IL-17 in type II diabetes mellitus (T2DM) immunopathogenesis and complications; molecular approaches.

Chronic inflammation has long been considered the characteristic feature of type II diabetes mellitus (T2DM) Immunopathogenesis. Pro-inflammatory cytokines are considered the central drivers of the inflammatory cascade leading to ß-cell dysfunction and insulin resistance (IR), two major pathologic events contributing to T2DM. Analyzing the cytokine profile of T2DM patients has also introduced interleukin-17 (IL-17) as an upstream regulator of inflammation, regarding its role in inducing the nuclear factor-kappa B (NF-κB) pathway. In diabetic tissues, IL-17 induces the expression of inflammatory cytokines and chemokines. Hence, IL-17 can deteriorate insulin signaling and ß-cell function by activating the JNK pathway and inducing infiltration of neutrophils into pancreatic islets, respectively. Additionally, higher levels of IL-17 expression in patients with diabetic complications compared to non-complicated individuals have also proposed a role for IL-17 in T2DM complications. Here, we highlight the role of IL-17 in the Immunopathogenesis of T2DM and corresponding pathways, recent advances in preclinical and clinical studies targeting IL-17 in T2DM, and corresponding challenges and possible solutions.

The new era of immunological treatment, last updated and future consideration of CAR T cell-based drugs.

Cancer treatment is one of the fundamental challenges in clinical setting, especially in relapsed/refractory malignancies. The novel immunotherapy-based treatments bring new hope in cancer therapy and achieve various treatment successes. One of the distinguished ways of cancer immunotherapy is adoptive cell therapy, which utilizes genetically modified immune cells against cancer cells. Between different methods in ACT, the chimeric antigen receptor T cells have more investigation and introduced a promising way to treat cancer patients. This technology progressed until it introduced six US Food and Drug Administration-approved CAR T cell-based drugs. These drugs act against hematological malignancies appropriately and achieve exciting results, so they have been utilized widely in cell therapy clinics. In this review, we introduce all CAR T cells-approved drugs based on their last data and investigate them from all aspects of pharmacology, side effects, and compressional. Also, the efficacy of drugs, pre- and post-treatment steps, and expected side effects are introduced, and the challenges and new solutions in CAR T cell therapy are in the last speech.

Platelet-derived extracellular vesicles: a new-generation nanostructured tool for chronic wound healing.

Chronic nonhealing wounds pose a serious challenge to regaining skin function and integrity. Platelet-derived extracellular vesicles (PEVs) are nanostructured particles with the potential to promote wound healing since they can enhance neovascularization and cell migration and reduce inflammation and scarring. This work provides an innovative overview of the technical laboratory issues in PEV production, PEVs' role in chronic wound healing and the benefits and challenges in its clinical translation. The article also explores the challenges of proper sourcing, extraction techniques and storage conditions, and discusses the necessity of further evaluations and combinational therapeutics, including dressing biomaterials, M2-derived exosomes, mesenchymal stem cells-derived extracellular vesicles and microneedle technology, to boost their therapeutic efficacy as advanced strategies for wound healing.

EG.5 (Eris) and BA.2.86 (Pirola) two new subvariants of SARS-CoV-2: a new face of old COVID-19.

BACKGROUND: The World Health Organization announced the end of the Coronavirus Disease of 2019 (COVID-19) global health emergency on May 5, 2023. However, the reports from different countries indicate an elevation in the number of COVID-19-related hospitalizations and deaths through the last months. The subvariant XBB.1.5 (Kraken) was the cause of 49.1% of COVID-19 cases by the end of January 2023. Although, the subvariant EG.5 (Eris) has surpassed the XBB.1.5 recently. EG.5 is a close subvariant descending from XBB.1.9.2 subvariant of Omicron. EG.5.1 is a sublineage carrying two crucial spike mutations F456L and Q52H. Up to now, it is not well-established whether its infectivity, severity, and immune evasion have shown any change or not. Also, BA.2.86 another subvariant of Omicron descending from BA.2 bears over 30 mutations which could affect its infectivity and transmissibility. METHODS: Scopus, PubMed, Google Scholar, and Google were searched with six keywords up to 20 November 2023 and highly reliable research and reports were selected to refer to in this article. PURPOSE: This brief review aims to overview the most reliable data about EG.5 and BA.2.86 based on scientific evidence. CONCLUSION: Based on the currently available data these two new subvariants have similar features with currently circulating variants of Omicron and are less immune evasive than ancestral SARS-CoV-2.

Chimeric Antigen Receptor (CAR)-Based Cell Therapy for Type 1 Diabetes Mellitus (T1DM); Current Progress and Future Approaches.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease that destroys insulin-producing pancreatic ß-cells. Insulin replacement therapy is currently the mainstay of treatment for T1DM; however, treatment with insulin does not ameliorate disease progression, as dysregulated immune response and inflammation continue to cause further pancreatic ß-cell degradation. Therefore, shifting therapeutic strategies toward immunomodulating approaches could be effective to prevent and reverse disease progression. Different immune-modulatory therapies could be used, e.g., monoclonal-based immunotherapy, mesenchymal stem cell, and immune cell therapy. Since immune-modulatory approaches could have a systemic effect on the immune system and cause toxicity, more specific treatment options should target the immune response against pancreatic ß-cells. In this regard, chimeric antigen receptor (CAR)-based immunotherapy could be a promising candidate for modulation of dysregulated immune function in T1DM. CAR-based therapy has previously been approved for a number of hematologic malignancies. Nevertheless, there is renewed interest in CAR T cells' " off-the-shelf " treatment for T1DM. Several pre-clinical studies demonstrated that redirecting antigen-specific CAR T cells, especially regulatory CAR T cells (CAR Tregs), toward the pancreatic ß-cells, could prevent diabetes onset and progression in diabetic mice models. Here, we aim to review the current progress of CAR-based immune-cell therapy for T1DM and the corresponding challenges, with a special focus on designing CAR-based immunomodulatory strategies to improve its efficacy in the treatment of T1DM.

Current progress of chimeric antigen receptor (CAR) T versus CAR NK cell for immunotherapy of solid tumors.

Equipping cancer-fighting immune cells with chimeric antigen receptor (CAR) has gained immense attention for cancer treatment. CAR-engineered T cells (CAR T cells) are the first immune-engineered cells that have achieved brilliant results in anti-cancer therapy. Despite promising anti-cancer features, CAR T cells could also cause fatal side effects and have shown inadequate efficacy in some studies. This has led to the introduction of other candidates for CAR transduction, e.g., Natural killer cells (NK cells). Regarding the better safety profile and anti-cancer properties, CAR-armored NK cells (CAR NK cells) could be a beneficial and suitable alternative to CAR T cells. Since introducing these two cells as anti-cancer structures, several studies have investigated their efficacy and safety, and most of them have focused on hematological malignancies. Solid tumors have unique properties that make them more resistant and less curable cancers than hematological malignancies. In this review article, we conduct a comprehensive review of the structure and properties of CAR NK and CAR T cells, compare the recent experience of immunotherapy with CAR T and CAR NK cells in various solid cancers, and overview current challenges and future solutions to battle solid cancers using CARNK cells.

The CAR macrophage cells, a novel generation of chimeric antigen-based approach against solid tumors.

Today, adoptive cell therapy has many successes in cancer therapy, and this subject is brilliant in using chimeric antigen receptor T cells. The CAR T cell therapy, with its FDA-approved drugs, could treat several types of hematological malignancies and thus be very attractive for treating solid cancer. Unfortunately, the CAR T cell cannot be very functional in solid cancers due to its unique features. This treatment method has several harmful adverse effects that limit their applications, so novel treatments must use new cells like NK cells, NKT cells, and macrophage cells. Among these cells, the CAR macrophage cells, due to their brilliant innate features, are more attractive for solid tumor therapy and seem to be a better candidate for the prior treatment methods. The CAR macrophage cells have vital roles in the tumor microenvironment and, with their direct effect, can eliminate tumor cells efficiently. In addition, the CAR macrophage cells, due to being a part of the innate immune system, attended the tumor sites. With the high infiltration, their therapy modulations are more effective. This review investigates the last achievements in CAR-macrophage cells and the future of this immunotherapy treatment method.

The role of heat shock proteins (HSPs) in type 2 diabetes mellitus pathophysiology.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by sustained hyperglycemia caused by impaired insulin signaling and secretion. Metabolic stress, caused by an inappropriate diet, is one of the major hallmarks provoking inflammation, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Heat shock proteins (HSPs) are a group of highly conserved proteins that have a crucial role in chaperoning damaged and misfolded proteins to avoid disruption of cellular homeostasis under stress conditions. To do this, HSPs interact with diverse intra-and extracellular pathways among which are the insulin signaling, insulin secretion, and apoptosis pathways. Therefore, HSP dysfunction, e.g. HSP70, may lead to disruption of the pathways responsible for insulin secretion and uptake. Consistently, the altered expression of other HSPs and genetic polymorphisms in HSP-producing genes in diabetic subjects has made HSPs hot research in T2DM. This paper provides a comprehensive overview of the role of different HSPs in T2DM pathogenesis, affected cellular pathways, and the potential therapeutic strategies targeting HSPs in T2DM.

Targeting the cGAS-STING pathway as an inflammatory crossroad in coronavirus disease 2019 (COVID-19).

CONTEXT AND OBJECTIVE: The emerging pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has imposed significant mortality and morbidity on the world. An appropriate immune response is necessary to inhibit SARS-CoV-2 spread throughout the body. RESULTS: During the early stages of infection, the pathway of stimulators of interferon genes (STING), known as the cGAS-STING pathway, has a significant role in the induction of the antiviral immune response by regulating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Interferon regulatory factor 3 (IRF3), two key pathways responsible for proinflammatory cytokines and type I IFN secretion, respectively. DISCUSSION: During the late stages of COVID-19, the uncontrolled inflammatory responses, also known as cytokine storm, lead to the progression of the disease and poor prognosis. Hyperactivity of STING, leading to elevated titers of proinflammatory cytokines, including Interleukin-I (IL-1), IL-4, IL-6, IL-18, and tissue necrosis factor-α (TNF-α), is considered one of the primary mechanisms contributing to the cytokine storm in COVID-19. CONCLUSION: Exploring the underlying molecular processes involved in dysregulated inflammation can bring up novel anti-COVID-19 therapeutic options. In this article, we aim to discuss the role and current studies targeting the cGAS/STING signaling pathway in both early and late stages of COVID-19 and COVID-19-related complications and the therapeutic potential of STING agonists/antagonists. Furthermore, STING agonists have been discussed as a vaccine adjuvant to induce a potent and persistent immune response.

CAR-NKT cell therapy: a new promising paradigm of cancer immunotherapy.

Today, cancer treatment is one of the fundamental problems facing clinicians and researchers worldwide. Efforts to find an excellent way to treat this illness continue, and new therapeutic strategies are developed quickly. Adoptive cell therapy (ACT) is a practical approach that has been emerged to improve clinical outcomes in cancer patients. In the ACT, one of the best ways to arm the immune cells against tumors is by employing chimeric antigen receptors (CARs) via genetic engineering. CAR equips cells to target specific antigens on tumor cells and selectively eradicate them. Researchers have achieved promising preclinical and clinical outcomes with different cells by using CARs. One of the potent immune cells that seems to be a good candidate for CAR-immune cell therapy is the Natural Killer-T (NKT) cell. NKT cells have multiple features that make them potent cells against tumors and would be a powerful replacement for T cells and natural killer (NK) cells. NKT cells are cytotoxic immune cells with various capabilities and no notable side effects on normal cells. The current study aimed to comprehensively provide the latest advances in CAR-NKT cell therapy for cancers.

Transforming growth factor ß (TGF-ß) pathway in the immunopathogenesis of multiple sclerosis (MS); molecular approaches.

INTRODUCTION: Multiple sclerosis (MS) is an acute demyelinating disease with an autoimmune nature, followed by gradual neurodegeneration and enervating scar formation. Dysregulated immune response is a crucial dilemma contributing to the pathogenesis of MS. The role of chemokines and cytokines, such as transforming growth factor-ß (TGF-ß), have been recently highlighted regarding their altered expressions in MS. TGF-ß has three isoforms, TGF-ß1, TGF-ß2, and TGF-ß3, that are structurally similar; however, they can show different functions. RESULTS: All three isoforms are known to induce immune tolerance by modifying Foxp3+ regulatory T cells. Nevertheless, there are controversial reports concerning the role of TGF-ß1 and 2 in the progression of scar formation in MS. At the same time, these proteins also improve oligodendrocyte differentiation and have shown neuroprotective behavior, two cellular processes that suppress the pathogenesis of MS. TGF-ß3 shares the same properties but is less likely contributes to scar formation, and its direct role in MS remains elusive. DISCUSSION: To develop novel neuroimmunological treatment strategies for MS, the optimal strategy could be the one that causes immune modulation, induces neurogenesis, stimulates remyelination, and prevents excessive scar formation. Therefore, regarding its immunological properties, TGF-ß could be an appropriate candidate; however, contradictory results of previous studies have questioned its role and therapeutic potential in MS. In this review article, we provide an overview of the role of TGF-ß in immunopathogenesis of MS, related clinical and animal studies, and the treatment potential of TGF-ß in MS, emphasizing the role of different TGF-ß isoforms.

Immune evasion of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); molecular approaches.

In December 2019, a new betacoronavirus, known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), caused an outbreak at the Wuhan seafood market in China. The disease was further named coronavirus disease 2019 (COVID-19). In March 2020, the World Health Organization (WHO) announced the disease to be a pandemic, as more cases were reported globally. SARS-CoV-2, like many other viruses, employs diverse strategies to elude the host immune response and/or counter immune responses. The infection outcome mainly depends on interactions between the virus and the host immune system. Inhibiting IFN production, blocking IFN signaling, enhancing IFN resistance, and hijacking the host's translation machinery to expedite the production of viral proteins are among the main immune evasion mechanisms of SARS-CoV-2. SARS-CoV-2 also downregulates the expression of MHC-I on infected cells, which is an additional immune-evasion mechanism of this virus. Moreover, antigenic modifications to the spike (S) protein, such as deletions, insertions, and also substitutions are essential for resistance to SARS-CoV-2 neutralizing antibodies. This review assesses the interaction between SARS-CoV-2 and host immune response and cellular and molecular approaches used by SARS-CoV-2 for immune evasion. Understanding the mechanisms of SARS-CoV-2 immune evasion is essential since it can improve the development of novel antiviral treatment options as well as vaccination methods.

Pulmonary Delivery of Levamisole Nanoparticles as an Immunomodulator Affecting Th and a Potential ADAM10 Inhibitor to Ameliorate Severe Allergic Asthma.

Asthma is a common chronic lung disease without absolute treatment, and hypersensitivity reactions and type 2 immune responses are responsible for asthma pathophysiology. ADAM10 as a metalloproteinase transmembrane protein is critical for development of Th2 responses, and levamisole as an anthelmintic drug has immunomodulatory effects, which not only regulates ADAM10 activity but also can suppress the bone marrow and neutrophil production. Therefore, in the present study, nanoparticles were used as a levamisole delivery system to reduce bone marrow suppression, and the immunomodulatory and ADAM10 inhibitory effects of levamisole were studied in allergic asthma. Asthmatic mice were treated with PLGA-levamisole nanoparticles. Then, AHR, BALF, and blood cell counts, levels of the IgG1 subclass, total and OVA-specific IgE, IL2, IL-4, IL-5, IL-10, IL-13, IL-17, IL-25, IL-33, INF-γ, and TNF-α, gene expression of FoxP3, T-bet, RORγt, PU.1, GATA3, FcεRII, CysLT1R, eotaxin, and ADAM10, and lung histopathology were evaluated. PLGA-LMHCl with considered characteristics could control airway hyper-responsiveness, eosinophils in the BALF, levels of immunoglobulins, Th2-, Th9-, and Th17-derived cytokines and pivotal genes, eosinophilic inflammation, hyperplasia of the goblet cell, and hyperproduction of mucus and could increase Th1- and Treg-derived cytokines and also pivotal genes. It could also modulate the ADAM10 activity and had no effect on the number of neutrophils in the bloodstream. The novel safe nanodrug had no side effect on the bone marrow to produce neutrophils and could control the allegro-immuno-inflammatory response of asthma.

Cell-Free Treatments: A New Generation of Targeted Therapies for Treatment of Ischemic Heart Disease.

Although recent progress in medicine has substantially reduced cardiovascular diseases (CVDs)-related mortalities, current therapeutics have failed miserably to be beneficial for all patients with CVDs. A wide array of evidence suggests that newly-introduced cell-free treatments (CFTs) have more reliable results in the improvement of cardiac function. The main regeneration activity of CFTs protocols is based on bypassing cells and using paracrine factors. In this article, we aim to compare various stem cell secretomes, a part of a CFTs strategy, to generalize their effective clinical outcomes for patients with CVDs. Data for this review article were collected from 70 published articles (original, review, randomized clinical trials (RCTs), and case reports/series studies done on human and animals) obtained from Cochrane, Science Direct, PubMed, Scopus, Elsevier, and Google Scholar) from 2015 to April 2020 using six keywords. Full-text/full-length articles, abstract, section of book, chapter, and conference papers in English language were included. Studies with irrelevant/insufficient/data, or undefined practical methods were excluded. CFTs approaches involved in growth factors (GFs); gene-based therapies; microRNAs (miRNAs); extracellular vesicles (EVs) [exosomes (EXs) and microvesicles (MVs)]; and conditioned media (CM). EXs and CM have shown more remarkable results than stem cell therapy (SCT). GF-based therapies have useful results as well as side effects like pathologic angiogenesis. Cell source, cell's aging and CM affect secretomes. Genetic manipulation of stem cells can change the secretome's components. Growing progression to end stage heart failure (HF), propounds CFTs as an advantageous method with practical and clinical values for replacement of injured myocardium, and induction of neovascularization. To elucidate the secrets behind amplifying the expansion rate of cells, increasing life-expectancy, and improving quality of life (QOL) for patients with ischemic heart diseases (IHDs), collaboration among cell biologist, basic medical scientists, and cardiologists is highly recommended.

47D11 Antibody-Engineered Exosomes for Targeted Delivery of Remdesivir in Patients with COVID-19: Dream or Principle? (A Critical Editorial Study).

Along with the high transmission rate of coronavirus disease 2019 infection in the last few months, the morbidity and mortality rate of coronavirus disease 2019 has been increased among critically-ill patients, especially the elderly or the ones with immunodeficiencies. So, there is an urgent need to develop more effective therapeutic agents through immunopathophysiological and immunotherapeutic-based strategies for these patients. Here, we hypothesize that mixing S1b-RBD-expressing mesenchymal stem cell-derived exosomes (which have been previously enriched with Remdesivir) with 47D11 antibody, can promisingly guarantee effective transferring of those targeted exosomes to the targeted microenvironment of coronavirus disease 2019 infection. In addition, it can induce their immunomodulatory properties, and anti-viral features, refraining from entrance of severe acute respiratory syndrome-related coronavirus-2 to angiotensin-converting enzyme 2-expressing cells.

Major severe acute respiratory coronavirus-2 (SARS-CoV-2) vaccine-associated adverse effects; benefits outweigh the risks.

INTRODUCTION: Since its emergence, there have been huge efforts to design vaccines against coronavirus disease 2019 (COVID-19) to inhibit its interpersonal spread. Global vaccine development is the most promising cost-effective method for overcoming the epidemic. However, following reports of post-vaccination thromboembolic adverse effects, there have been raising concerns about the safety profile of the COVID-19 vaccine. AREAS COVERED: We aimed to review the recent Food and Drug Administration (FDA)-approved vaccines and identify the organ-based major complications of COVID-19 vaccines based on reliable published studies. To find high-quality and large-scale observational, clinical trial, and cohort studies, PubMED, Scholar, Embase, and Web of Science were searched using keywords: COVID-19, SARS-CoV-2, vaccine, Pfizer (BNT162b2), Johnson and Johnson (Ad26.COV2), Moderna (mRNA-1273), Oxford AstraZeneca (ChAdOx1nCoV19), Coronavac (Sinovac), BBIBP-CorV (Sinopharm), adverse effect, and complication. To include all relevant articles, backward searching was also done on similar article citations. Case reports, studies including less than 10 participants, and biased articles were excluded. EXPERT OPINION: Based on data from high-quality and population-based studies, major adverse effects are divided into four major organ-specific groups, including cardiovascular, neurologic, hematologic, and immune-allergic side effects. The incidence of most of these side effects is not different between vaccinated and normal populations, and currently, the benefits of vaccination against COVID-19 are greater than the mortality and morbidity risks of COVID-19 infection. However, further studies, specifically systematic review and meta-analysis, are still indicated to investigate further unknown side effects of these vaccines and the existence of causality between the vaccine and reported adverse events.

Endocrine and metabolic complications of COVID-19: lessons learned and future prospects.

Coronavirus disease 2019 (COVID-19) is well known for its respiratory complications; however, it can also cause extrapulmonary manifestations, including cardiovascular, thrombotic, renal, gastrointestinal, neurologic, and endocrinological symptoms. Endocrinological complications of COVID-19 are rare but can considerably impact the outcome of the patients. Moreover, preexisting endocrinologic disorders can affect the severity of COVID-19. Thyroid, pancreas, adrenal, neuroendocrine, gonadal, and parathyroid glands are the main endocrinologic organs that can be targeted by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Endocrinological complications of COVID-19 are rare but can significantly deteriorate the patients' prognosis. Understanding the interaction between COVID-19 and the endocrine system can provide a potential treatment option to improve the outcome of COVID-19. In this article, we aim to review the short-term and long-term organ-based endocrinological complications of COVID-19, the pathophysiology, the influence of each complication on COVID-19 prognosis, and potential therapeutic interventions based on current published data. Moreover, current clinical trials of potential endocrinological interventions to develop therapeutic strategies for COVID-19 have been discussed.

OMICRON: Virology, immunopathogenesis, and laboratory diagnosis.

Since its emersion, coronavirus disease 2019 (COVID-19) has been a significant global dilemma. Several mutations in the severe acute respiratory virus (SARS-Co-2) genome has given rise to different variants with various levels of transmissibility, severity and mortality. Up until November 2021, the variants of concern declared by the World Health Organization were Alpha, Beta, Delta and Gamma. Since then, a novel variant named Omicron (B.1.1.529) has been developed. BA.1, BA.1.1, BA.2 and BA.3 are four known subvariants of Omicron. The Omicron variant involves new mutations in its spike protein, most of which are in its receptor binding site, and increase its transmissibility and decrease its antibody and vaccine response. Understanding the virology and mutations of Omicron is necessary for developing diagnostic and therapeutic methods. Moreover, important issues, such as the risk of re-infection, the response to different kinds of vaccines, the need for a booster vaccine dose and the increased risk of Omicron infection in pediatrics, need to be addressed. In this article, we provide an overview of the biological and immunopathological properties of Omicron and its subvariants, its clinical signs and symptoms, Omicron and pediatrics, vaccines against Omicron, re-infection with Omicron, diagnostic approaches and specific challenges of Omicron in the successful control and management of the rapid global spread of this variant.

Cellular and biological factors involved in healing wounds and burns and treatment options in tissue engineering.

Severe traumatic wounds and burns have a high chance of mortality and can leave survivors with many functional disabilities and cosmetic problems, including scars. The healing process requires a harmonious interplay of various cells and growth factors. Different structures of the skin house numerous cells, matrix components and growth factors. Any disturbance in the balance between these components can impair the healing process. The function of cells and growth factors can be manipulated and facilitated to aid tissue repair. In the current review, the authors focus on the importance of the skin microenvironment, the pathophysiology of various types of burns, mechanisms and factors involved in skin repair and wound healing and regeneration of the skin using tissue engineering approaches.

Wounds and ulcers, especially burn wounds, are major causes of morbidity and mortality and pose a significant burden for individuals and societies. The skin has numerous structures that play important roles in wound healing via cells and growth factors. Tissue engineering and regenerative medicine represent a rather new field that focuses on manipulating cells and growth factors, aiming to facilitate repair and regeneration of injured tissues and organs. This review focuses on different burn injuries that can result in nonhealing wounds, provides an overview of several cells and growth factors that are involved in the healing process of the skin and introduces various strategies practiced in tissue engineering with regard to cutaneous wound healing.