Efferocytosis: a double-edged sword in microbial immunity.

Efferocytosis is characterized as the rapid and efficient process by which dying or dead cells are removed. This type of clearance is initiated via "find-me" signals, and then, carries on by "eat-me" and "don't-eat-me" ones. Efferocytosis has a critical role to play in tissue homeostasis and innate immunity. However, some evidence suggests it as a double-edged sword in microbial immunity. In other words, some pathogens have degraded efferocytosis by employing efferocytic mechanisms to bypass innate immune detection and promote infection, despite the function of this process for the control and clearance of pathogens. In this review, the efferocytosis mechanisms from the recognition of dying cells to phagocytic engulfment are initially presented, and then, its diverse roles in inflammation and immunity are highlighted. In this case, much focus is also laid on some bacterial, viral, and parasitic infections caused by Mycobacterium tuberculosis (M. tb), Mycobacterium marinum (M. marinum), Listeria monocytogenes (L. monocytogenes), Chlamydia pneumoniae (CP), Klebsiella pneumoniae (KP), Influenza A virus (IAV), human immunodeficiency virus (HIV), and Leishmania, respectively.

CRISPR: A Promising Tool for Cancer Therapy.

The clustered regularly interspaced short palindromic repeats system, called CRISPR, as one of the major technological advances, allows geneticists and researchers to perform genome editing. This remarkable technology is quickly eclipsing zinc-finger nucleases (ZFNs) and other editing tools, and its ease of use and accuracy have thus far revolutionized genome editing, from fundamental science projects to medical research and treatment options. This system consists of two key components: a CRISPR-associated (Cas) nuclease, which binds and cuts deoxyribonucleic acid (DNA) and a guide ribonucleic acid (gRNA) sequence, directing the Cas nuclease to its target site. In the research arena, CRISPR has been up to now exploited in various ways alongside gene editing, such as epigenome modifications, genome-wide screening, targeted cancer therapies, and so on. This article reviews the current perceptions of the CRISPR/Cas systems with special attention to studies reflecting on the relationship between the CRISPR/Cas systems and their role in cancer therapy.

Are levels of adipokines and micronutrients different in male adult smokers and non-smokers? A case-control study.

OBJECTIVE: Smoking is a common public problem leading to increases in oxidative stress and decreases in the levels of some micronutrients, finally affecting adipokine levels. The aim of this study was to compare the serum levels of omentin (intelectin-1), chemerin, TNF-α, and some micronutrient intakes in male smokers and non-smokers. METHODS: 40 male smokers and 40 male non-smokers with a mean age of 38.6±14.1 years were included in this study. Serum levels of omentin, chemerin, and TNF-α were measured. To calculate the daily intake of energy, carbohydrate, protein, fat, and some of the micronutrients, the 24-h recall and semi-quantitative food frequency questionnaire (FFQ) was used. RESULTS: Omentin, chemerin, and TNF-α levels in male smokers were lower than non-smokers, but these differences were not statistically significant. However, after adjustment for total and saturated fat intakes and age, omentin (ß=138.4, p=0.027) and TNF-α (ß=144.5, p=0.015) revealed significant differences. CONCLUSION: The serum levels of omentin, chemerin, TNF-α, and some micronutrient intakes were not significantly different between smokers and non-smokers. Further population studies are needed to clarify this subject.

The effect of Vitamin C and Zn supplementation on the immune system and clinical outcomes in COVID-19 patients.

SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus-2) is the most dangerous form of the coronavirus, which causes COVID-19. In patients with severe COVID-19, the immune system becomes markedly overactive. There is evidence that supplementation with select micronutrients may play a role in maintaining immune system function in this patient population. Throughout the COVID-19 pandemic, significant emphasis has been placed on the importance of supplementing critical micronutrients such as Vitamin C and Zinc (Zn) due to their immunomodulatory effects. Viral infections, like COVID-19, increase physiological demand for these micronutrients. Therefore, the purpose of this review was to provide comprehensive information regarding the potential effectiveness of Vitamin C and Zn supplementation during viral infection and specifically COVID-19. This review demonstrated a relation between Vitamin C and Zn deficiency and a reduction in the innate immune response, which can ultimately make patients with COVID-19 more vulnerable to viral infection. As such, adequate intake of Vitamin C and Zn, as an adjunctive therapeutic approach with any necessary pharmacological treatment(s), may be necessary to mitigate the adverse physiological effects of COVID-19. To truly clarify the role of Vitamin C and Zn supplementation in the management of COVID-19, we must wait for the results of ongoing randomized controlled trials. The toxicity of Vitamin C and Zn should also be considered to prevent over-supplementation. Over-supplementation of Vitamin C can lead to oxalate toxicity, while increased Zn intake can reduce immune system function. In summary, Vitamin C and Zn supplementation may be useful in mitigating COVID-19 symptomology.

Effect of diabetes on efferocytosis process.

Diabetes is a complex of genetic, metabolic, and autoimmune disorders that are characterized by hyperglycemia. Elevated apoptotic cell count following defective clearance of dead cells that can cause chronic inflammation is a hallmark of the diabetic wound. Effective dead cell clearance is a prerequisite for rapid inflammation resolution and successful recovery. Efferocytosis is a multistep process in which phagocytes engulf the dead cells. Cell body elimination is of great significance in disease and homeostasis. Recent research has clarified that diabetic wounds have an enhanced load of the apoptotic cell, which is partly attributed to the dysfunction of macrophages in apoptotic clearance at the site of the diabetic wounds. In the current work, we highlight the pathways implicated in efferocytosis, from the diagnosis of apoptotic cells to the phagocytic swallowing and the homeostatic resolution, and explain the possible pathophysiological episodes occurring when the proceeding is abrogated. Also, we describe the last development in the management of inflammation in diabetes wound and future directions of surveillance.

Dual Blockade of PD-1 and LAG3 Immune Checkpoints Increases Dendritic Cell Vaccine Mediated T Cell Responses in Breast Cancer Model.

PURPOSE: Increasing the efficiency of unsuccessful immunotherapy methods is one of the most important research fields. Therefore, the use of combination therapy is considered as one of the ways to increase the effectiveness of the dendritic cell (DC) vaccine. In this study, the inhibition of immune checkpoint receptors such as LAG3 and PD-1 on T cells was investigated to increase the efficiency of T cells in response to the DC vaccine. METHODS: We used trimethyl chitosan-dextran sulfate-lactate (TMC-DS-L) nanoparticles (NPs) loaded with siRNA molecules to quench the PD-1 and LAG3 checkpoints' expression. RESULTS: Appropriate physicochemical characteristics of the generated NPs led to efficient inhibition of LAG3 and PD-1 on T cells, which was associated with increased survival and activity of T cells, ex vivo. Also, treating mice with established breast tumors (4T1) using NPs loaded with siRNA molecules in combination with DC vaccine pulsed with tumor lysate significantly inhibited tumor growth and increased survival in mice. These ameliorative effects were associated with increased anti-tumor T cell responses and downregulation of immunosuppressive cells in the tumor microenvironment and spleen. CONCLUSION: These findings strongly suggest that TMC-DS-L NPs loaded with siRNA could act as a novel tool in inhibiting the expression of immune checkpoints in the tumor microenvironment. Also, combination therapy based on inhibition of PD-1 and LAG3 in combination with DC vaccine is an effective method in treating cancer that needs to be further studied.

MicroRNAs and Efferocytosis: Implications for Diagnosis and Therapy.

About 10-100 billion cells are generated in the human body in a day, and accordingly, 10- 100 billion cells predominantly die for maintaining homeostasis. Dead cells generated by apoptosis are also rapidly engulfed by macrophages (Mθs) to be degraded. In case of the inefficient engulfment of apoptotic cells (ACs) via Mθs, they experience secondary necrosis and thus release intracellular materials, which display damage-associated molecular patterns (DAMPs) and result in diseases. Over the last decades, researchers have also reflected on the significant contribution of microRNAs (miRNAs) to autoimmune diseases through the regulation of Mθs functions. Moreover, miRNAs have shown intricate involvement with completely adjusting basic Mθs functions, such as phagocytosis, inflammation, efferocytosis, tumor promotion, and tissue repair. In this review, the mechanism of efferocytosis containing "Find-Me", "Eat-Me", and "Digest-Me" signals is summarized and the biogenesis of miRNAs is briefly described. Finally, the role of miRNAs in efferocytosis is discussed. It is concluded that miRNAs represent promising treatments and diagnostic targets in impaired phagocytic clearance, which leads to different diseases.

Xanthohumol: An underestimated, while potent and promising chemotherapeutic agent in cancer treatment.

Today, there is a growing interest nowadays in the use of herbal substances as cancer therapeutic agents. Over recent years, Xanthohumol (XTL) has been brought out as a prenylated chalcone that is found in hops (Humulus lupulus) and beer. XTL is being investigated for its potential properties, and it has been found to have various biological effects, including anti-microbial, anti-viral, and immunomodulatory. Other than these biological effects, it has also been found that XTL exerts anti-tumor effects. In the beginning, XTL, by modulating cell signaling pathways, including ERK, AKT, NF-κB, AMPK, Wnt/ß-catenin, and Notch signaling in cancer cells, inhibits tumor cell functions. Moreover, XTL, by inducing apoptotic pathways, either intrinsic or extrinsic, promotes cancer cell death and arrests the cell cycle. Furthermore, XTL inhibits metastasis, angiogenesis, cancer stemness, drug resistance, cell respiration, etc., which results in tumor aggressiveness inhibition. XTL has low solubility in water, and it has been hypothesized that some modifications, including biotinylation, can improve its pharmacogenetic characteristics. Additionally, XTL derivates such as dihydroXTL and tetrahydroXTL can be helpful for more anti-tumor activities. Using XTL with other anti-tumor agents is another approach to overcome tumor cell resistance. XTL or its derivatives, it is believed, might provide novel chemotherapeutic methods in future cancer therapy.

Curcumin as a Natural Modulator of B Lymphocytes: Evidence from In Vitro and In Vivo Studies.

B cells are the only player of humoral immune responses by the production of various types of antibodies. However, B cells are also involved in the pathogenesis of several immune-mediated diseases. Moreover, different types of B cell lymphoma have also been characterized. Selective depletion of B cells by anti-CD20 and other B cell-depleting agents in the clinic can improve a wide range of immune-mediated diseases. B cells' capacity to act as cytokine-producing cells explains how they can control immune cells' activity and contribute to disease pathogenesis. Thus, researchers investigated a safe, low-cost, and effective treatment modality for targeting B cells. In this respect, curcumin, the biologically active ingredient of turmeric, has a wide range of pharmacological activities. Evidence showed that curcumin could affect various immune cells, such as monocytes and macrophages, dendritic cells, and T lymphocytes. However, there are few pieces of evidence about the effects of curcumin on B cells. This study aims to review the available evidence about curcumin's modulatory effects on B cells' proliferation, differentiation, and function in different states. Apart from normal B cells, the modulatory effects of curcumin on B cell lymphoma will also be discussed.

Berberine as a natural modulator of inflammatory signaling pathways in the immune system: Focus on NF-κB, JAK/STAT, and MAPK signaling pathways.

Three main inflammatory signaling pathways include nuclear factor-κB (NF-κB), Janus kinases/Signal transducer and activator of transcriptions (JAKs/STATs), and mitogen-activated protein kinases (MAPKs) play crucial roles in inducing, promoting, and regulating inflammatory responses in the immune system. Importantly, the breakdown of mechanisms that tightly regulate inflammatory signaling pathways can be the underlying cause of uncontrolled inflammatory responses and be associated with the generation and development of several inflammatory diseases. Hence, therapeutic strategies targeting inflammatory signaling pathways and their downstream components may promise to treat inflammatory diseases. Studies over the past two decades have provided important information on the polytrophic pharmacological and biochemical properties of berberine (BBR) as a naturally occurring compound, such as antioxidant, antitumor, antimicrobial, and antiinflammatory activates. Interestingly, the modulatory effects of BBR on inflammatory signaling cascades, which lead to the inhibition of inflammation, have been widely investigated in several in vitro and in vivo studies. For the first time, herein, this comprehensive review attempts to put together these studies and provide important insight into the modulatory effects of BBR on NF-κB, JAKs/STATs, and MAPKs signaling pathways in vitro in various types of immune cells and in vivo in several experimental inflammatory diseases. As the second achievement of this review, we also explore the therapeutic efficacy and antiinflammatory effects of BBR regarding its modulatory action.

Combination Cancer Immunotherapy with Dendritic Cell Vaccine and Nanoparticles Loaded with Interleukin-15 and Anti-beta-catenin siRNA Significantly Inhibits Cancer Growth and Induces Anti-Tumor Immune Response.

PURPOSE: The invention and application of new immunotherapeutic methods can compensate for the inefficiency of conventional cancer treatment approaches, partly due to the inhibitory microenvironment of the tumor. In this study, we tried to inhibit the growth of cancer cells and induce anti-tumor immune responses by silencing the expression of the ß-catenin in the tumor microenvironment and transmitting interleukin (IL)-15 cytokine to provide optimal conditions for the dendritic cell (DC) vaccine. METHODS: For this purpose, we used folic acid (FA)-conjugated SPION-carboxymethyl dextran (CMD) chitosan (C) nanoparticles (NPs) to deliver anti-ß-catenin siRNA and IL-15 to cancer cells. RESULTS: The results showed that the codelivery of ß-catenin siRNA and IL-15 significantly reduced the growth of cancer cells and increased the immune response. The treatment also considerably stimulated the performance of the DC vaccine in triggering anti-tumor immunity, which inhibited tumor development and increased survival in mice in two different cancer models. CONCLUSIONS: These findings suggest that the use of new nanocarriers such as SPION-C-CMD-FA could be an effective way to use as a novel combination therapy consisting of ß-catenin siRNA, IL-15, and DC vaccine to treat cancer.

The role of efferocytosis in neuro-degenerative diseases.

Efferocytosis has a critical role in maintaining tissues and organs' homeostasis by removing apoptotic cells. It is essential for human health, and disturbances in efferocytosis may result indifferent illnesses. In case of inadequate clearance of the dead cells, the content in the cells would be released. In fact, it induces some damages to the tissue and leads to the prolonged inflammation, so unsuitable phagocytosis of the apoptotic cells is involved in occurrence as well as expansion of numerous human chronic inflammatory diseases. Studies have shown age dependence of the neuro-degenerative diseases, which are largely due to the neuro-inflammation and the loss of neurons and thus cause the brain's functional disorders. Efferocytosis is coupled to anti-inflammatory responses that contribute to the elimination of the dying neurons in neuro-degenerative diseases, so its disruption may make a risk factor in numerous human chronic inflammatory diseases such as multiple sclerosis, Alzheimer's disease, glioblastoma, and Rett syndrome. This study is a review of the efferocytosis molecular pathways and their role in neuro-degenerative diseases in order to discover a new treatment option to cure patients.

The interaction of Helicobacter pylori with cancer immunomodulatory stromal cells: New insight into gastric cancer pathogenesis.

Gastric cancer is the fourth most common cause of cancer-linked deaths in the world. Gastric tumor cells have biological characteristics such as rapid proliferation, high invasiveness, and drug resistance, which result in recurrence and poor survival. Helicobacter pylori (H. pylori) has been proposed as a first-class carcinogen for gastric cancer according to the 1994 world health organization (WHO) classification. One of the important mechanisms by which H. pylori affects the gastric environment and promotes carcinogenesis is triggering inflammation. H. pylori induces an inflammatory response and a plethora of different signal transduction processes, leading to gastric mucosal disturbance, chronic gastritis, and a multi-step complex pathway that initiates carcinogenesis. It seems undeniable that the interaction between various cell types, including immune cells, gastric epithelium, glands, and stem cells, is vital for the progression and development of carcinogenesis concerning H. pylori. The interactions of H. pylori with surrounding cells play a key role in cancer progression. In this review, we discuss the interplay between H. pylori and tumor-supportive cells, including mesenchymal stem cells (MSCs), cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and myeloid derived-suppressor cells (MDSCs) in gastric cancer. It is hoped that clarifying the specific mechanisms for 'cross-talk' between H. pylori and these cells will provide promising strategies for developing new treatments.

The Potential Use of Mesenchymal Stem Cells and Their Derived Exosomes for Orthopedic Diseases Treatment.

Musculoskeletal disorders (MSDs) are conditions that can affect muscles, bones, and joints. These disorders are very painful and severely limit patients' mobility and are more common in the elderly. MSCs are multipotent stem cells isolated from embryonic (such as the umbilical cord) and mature sources (such as adipose tissue and bone marrow). These cells can differentiate into various cells such as osteoblasts, adipocytes, chondrocytes, NP-like cells, Etc. Due to MSC characteristics such as immunomodulatory properties, ability to migrate to the site of injury, recruitment of cells involved in repair, production of growth factors, and large amount production of extracellular vesicles, these cells have been used in many regenerative-related medicine studies. Also, MSCs produce different types of EVs, such as exosomes, to the extracellular environment. Exosomes reflect MSCs' characteristics and do not have cell therapy-associated problems because they are cell-free. These vesicles carry proteins, nucleic acids, and lipids to the host cell and change their function. This review focuses on MSCs and MSCs exosomes' role in repairing dense connective tissues such as tendons, cartilage, invertebrate disc, bone fracture, and osteoporosis treatment.

Arctigenin, an anti-tumor agent; a cutting-edge topic and up-to-the-minute approach in cancer treatment.

Today, herbal-derived compounds are being increasingly studied in cancer treatment. Over the past decade, Arctigenin has been introduced as a bioactive dibenzylbutyrolactone lignan which is found in Chinese herbal medicines. In addition to anti-microbial, anti-inflammatory, immune-modulatory functions, Arctigenin has attracted growing attention due to its anti-tumor capabilities. It has been shown that Arctigenin can induce apoptosis and necrosis and abolish drug resistance in tumor cells by inducing apoptotic signaling pathways, caspases, cell cycle arrest, and the modulating proteasome. Moreover, Arctigenin mediates other anti-tumor functions through several mechanisms. It has been demonstrated that Arctigenin can act as an anti-inflammatory compound to inhibit inflammation in the tumor microenvironment. It also downregulates factors involved in tumor metastasis and angiogenesis, such as matrix metalloproteinases, N-cadherin, TGF-ß, and VEGF. Additionally, Arctigenin, through modulation of MAPK signaling pathways and stress-related proteins, is able to abolish tumor cell growth in nutrient-deprived conditions. Due to the limited solubility of Arctigenin in water, it is suggested that modification of this compound through amino acid esterification can improve its pharmacogenetic properties. Collectively, it is hoped that using Arctigenin or its derivates might introduce new chemotherapeutic approaches in future treatment.

Antennapedia-derived positively-charged peptide faces multiple problems upon their usage as targeting ligand for liposomal doxorubicin.

The positively-charged peptide antp derived from Antennapedia transcription protein is demonstrated to mediate the liposome translocation across the cell membrane. In the current investigation, we prepared a stable liposomal doxorubicin (Dox) formulation and targeted it with the antp peptide from 0 to 200 ligand/liposome. These antp-containing liposomes were investigated in terms of physical stability on storage in the refrigerator and upon incubation in blood. Also, other features like cell binding, uptake, biodistribution, and treatment efficiency were evaluated in C26 colon carcinoma BALB/c mice. The Antp in liposomes resulted in enhanced particle growth with the development of the enormously large liposomes from 2000 to 6000 nm. Upon incubation in blood, these large liposomes were removed. The antp also enhanced the cell binding affinity and cell uptake rate of the liposomes and resulted in the restriction of the cancer cell proliferation, but it failed to improve the chemotherapeutic property of the Dox-liposome. The i.v. injection of antp-liposomes (15 mg Dox/kg) caused severe body weight loss and early death incidence due to probably increased toxicity. The antp targeting offered no advantage to the Dox-liposome in the delivery of Dox to the tumor, and failed to enhance the treatment efficiency of the liposomes.

The effect of RGD-targeted and non-targeted liposomal Galbanic acid on the therapeutic efficacy of pegylated liposomal doxorubicin: From liposomal preparation to in-vivo studies.

The anti-cancer therapeutic application of Galbanic acid (Gba) as a strong antiangiogenic sesquiterpene coumarin has been limited due to its low water solubility. This issue necessitates developing new liposomal formulations for the efficient delivery of Gba in vivo. In this study, various liposomal formulations were prepared by a thin-film hydration method, and Gba was incorporated into the liposomal bilayers, which consequently increased its release profile compared to formulations in our previous study prepared by remote loading methods. The most stable formulation with desired properties was selected and decorated with RGD peptide (cyclo [Arg-Gly-Asp-D-Tyr-Cys]) to target tumor vasculature actively. The fluorescently-labeled model liposomes showed that the targeting could improve the receptor-mediated endocytosis of the liposomes higher than those prepared in our previous study in vitro in human umbilical vein endothelial cells (HUVECs), which was confirmed by chicken chorioallantoic membrane angiogenesis (CAM) model in vivo. Although not significant, it also could increase the accumulation of liposomes in colon tumors. In BALB/c mice bearing colon cancer, not only non-targeted Gba liposomes but also even RGD-targeted ones combinatorial therapy with pegylated liposomal doxorubicin could improve the anti-tumor efficacy as compared to their monotherapy. These outcomes have strong consequences for cancer therapy.