancer properties. The compounds investigated in this study (MM134, -6, -7, and 9) were found to have antiproliferative activity against BxPC-3 and PC-3 cancer cell lines in micromolar concentrations (IC50 0.11-0.33 µM). Here, we studied the genotoxic potential of the tested compounds with alkaline and neutral comet assays, accompanied by immunocytochemical detection of phosphorylated γH2AX. We found that pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides induce significant levels of DNA damage in BxPC-3 and PC-3 cells without causing genotoxic effects in normal human lung fibroblasts (WI-38) when used in their respective IC50 concentrations (except for MM134) and showed a dose-dependent increase in DNA damage following 24 h incubation of tested cancer cells with these agents. Furthermore, the influence of MM compounds on DNA damage response (DDR) factors was assessed using molecular docking and molecular dynamics simulation.

Discovery of adapalene and dihydrotachysterol as antiviral agents for the Omicron variant of SARS-CoV-2 through computational drug repurposing.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been significantly paralyzing the societies, economies and health care systems around the globe. The mutations on the genome of SARS-CoV-2 led to the emergence of new variants, some of which are classified as "variant of concern" due to their increased transmissibility and better viral fitness. The Omicron variant, as the latest variant of concern, dominated the current COVID-19 cases all around the world. Unlike the previous variants of concern, the Omicron variant has 15 mutations on the receptor-binding domain of spike protein and the changes in the key amino acid residues of S protein can enhance the binding ability of the virus to hACE2, resulting in a significant increase in the infectivity of the Omicron variant. Therefore, there is still an urgent need for treatment and prevention of variants of concern, particularly for the Omicron variant. In this study, an in silico drug repurposing was conducted through the molecular docking of 2890 FDA-approved drugs against the mutant S protein of SARS-CoV-2 for Omicron variant. We discovered promising drug candidates for the inhibition of alarming Omicron variant such as quinestrol, adapalene, tamibarotene, and dihydrotachysterol. The stability of ligands complexed with the mutant S protein was confirmed using MD simulations. The lead compounds were further evaluated for their potential use and side effects based on the current literature. Particularly, adapalene, dihydrotachysterol, levocabastine and bexarotene came into prominence due to their non-interference with the normal physiological processes. Therefore, this study suggests that these approved drugs can be considered as drug candidates for further in vitro and in vivo studies to develop new treatment options for the Omicron variant of SARS-CoV-2.

AP-2δ Is the Most Relevant Target of AP-2 Family-Focused Cancer Therapy and Affects Genome Organization.

Formerly hailed as "undruggable" proteins, transcription factors (TFs) are now under investigation for targeted therapy. In cancer, this may alter, inter alia, immune evasion or replicative immortality, which are implicated in genome organization, a process that accompanies multi-step tumorigenesis and which frequently develops in a non-random manner. Still, targeting-related research on some TFs is scarce, e.g., among AP-2 proteins, which are known for their altered functionality in cancer and prognostic importance. Using public repositories, bioinformatics tools, and RNA-seq data, the present study examined the ligandability of all AP-2 members, selecting the best one, which was investigated in terms of mutations, targets, co-activators, correlated genes, and impact on genome organization. AP-2 proteins were found to have the conserved "TF_AP-2" domain, but manifested different binding characteristics and evolution. Among them, AP-2δ has not only the highest number of post-translational modifications and extended strands but also contains a specific histidine-rich region and cleft that can receive a ligand. Uterine, colon, lung, and stomach tumors are most susceptible to AP-2δ mutations, which also co-depend with cancer hallmark genes and drug targets. Considering AP-2δ targets, some of them were located proximally in the spatial genome or served as co-factors of the genes regulated by AP-2δ. Correlation and functional analyses suggested that AP-2δ affects various processes, including genome organization, via its targets; this has been eventually verified in lung adenocarcinoma using expression and immunohistochemistry data of chromosomal conformation-related genes. In conclusion, AP-2δ affects chromosomal conformation and is the most appropriate target for cancer therapy focused on the AP-2 family.

Computational Bioprospecting Guggulsterone against ADP Ribose Phosphatase of SARS-CoV-2.

Coronavirus Disease-2019 (COVID-19) is a highly contagious disease caused by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). The World Health Organization (WHO) classified the disease a as global public health hazard on 11 March 2020. Currently, there are no adequate measures to combat viral infections, including COVID-19, and the medication guidelines for the management of COVID-19 are dependent on previous findings from SARS-CoV and MERS-CoV research. Natural products have achieved widespread acceptance around the world as a means of enhancing healthcare and disease prevention. Plants are a potential source of antiviral factors such as flavonoids, phenolic acids, terpenoids, and others. Some of these agents exhibit a broad spectrum of antiviral activity. This study aimed to screen herbal leads for possible inhibitors of the SARS-CoV-2 ADP Ribose Phosphatase enzyme (ARP). Guggulsterone was found to be highly stabilized within the active site of the viral ARP enzyme by molecular dynamic simulation with very little fluctuation throughout the simulation timeframe of 100 ns. Thus, guggulsterone can be further used to develop a safe and competent medication for evolving therapy against SARS-CoV-2 in post-preclinical and clinical trials.