New insights in application of mesenchymal stem cells therapy in tumor microenvironment: pros and cons.

Multipotent mesenchymal stem cells (MSCs) are widely accepted as a useful tool for cell-based therapy of various diseases including malignancies. The therapeutic effects of MSCs are mainly attributed to their immunomodulatory and immunosuppressive properties. Despite the promising outcomes of MSCs in cancer therapy, a growing body of evidence implies that MSCs also show tumorigenic properties in the tumor microenvironment (TME), which might lead to tumor induction and progression. Owing to the broad-spectrum applications of MSCs, this challenge needs to be tackled so that they can be safely utilized in clinical practice. Herein, we review the diverse activities of MSCs in TME and highlight the potential methods to convert their protumorigenic characteristics into onco-suppressive effects.

Regenerative potential of mesenchymal stromal cells in wound healing: unveiling the influence of normoxic and hypoxic environments.

The innate and adaptive immune systems rely on the skin for various purposes, serving as the primary defense against harmful environmental elements. However, skin lesions may lead to undesirable consequences such as scarring, accelerated skin aging, functional impairment, and psychological effects over time. The rising popularity of mesenchymal stromal cells (MSCs) for skin wound treatment is due to their potential as a promising therapeutic option. MSCs offer advantages in terms of differentiation capacity, accessibility, low immunogenicity, and their central role in natural wound-healing processes. To accelerate the healing process, MSCs promote cell migration, angiogenesis, epithelialization, and granulation tissue development. Oxygen plays a critical role in the formation and expansion of mammalian cells. The term "normoxia" refers to the usual oxygen levels, defined at 20.21 percent oxygen (160 mm of mercury), while "hypoxia" denotes oxygen levels of 2.91 percent or less. Notably, the ambient O2 content (20%) in the lab significantly differs from the 2%-9% O2 concentration in their natural habitat. Oxygen regulation of hypoxia-inducible factor-1 (HIF-1) mediated expression of multiple genes plays a crucial role in sustaining stem cell destiny concerning proliferation and differentiation. This study aims to elucidate the impact of normoxia and hypoxia on MSC biology and draw comparisons between the two. The findings suggest that expanding MSC-based regenerative treatments in a hypoxic environment can enhance their growth kinetics, genetic stability, and expression of chemokine receptors, ultimately increasing their effectiveness.

Double-edged sword of JAK/STAT signaling pathway in viral infections: novel insights into virotherapy.

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) is an intricate signaling cascade composed of various cytokines, interferons (IFN, growth factors, and other molecules. This pathway provides a delicate mechanism through which extracellular factors adjust gene expression, thereby acting as a substantial basis for environmental signals to influence cell growth and differentiation. The interactions between the JAK/STAT cascade and antiviral IFNs are critical to the host's immune response against viral microorganisms. Recently, with the emergence of therapeutic classes that target JAKs, the significance of this  cascade has been recognized in an unprecedented way. Despite the functions of the JAK/STAT pathway in adjusting immune responses against viral pathogens, a vast body of evidence proposes the role of this cascade in the replication and pathogenesis of viral pathogens. In this article, we review the structure of the JAK/STAT signaling cascade and its role in immuno-inflammatory responses. We also highlight the paradoxical effects of this pathway in the pathogenesis of viral infections. Video Abstract.

Application of hypoxia-mesenchymal stem cells in treatment of anaerobic bacterial wound infection: wound healing and infection recovery.

Mesenchymal stromal cells, commonly referred to as MSCs, are a type of multipotent stem cells that are typically extracted from adipose tissue and bone marrow. In the field of tissue engineering and regenerative medicine, MSCs and their exosomes have emerged as revolutionary tools. Researchers are now devoting greater attention to MSCs because of their ability to generate skin cells like fibroblasts and keratinocytes, as well as their distinctive potential to decrease inflammation and emit pro-angiogenic molecules at the site of wounds. More recent investigations revealed that MSCs can exert numerous direct and indirect antimicrobial effects that are immunologically mediated. Collectively, these antimicrobial properties can remove bacterial infections when the MSCs are delivered in a therapeutic setting. Regardless of the positive therapeutic potential of MSCs for a multitude of conditions, transplanted MSC cell retention continues to be a major challenge. Since MSCs are typically administered into naturally hypoxic tissues, understanding the impact of hypoxia on the functioning of MSCs is crucial. Hypoxia has been postulated to be among the factors determining the differentiation of MSCs, resulting in the production of inflammatory cytokines throughout the process of tissue regeneration and wound repair. This has opened new horizons in developing MSC-based systems as a potent therapeutic tool in oxygen-deprived regions, including anaerobic wound infection sites. This review sheds light on the role of hypoxia-MSCs in the treatment of anaerobic bacterial wound infection in terms of both their regenerative and antimicrobial activities.

Divergent functions of NLRP3 inflammasomes in cancer: a review.

The cancer is a serious health problem, which is The cancer death rate (cancer mortality) is 158.3 per 100,000 men and women per year (based on 2013-2017 deaths). Both clinical and translational studies have demonstrated that chronic inflammation is associated with Cancer progression. However, the precise mechanisms of inflammasome, and the pathways that mediate this phenomenon are not fully characterized. One of the most recently identified signaling pathways, whose activation seems to affect many metabolic disorders, is the "inflammasome" a multiprotein complex composed of NLRP3 (nucleotide-binding domain and leucine-rich repeat protein 3), ASC (apoptosis associated speck-like protein containing a CARD), and procaspase-1. NLRP3 inflammasome activation leads to the processing and secretion of the proinflammatory cytokines interleukin-1ß (IL-1ß) and IL-18. The goal of this paper is to review new insights on the effects of the NLRP3 inflammasome activation in the complex mechanisms of crosstalk between different organs, for a better understanding of the role of chronic inflammation in cancer pathogenesis. We will provide here a perspective on the current research on NLRP3 inflammasome, which may represent an innovative therapeutic target to reverse the malignancy condition consequences of the inflammation. Video Abstract.

Mesenchymal stem cell therapy for non-healing diabetic foot ulcer infection: New insight.

Diabetic foot ulcer (DFU) is considered the most catastrophic complication of diabetes mellitus (DM), leading to repeated hospitalizations, infection, gangrene, and finally amputation of the limb. In patients suffering from diabetes mellitus, the wound-healing process is impaired due to various factors such as endothelial dysfunction and synthesis of advanced glycation end-products, hence, conventional therapeutic interventions might not be effective. With increasing therapeutic applications of mesenchymal stem cells (MSCs) in recent years, their potential as a method for improving the wound-healing process has gained remarkable attention. In this field, mesenchymal stem cells exert their beneficial effects through immunomodulation, differentiation into the essential cells at the site of ulcers, and promoting angiogenesis, among others. In this article, we review cellular and molecular pathways through which mesenchymal stem cell therapy reinforces the healing process in non-healing Diabetic foot ulcers.

The role of microRNA-30c in targeting interleukin 6, as an inflammatory cytokine, in the mesenchymal stem cell: a therapeutic approach in colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) is the third most prevalent cancer and the second significant cause of cancer-associated death worldwide. The microRNA-30 is a substantial member of the miRNA family and plays a vital role in expanding several cancers. This microRNA potentially targets interleukin 6 as an inflammatory cytokine in CRC. MATERIALS AND METHODS: MSCs were isolated and identified from mice bone marrow and then transduced with lentiviruses containing miR-30C. Transfected MSCs were collected to evaluate IL-6 levels, CT-26 cells were also co-cultured with MSCs, and the effect of apoptosis and IL-6 on the supernatant was assessed. RESULTS: Our result showed the expression of IL-6 mRNA and the level of protein were decreased in the supernatant of miR-30-transduced MSC cells compared to the control group. In addition, the rate of apoptosis was assessed, and the obtained data revealed the induction of apoptosis in CT-26 cells when they are in the vicinity of miR-30c-transduced MSCs. DISCUSSION AND CONCLUSION: We demonstrated that downregulation of miR-30c was significantly correlated with CRC progression and survival. So, the present study elucidated the anticancer effects of miR-30c in CRC and presented a novel target for CRC therapy.

COVID-19 and the potential of Janus family kinase (JAK) pathway inhibition: A novel treatment strategy.

Recent evidence proposed that the severity of the coronavirus disease 2019 (COVID-19) in patients is a consequence of cytokine storm, characterized by increased IL-1ß, IL-6, IL-18, TNF-α, and IFN-γ. Hence, managing the cytokine storm by drugs has been suggested for the treatment of patients with severe COVID-19. Several of the proinflammatory cytokines involved in the pathogenesis of COVID-19 infection recruit a distinct intracellular signaling pathway mediated by JAKs. Consequently, JAK inhibitors, including baricitinib, pacritinib, ruxolitinib, and tofacitinib, may represent an effective therapeutic strategy for controlling the JAK to treat COVID-19. This study indicates the mechanism of cytokine storm and JAK/STAT pathway in COVID-19 as well as the medications used for JAK/STAT inhibitors.

MicroRNA-30c delivered by bone marrow-mesenchymal stem cells induced apoptosis and diminished cell invasion in U-251 glioblastoma cell line.

BACKGROUND: Glioblastoma multiform (GBM) is the most belligerent and prevalent brain malignancy among adults. Due to the blood-brain barrier (BBB), drug administration is confronted by massive challenges, making resectional surgery the only treatment pipeline. MicroRNAs have recently absorbed the attention of studies for correlating with the progression of various malignancies. miR-30c has been reported to play a role in cell proliferation, metabolism, and apoptosis process. For instance, miR-30c has been reported to regulate apoptosis through the TNF-related apoptosis-inducing ligand (TRAIL). miR-30c also targets IL-6, which further induces apoptosis. Besides, miR-30c inhibits glioma proliferation and its migratory ability. Besides, the overexpression of miR-30c arrested cells at G0 as well as dampening their migration and invasion. However, it has been shown that the expression level of miR-30c was low in glioma. MSCs can migrate toward tumor cells which is called tumor-tropism, in which they are capable of delivering engineered miR-30c based on gap junction and non-intimacy mechanisms. MATERIAL AND METHODS: MiR-30c was cloned into pCDH-CMV-MCS-EF1-copGFP vector utilizing XbaI and EcoRI in order to construct pCDH-miR-30c. Then psPAX2, pMD2.G, and pCDH-miR-30c were co-transfected into Hek-293T to yield lenti-miR-30c virus particles. Next, bone marrow-mesenchymal stem cells (BM-MSCs) were Transduced with lenti-miR-30c. Thereafter, we co-cultured U-251 cell line with BM-MCSs-miR-30c and evaluated the apoptosis rate and the relative expression level of IL-6, Klf4, Sox2, c-Myc, and Oct4 using Real-Time PCR and flow cytometry. RESULTS: Wound healing assays represented low migratory ability in U-251 cells treated with BM-MSCs-miR-30c. Plus, apoptosis assay using Annexin V/7AAD showed an increased number of apoptotic U-251 cells following the treatment. miR-30 targeted IL-6 and induced apoptosis. It also impacted on the self-renewal and the anti-apoptotic cluster of genes, namely Klf4, Sox2, c-Myc, and Oct4, to induce apoptosis and dwindle the migration and invasion.