Flavonoid compounds and their synergistic effects: Promising approaches for the prevention and treatment of psoriasis with emphasis on keratinocytes - A systematic and mechanistic review.

Psoriasis, a chronic autoimmune skin disorder, causes rapid and excessive skin cell growth due to immune system dysfunction. Numerous studies have shown that flavonoids have anti-psoriatic effects by modulating various molecular mechanisms involved in inflammation, cytokine production, keratinocyte proliferation, and more. This study reviewed experimental data reported in scientific literature and used network analysis to identify the potential biological roles of flavonoids' targets in treating psoriasis. 947 records from Web of Sciences, ScienceDirect database, Scopus, PubMed, and Cochrane library were reviewed without limitations until June 26, 2023. 66 articles were included in the systematic review. The ten genes with the highest scores, including interleukin (IL)-10, IL-12A, IL-1ß, IL-6, Tumor necrosis factor-α (TNF-α), Janus kinase 2 (JAK 2), Jun N-terminal kinase (JUN), Proto-oncogene tyrosine-protein kinase Src (SRC), Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and Signal transducer and activator of transcription 3 (STAT3), were identified as the hub genes. KEGG pathway analysis identified connections related to inflammation and autoimmune responses, which are key characteristics of psoriasis. IL-6, STAT3, and JUN's presence in both hub and enrichment genes suggests their important role in flavonoid's effect on psoriasis. This comprehensive study highlights how flavonoids can target biological processes in psoriasis, especially when combined for enhanced effectiveness.

Molecular mechanisms involved in therapeutic effects of natural compounds against cisplatin-induced cardiotoxicity: a review.

Cisplatin is a widely used chemotherapeutic agent for the treatment of various cancers. However, the clinical use of cisplatin is limited by its cardiotoxic side effects. The primary mechanisms implicated in this cardiotoxicity include mitochondrial dysfunction, oxidative stress, inflammation, and apoptotic. Numerous natural compounds (NCs) have been introduced as promising protective factors against cisplatin-mediated cardiac damage. The current review summarized the potential of various NCs as cardioprotective agents at the molecular levels. These compounds exhibited potent antioxidant and anti-inflammatory effects by interaction with the PI3K/AKT, AMPK, Nrf2, NF-κB, and NLRP3/caspase-1/GSDMD pathways. Generally, the modulation of these signaling pathways by NCs represents a promising strategy for improving the therapeutic index of cisplatin by reducing its cardiac side effects.

Exosomes in renal cell carcinoma: challenges and opportunities.

Renal cell carcinoma (RCC) is the most common type of kidney cancer that accounts for approximately 2-3% of adult malignancies. Among the primary treatment methods for this type of cancer are surgery and targeted treatment. Still, due to less than optimal effectiveness, there are problems such as advanced distant metastasis, delayed diagnosis, and drug resistance that continue to plague patients. In recent years, therapeutic advances have increased life expectancy and effective treatment in renal cell carcinoma patients. One of these methods is the use of stem cells. Although the therapeutic effects of stem cells, especially mesenchymal stem cells, are still impressive, today, extracellular vesicles (EVs) as carrying molecules and various mediators in intercellular communications, having a central role in tumorigenesis, metastasis, immune evasion, and drug response, and on the other hand, due to its low immunogenicity and strong regulatory properties of the immune system, has received much attention from researchers and doctors. Despite the increasing interest in exosomes as the most versatile type of EVs, the heterogeneity of their efficacy presents challenges and, on the other hand, exciting opportunities for diagnostic and clinical interventions.In the upcoming article, we will review the various aspects of exosomes' effects in the prevention, treatment, and progress of renal cell carcinoma and also ways to optimize them to strengthen their positive sides.

Management of oxidative stress for cell therapy through combinational approaches of stem cells, antioxidants, and photobiomodulation.

Over the recent decades, stem cell-based therapies have been considered as a beneficial approach for the treatment of various diseases. In these types of therapies, the stem cells and their products are used as treating agents. Despite the helpful efficacy of stem cell-based therapies, there may be challenges. Oxidative stress (OS) is one of these challenges that can affect the therapeutic properties of stem cells. Therefore, it seems that employing strategies for the reduction of OS in combination with stem cell therapy can lead to better results of these therapies. Based on the available evidence, antioxidant therapy and photobiomodulation (PBM) are strategies that can regulate the OS in the cells. Antioxidant therapy is a method in which various antioxidants are used in the therapeutic processes. PBM is also the clinical application of light that gained importance in medicine. Antioxidants and PBM can regulate OS by the effect on mitochondria as an important source of OS in the cells. Considering the importance of OS in pathologic pathways and its effect on the treatment outcomes of stem cells, in the present review first the stem cell therapy and effects of OS on this type of therapy are summarized. Then, antioxidant therapy and PBM as approaches for reducing OS with a focus on mitochondrial function are discussed. Also, a novel combination treatment with the hope of achieving better and more stable outcomes in the treatment process of diseases is proposed.

CD147 and MMPs as key factors in physiological and pathological processes.

Cluster of differentiation 147 (CD147) or extracellular matrix metalloproteinase inducer (EMMPRIN) is a transmembrane glycoprotein that induces the synthesis of matrix metalloproteinases (MMPs). MMPs, as zinc-dependent proteases and versatile enzymes, play critical roles in the degradation of the extracellular matrix (ECM) components, cleaving of the receptors of cellular surfaces, signaling molecules, and other precursor proteins, which may lead to attenuation or activation of such targets. CD147 and MMPs play essential roles in physiological and pathological conditions and any disorder in the expression, synthesis, or function of CD147 and MMPs may be associated with various types of disease. In this review, we have focused on the roles of CD147 and MMPs in some major physiological and pathological processes.

Cerebral microvascular complications associated with SARS-CoV-2 infection: How did it occur and how should it be treated?

Cerebral microvascular disease has been reported as a central feature of the neurological disorders in patients with SARS-CoV-2 infection that may be associated with an increased risk of ischemic stroke. The main pathomechanism in the development of cerebrovascular injury due to SARS-CoV-2 infection can be a consequence of endothelial cell dysfunction as a structural part of the blood-brain barrier (BBB), which may be accompanied by increased inflammatory response and thrombocytopenia along with blood coagulation disorders. In this review, we described the properties of the BBB, the neurotropism behavior of SARS-CoV-2, and the possible mechanisms of damage to the CNS microvascular upon SARS-CoV-2 infection.

The potential roles of amino acids and their major derivatives in the management of multiple sclerosis.

Recently, we reviewed the important role of carbohydrates and lipids metabolism in different clinical aspects of multiple sclerosis (MS) disease. In the current paper, we aimed to review the contribution of amino acids and their major derivatives to different clinical outcomes of the disease, including etiology, pathogenesis, diagnosis, prognosis, and treatment. In this line, Thr (threonine), Phe (phenylalanine), Glu (glutamate), Trp (tryptophan), and Sero (serotonin) are the main examples of biomolecules that have been suggested for MS therapy. It has been concluded that different amino acids and their derivatives might be considered prominent tools for the clinical management of MS disease.

An overview of immune checkpoint therapy in autoimmune diseases.

Immune checkpoint receptors are critical regulators of initiation and termination of effective immune responses as well as maintain self-tolerance. Since the successful use of immune checkpoint inhibitors in cancer immunotherapy, they gained huge interest to be used in autoimmune diseases treatment. Indeed, abatacept (CTLA4-Ig), as immune checkpoint inhibitors has made major advancement in the treatment of rheumatoid arthritis patients who have failed to respond to csDMARDs or TNF-α inhibitor. Over the past decade, an increasing number of new immune checkpoints have been detected and lots of investigations are in progress to address their potential as possible targets of effective novel immunotherapy. Here we focus on the biological functions and structures of these immune checkpoints, their pharmacological mechanisms, pathogenesis, therapeutic effects, and their related adverse events. We also discuss the application of agonistic or antagonistic agents targeting co-inhibitory or co-stimulatory checkpoints for the treatment of autoimmune diseases. Furthermore, we summarize previous and recent clinical trials utilizing these immune checkpoints in autoimmune diseases. Obviously, the characterization of such processes might help to develop more effective therapeutic agents in the future.

HIF-1α in the Crosstalk Between Reactive Oxygen Species and Autophagy Process: A Review in Multiple Sclerosis.

Cellular stress can lead to the production of reactive oxygen species (ROS) while autophagy, as a catabolic pathway, protects the cells against stress. Autophagy in its turn plays a pivotal role in the pathophysiology of multiple sclerosis (MS). In the current review, we first summarized the contribution of ROS and autophagy to MS pathogenesis. Then probable crosstalk between these two pathways through HIF-1α for the first time has been proposed with the hope of employing a better understanding of MS pathophysiology and probable therapeutic approaches.

Carbohydrate and lipid metabolism in multiple sclerosis: Clinical implications for etiology, pathogenesis, diagnosis, prognosis, and therapy.

Multiple sclerosis (MS) is a complicated autoimmune disease characterized by inflammatory and demyelinating events in the central nervous system. The exact etiology and pathogenesis of MS have not been elucidated. However, a set of metabolic changes and their effects on immune cells and neural functions have been explained. This review highlights the contribution of carbohydrates and lipids metabolism to the etiology and pathogenesis of MS. Then, we have proposed a hypothetical relationship between such metabolic changes and the immune system in patients with MS. Finally, the potential clinical implications of these metabolic changes in diagnosis, prognosis, and discovering therapeutic targets have been discussed. It is concluded that research on the pathophysiological alterations of carbohydrate and lipid metabolism may be a potential strategy for paving the way toward MS treatment.

Current Advances in the Use of Nanophytomedicine Therapies for Human Cardiovascular Diseases.

Considering the high prevalence of cardiovascular diseases (CVDs), the primary cause of death during the last several decades, it is necessary to develop proper strategies for the prevention and treatment of CVDs. Given the excessive side effects of current therapies, alternative therapeutic approaches like medicinal plants and natural products are preferred. Lower toxicity, chemical diversity, cost-effectiveness, and proven therapeutic potentials make natural products superior compared to other products. Nanoformulation methods improve the solubility, bioavailability, circulation time, surface area-to-volume ratio, systemic adverse side effects, and drug delivery efficiency of these medications. This study intended to review the functionality of the most recent nanoformulated medicinal plants and/or natural products against various cardiovascular conditions such as hypertension, atherosclerosis, thrombosis, and myocardial infarction. Literature review revealed that curcumin, quercetin, and resveratrol were the most applied natural products, respectively. Combination therapy, conjugation, or fabrication of nanoparticles and nanocarriers improved the applications and therapeutic efficacy of herbal- or natural-based nanoformulations. In the context of CVDs prevention and/or treatment, available data suggest that natural-based nanoformulations are considerably efficient, alone or in blend with other herbal/synthetic medicines. However, clinical trials are mandatory to elucidate the safety, cardioprotective effect, and mechanism of actions of nanophytomedicines.

The Construction and Characterization of 1F5 Chimeric Anti-CD20 Monoclonal Antibodies: An Efficient Splicing by Overlap Extension-polymerase Chain Reaction Technique.

Despite the unparalleled success of anti-CD20-targeted immunotherapy, the currently available mAbs are not sufficiently efficacious in the treatment of lymphoma. 1F5 is one of a panel of anti-CD20 mAbs that was used in the B-cell lymphoma serotherapy. Despite the efficacy of murine 1F5 mAbs in lymphoma patients, the 1F5 chimeric antibodies with human effector functionality are yet to be approved and widely used in the treatment of lymphoma. In this study, the conversion of 1F5 mAb from mouse IgG2a to human-mouse chimeric IgG1 was achieved and the chimeric antibody was partially characterized. We constructed the 1F5 chimeric mouse-human anti-CD20 antibody genes using an efficient Splicing by overlap extension-polymerase chain reaction (SOE-PCR) technique and cloned the chimeric heavy and light genes in pBudCE4.1mammalian expression vector, followed by purification of the expressed chimeric 1F5 mAbs using affinity chromatography. Our investigation also included the biological properties of purified chimeric antibodies. The generated 1F5 chimeric mAbs mediate complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) against Raji and Daudi Burkitt's lymphoma cell lines, which were comparable with rituximab and exhibit superior reduction in cell viability in vitro, compared to rituximab. The current study indicated that the generated chimeric 1F5 mAbs has potential CDC and ADCC activity which was comparable with rituximab whereas it exhibits a superior reduction in cell viability, compared to rituximab. Our work contributes to future studies involving in vivo biological functions and the application of the 1F5 chimeric antibody.

Irreversible thermal inactivation and conformational lock of alpha glucosidase.

In the present work, we studied the structure-activity relationship and kinetics of thermal inactivation of α-glucosidase A (AglA) in a 50 mM potassium phosphate buffer at pH 6.8 using p-nitrophenyl α-d-glucopyranoside (pNPG) as the synthetic substrate following absorbance at 410 nm by UV-Vis spectrophotometer. The interface structure and residual activity plot were analyzed via biochemical measurements by means of conformational lock theory, as well. The thermal inactivation curves were plotted in temperature interval from 30 to 50 °C. Based on experimental and structural data we suggested intermediates during inactivation before the loss of enzyme activity. Arrhenius plot for thermal inactivation rate constant showed biphasic appearance related to before and after 45°C temperature. The contact areas between two subunits were ruptured and unlocked stepwise during dimer dissociation. Cleavage of these areas induced the dissociation of the subunits along with destruction of the active centers and subsequently the loss of activity. It seems that the contact areas interact with active centers by conformational changes involving secondary structural elements.

Natural AMPK Activators in Cardiovascular Disease Prevention.

Cardiovascular diseases (CVD), as a life-threatening global disease, is receiving worldwide attention. Seeking novel therapeutic strategies and agents is of utmost importance to curb CVD. AMP-activated protein kinase (AMPK) activators derived from natural products are promising agents for cardiovascular drug development owning to regulatory effects on physiological processes and diverse cardiometabolic disorders. In the past decade, different therapeutic agents from natural products and herbal medicines have been explored as good templates of AMPK activators. Hereby, we overviewed the role of AMPK signaling in the cardiovascular system, as well as evidence implicating AMPK activators as potential therapeutic tools. In the present review, efforts have been made to compile and update relevant information from both preclinical and clinical studies, which investigated the role of natural products as AMPK activators in cardiovascular therapeutics.

A case-control study on the SNP309T → G and 40-bp Del1518 of the MDM2 gene and a systematic review for MDM2 polymorphisms in the patients with breast cancer.

OBJECTIVE: The current research was conducted to study the association between the SNP309 and del1518 polymorphisms with the breast cancer in the patients with the Kurdish ethnic background from western Iran. Also, a systematic review of the relevant case-control studies on the MDM2 polymorphisms in the patients with breast cancer was performed. METHODOLOGY: Two mL of peripheral blood was taken from 100 patients with breast cancer and 100 healthy individuals. The frequencies of MDM2 SNP309 and del1518 genotypes and alleles were determined using the PCR-RFLP and PCR methods, respectively. RESULTS: The frequency of the TT, TG, and GG of MDM2-SNP309 genotypes in the patients was obtained as 23%, 52%, and 25%, and they were equal to 22%, 40%, and 38% in the control group, respectively. Also, considering the MDM2-del1518 polymorphism, the frequencies of ins/ins, ins/del, and del/del genotypes were equal to 52%, 41%, and 7% in the breast cancer group and they were equal to 62, 30, and 8% in the control group, respectively. Analysis of the results indicated that the GG genotype plays a protective role for the breast cancer in the recessive model (GG vs TT + TG) of SNP309 (χ2  = 3.916, P = .048, and OR = 0.54). CONCLUSION: Our findings revealed that the GG genotype of MDM2-SNP309 can play a protective role in the breast cancer disease. Also, our systematic review indicated that the SNP309, SNP285, and del1518 of MDM2 gene in different populations mostly did not have a significant association with the risk of breast cancer.

Heterologous expression, purification, and refolding of SRY protein: role of L-arginine as analyzed by simulation and practical study.

Escherichia coli is a widely-used cell factory for recombinant protein production, nevertheless, high amount of produced protein is seen in aggregated form. The purpose of this study was to improve the solubility of recombinant bovine sex-determining region Y protein (rbSRY) by exploring the effect of temperature, inducer, and water-arginine mixed solvent. Codon-optimized rbSRY expressed in Rosetta-gami B (DE3) pLysS and purified by NI-NTA His-select affinity chromatography in the native and denaturing conditions. A three-dimensional model of SRY was built and studied through molecular dynamics simulations in water and in the presence of L-arginine as co-solvent. Results indicated the significant effects of temperature and IPTG concentration (P < 0.001) on the solubility of rbSRY. The binding activity of native, inclusion bodies and refolded fractions to anti-rbSRY monoclonal antibody were concentration-dependent (P < 0.001). Based on molecular modeling results, the propensity of fragments in the N-terminal domain to form ß-sheet and the relative instability of α-helices in terminal domains are the probable reasons for the high aggregation potential of SRY, which are mitigated in the presence of L-arginine. Altogether, our rbSRY protein was properly produced and applying appropriate culture conditions could help enhance its solubility, refold inclusion bodies, and improve its activity upon refolding.

The Antimicrobial Peptide, Nisin, Synergistically Enhances the Cytotoxic and Apoptotic Effects of Rituximab Treatment on Human Burkitt's Lymphoma Cell Lines.

BACKGROUND: Non-Hodgkin's lymphomas comprise the most common hematological cancers worldwide and consist of a heterogenous group of malignancies affecting the lymphoid system. Treatment of non-Hodgkin's lymphoma has been significantly enhanced with the addition of Rituximab to the standard chemotherapy regimen. However, even with the advancement of treatment patients continue to relapse and develop resistance to Rituximab, rendering subsequent treatments unsuccessful. The use of novel drugs with unique antitumor mechanisms has gained considerable attention. In this study, we explored the in vitro anti-cancer effects of the combined therapy of Rituximab and Nisin on human Burkitt's lymphoma cells. METHODS: The human Burkitt's lymphoma cells lines, Raji and Daudi, were treated with Nisin, Rituximab, or a combination of the two agents at various concentrations. Cytotoxicity following treatment was determined using cell viability assay. The degree of apoptosis was verified via flow cytometric analysis using FITC annexin V/PI staining. RESULTS: Our findings show that the combined treatment of Rituximab and Nisin results in a more significant reduction in the survival of Raji and Daudi Burkitt's lymphoma cells, compared to Nisin or Rituximab treatment alone. Additionally, our results indicate that Nisin can induce a significant degree of apoptosis in the Burkitt's lymphoma cells compared to the negative controls. However, the addition of Nisin to the Rituximab treatment synergistically enhances the apoptotic antitumor effect. CONCLUSION: This study demonstrates the synergistic antitumor effect of Nisin treatment in vitro to enhance tumor cell apoptosis and the potential value of Nisin as an adjunct therapy in the treatment of lymphoma.

Phytochemicals: Potential Therapeutic Interventions Against Coronavirus-Associated Lung Injury.

Since the outbreak of coronavirus disease 2019 (COVID-19) in December 2019, millions of people have been infected and died worldwide. However, no drug has been approved for the treatment of this disease and its complications, which urges the need for finding novel therapeutic agents to combat. Among the complications due to COVID-19, lung injury has attained special attention. Besides, phytochemicals have shown prominent anti-inflammatory effects and thus possess significant effects in reducing lung injury caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Also, the prevailing evidence reveales the antiviral effects of those phytochemicals, including anti-SARS-CoV activity, which could pave the road in providing suitable lead compounds in the treatment of COVID-19. In the present study, candidate phytochemicals and related mechanisms of action have been shown in the treatment/protection of lung injuries induced by various methods. In terms of pharmacological mechanism, phytochemicals have shown potential inhibitory effects on inflammatory and oxidative pathways/mediators, involved in the pathogenesis of lung injury during COVID-19 infection. Also, a brief overview of phytochemicals with anti-SARS-CoV-2 compounds has been presented.

Nanoformulations of natural products for management of metabolic syndrome.

Metabolic syndrome is a common metabolic disorder which has become a public health challenge worldwide. There has been growing interest in medications including natural products as complementary or alternative choices for common chemical therapeutics regarding their limited side effects and ease of access. Nanosizing these compounds may help to increase their solubility, bioavailability, and promisingly enhance their efficacy. This study, for the first time, provides a comprehensive overview of the application of natural-products-based nanoformulations in the management of metabolic syndrome. Different phytochemicals including curcumin, berberine, Capsicum oleoresin, naringenin, emodin, gymnemic acid, resveratrol, quercetin, scutellarin, stevioside, silybin, baicalin, and others have been nanosized hitherto, and their nanosizing method and effect in treatment and alleviating metabolic syndrome have been reviewed and discussed in this study. It has been discovered that there are several pathways or molecular targets relevant to metabolic disorders which are affected by these compounds. Various natural-based nanoformulations have shown promising effect in treatment of metabolic syndrome, and therefore can be considered as future candidates instead of or in conjunction with pharmaceutical drugs if they pass clinical trials successfully.

Construction and characterization of monoclonal antibodies against the extracellular domain of B-lymphocyte antigen CD20 using DNA immunization method.

To date, several new anti-CD20 monoclonal antibodies (mAbs) have been developed for potential efficacies compared with familiar mAb rituximab. Despite the recent advances in development of anti-CD20 mAbs for the treatment of B cell malignancies, the efforts should be continued to develop novel antibodies with improved properties. However, the development of mAbs against CD20 as a multi-transmembrane protein is challenging due to the difficulty of providing a lipid environment that can maintain native epitopes. To overcome this limitation, we describe a simple and efficient DNA immunization strategy for the construction of a novel anti-CD20 mAb with improved anti-tumour properties. Using a DNA immunization strategy that includes intradermal (i.d.) immunization with naked plasmid DNA encoding the CD20 gene, we generated the hybridoma cell line D4, which secretes functional mAbs against an extracellular epitope of CD20. Immunocytochemistry analysis and a cell-based enzyme-linked immunosorbent assay using a Burkitt's lymphoma cell line showed that D4 mAbs are capable of binding to native extracellular epitopes of CD20. Moreover, the binding specificity of D4 mAbs was determined by western blot analysis. Cell proliferation was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was detected by the annexin V/propidium iodide staining and dye exclusion assay. The results showed that D4 anti-CD20 mAbs produced by DNA immunization exhibit potent growth inhibitory activity and have superior direct B-cell cytotoxicity compared to rituximab. We propose that antibody-induced apoptosis is one of the mechanisms of cell growth inhibition. Taken together, the data reported here open the path to DNA-based immunization for generating pharmacologically active monoclonal antibodies against CD20. In addition, the data support future in vivo animal testing and subsequent procedures to produce a potential therapeutic mAb.