Investigating the Effects of Hydro-alcoholic Urtica Dioica Extract and Retinoic Acid on Follicular Development: An Animal Study.

Background: Urtica dioica (UD), as a natural antioxidant, has positive effects on oocyte maturation. This study aimed to investigate the effects of hydro-alcoholic UD extract and retinoic acid on follicular development in an in vitro fertilization (IVF) condition. Methods: A total of 40 female Wistar rats were randomly divided into 5 groups: group 1 received normal saline, group 2 was given 25 mg/kg retinoic acid, group 3 was administered with 100 mg/kg UD extract, group 4 was treated with retinoic acid plus UD extract, and group 5 received 10 mg/kg olive oil. The histomorphometric parameters were analyzed, including the number of follicles, follicular atrophy, fertilized oocytes, 2-cell embryos, dead embryos, and blastocysts. Results: Retinoic acid caused a significant increase in the primary, preantral, and atretic follicles and a substantial decrease in the corpus luteum compared with the control group (p<0.001). The number of preantral, antral follicles, and corpus luteum was significantly higher in group 3 compared with group 1 (p<0.001). Moreover, coadministration of UD plus retinoic acid (group 4) significantly reduced the atretic follicles (p<0.05). Conclusion: Based on the results, UD herbal extract, as a natural antioxidant agent, could reduce the adverse effects of retinoic acid on oocyte maturation in an IVF condition.

Advances in Biosensing of Chemical Food Contaminants Based on the MOFs-Graphene Nanohybrids.

Food safety issue is becoming an international challenge for human health owing to the presence of contaminants. In this context, reliable, rapid, and sensitive detecting technology is extremely demanded to establish food safety assurance systems. MOFs (Metal-organic frameworks) are a new type of porous crystalline material with particular physical and chemical characteristics presented in food safety requirements. (Bio)sensors driven MOF materials have emerged as a promising alternative and complementary analytical techniques, owing to their great specific area, high porosity, and uniform and fine-tunable pore buildings. Nevertheless, the insufficient stability and electrical conductivity of classical MOFs limit their utilization. Employing graphene-derived nanomaterials with high functional elements as patterns for the MOF materials not only improves the structural instability and poor conductivity but also impedes the restacking and aggregation between graphene layers, thus significantly extending the MOFs application. A review of MOFs-graphene-based material used in food contamination detection is urgently needed for encouraging the advance of this field. Herein, this paper systematically outlines current breakthroughs in MOF-graphene-based nanoprobes, outlines their principles, and illustrates their employments in identifying mycotoxins, heavy metal ions, pathogens, antibiotics, and pesticides, referring to their multiplexing and sensitivity ability. The challenges and limitations of applying MOF-graphene composite for precise and efficient assessment of food were also debated. This paper would maybe offer some inspired concepts for an upcoming study on MOF-based composites in the food security context.

PCSK9 pathway-noncoding RNAs crosstalk: Emerging opportunities for novel therapeutic approaches in inflammatory atherosclerosis.

A variety of mechanisms contribute to the occurrence and development of inflammatory atherosclerosis (IA), resulting in cardiovascular disease. PCSK9 (proprotein convertase subtilisin/ kexin type 9) has now been recognized as a key player in the pathophysiology of atherosclerosis. Following PCSK9 activation, LDL receptors (LDLR) are degraded and as a result, LDL cholesterol (LDLC) levels are increased. Increasing evidence reports that the PCSK9 axis mediates IA through different pathways, such as LDLR, LOX1, NF-kB, and TLR4. In recent years, PCSK9 pathway dysregulation has been identified as one of the fundamental mechanisms involved in IA. Recently, the importance of epigenetic factors, in particular, in non-coding RNAs, including miRNAs and long ncRNAs (lncRNAs) as well as circular RNAs (circRNAs) in the regulation of physiological and pathological events has received great attention. In this regard, an expanding body of research has revealed that different ncRNAs play important roles in the progression of inflammatory atherosclerosis through targeting genes related to the PCSK9 pathway at the post-transcriptional level. Of importance, the current study aimed to review the relationship between the various ncRNAs and PCSK9 pathway to identify the molecular mechanisms underlying IA pathogenesis as well as to introduce the novel PCSK9 pathway-related therapeutic interventions in combating IA.

Protective effects of summer savory (Satureja hortensis) oil on growth, biochemical, and immune system performance of common carp exposed to pretilachlor herbicide.

There are many reports on the deleterious effects of herbicides on aquatic organisms which lead to tremendous biological, environmental and economical damage. In this regard, in the present study, the protective effect of summer savory (Satureja hortensis) essential oil (SEO) against pretilachlor, one of the most used herbicides was investigated in common carp (Cyprinus carpio). The fish assigned to six treatment groups (T1: control treatment; T2: 25% LC50 pretilachlor herbicide; T3: 50% LC50 pretilachlor herbicide; T4: 1% SEO; T5: 25% LC50 pretilachlor herbicide + 1% SEO; and T6: 25% LC50 pretilachlor herbicide + 1% SEO) for 21 days. The results showed that the SEO-containing treatments significantly increased the survival rate (SR) (P < 0.05). The highest final weight (FW), specific growth rate (SGR), and feed conversion ratio (FCR) were observed in the T4 treatment (P < 0.05). There was a significant increase in glucose (GLU) level in pretilachlor treatments and a significant decrease in SEO-containing treatments compared to the control (P < 0.05). The significantly highest total protein (TP) content was observed in T4 treatment containing SEO. Cholesterol (CHOL) and triglyceride (TRIG) levels decreased in SEO-containing treatments with the lowest level in T4 treatment (P < 0.05). Alternative complement pathway activity (ACH50), activity levels of superoxide dismutase (SOD), and glutathione peroxidase (GPX) showed an increasing trend in SEO-containing treatments with the highest level in T4 treatment (P < 0.05). The activity of liver enzymes showed a significantly lowest level in T4 treatment. To conclude, our findings revealed that the use of SEO in fish exposed to pretilachlor herbicide could improve growth, strengthen the immune system and exert a protective effect on common carp.

Effect of tomato consumption on inflammatory markers in health and disease status: A systematic review and meta-analysis of clinical trials.

BACKGROUND AND AIMS: Inflammation is a major cause of chronic diseases. Several studies have investigated the effects of tomato intake on inflammatory biomarkers; however, the results are equivocal. Therefore, the present study aimed to systematically review and analyses randomized clinical trials (RCTs) assessing the effects of tomato intake on inflammatory biomarkers in adults. METHODS: A systematic search was performed in PubMed, Scopus, ISI Web of Science, and Cochrane Library databases to find RCTs related to the effect of tomato intake on inflammatory markers, including C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α), up to November 2021. Meta-analyses were performed using the random-effects model. RESULTS: A total of 465 subjects sourced from seven eligible RCTs (8 treatment arms) were entered into the analysis. Pooled effect size of articles indicated that tomato intake was not significantly effective on CRP (WMD: 0.13 mg/dL, 95% CI: -0.09 to 0.36; P = 0.23, I2: 83.9%) and IL-6 (Hedges' g = -0.12; 95% CI -0.36, 0.13; P = 0.34, I2: 0.0%) levels compared to the control group. But it can significantly reduce TNF-α (Hedges' g = -0.45; 95% CI -0.76, -0.13; P = 0.005, I2: 0.0%) levels. CONCLUSION: Generally, the present study showed that tomato intake has no significant effect on serum CRP, and IL-6 concentrations, but can reduce serum TNF-α levels significantly. However, additional well-designed studies that include more diverse populations and longer duration are warranted.

Mesenchymal stromal/stem cells and their exosomes application in the treatment of intervertebral disc disease: A promising frontier.

Today, the application of mesenchymal stromal/stem cells (MSCs) and their exosomes to treat degenerative diseases has received attention. Due to the characteristics of these cells, such as self-renewability, differentiative and immunomodulatory effects, their use in laboratory and clinical studies shows promising results. However, the allogeneic transplantation problems of MSCs limit the use of these cells in the clinic. Scientists propose the application of exosomes to use from the therapeutic effect of MSCs and overcome their defects. These vesicles change the target cell behaviour and transcription profile by transferring various cargo such as proteins, mi-RNAs, and lipids. One of the degenerative tissue diseases in which MSCs and their exosomes are used in their treatment is intervertebral disc disease (IDD). Different factors such as genetics, nutrition, ageing, and environmental factors play a significant role in the onset and progression of this disease. These factors affect the cellular and molecular properties of the disc, leading to tissue destruction. Nucleus pulposus cells (NPCs) are among the most important cells involved in the pathogenesis of disc degeneration. MSCs exert their therapeutic effects by differentiating, reducing apoptosis, increasing proliferation, and decreasing senescence in NPCs. In addition, the use of MSCs and their exosomes also affects the annulus fibrosus and cartilaginous endplate cells in disc tissue and prevents disc degeneration progression.

Applications of Microfluidic Devices in the Diagnosis and Treatment of Cancer: A Review Study.

Many cancer-related deaths are reported annually due to a lack of appropriate diagnosis and treatment strategies. Microfluidic technology, as new creativity has a great impact on automation and miniaturization via handling a small volume of materials and samples (in microliter to femtoliter range) to set up the system. Microfluidic devices not only detect various cancer-diagnostic factors from biological fluids but also can produce proper nanoparticles for drug delivery. With the contribution of microfluidics; multiple treatments for cancer such as chemotherapy, radiation therapy, and gene delivery can be implemented and studied. Hence, Microfluidics can be worth for the cancer field because of its high Throughput, high sensitivity, less material use, and low expense. In this review study, we intend to look at positive microfluidics prospects, features, benefits, and clinical applications.

Vitamin D Receptor gene polymorphisms and susceptibility to type 2 diabetes: evidence from a meta-regression and meta-analysis based on 47 studies.

BACKGROUND: Evidence from various studies suggest that vitamin D receptor (VDR) gene polymorphisms are associated with type 2 diabetes (T2D); However, these results have been disputable. Here we conducted a meta-analysis to comprehensively evaluate the effect of VDR gene polymorphisms and susceptibility to T2D. METHODS: All relevant studies reporting the association between VDR gene polymorphisms and susceptibility to T2D published up to August 2020 were identified by comprehensive systematic database search in web of science, Scopus, and Medline. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to measure strength of association. The methodological quality of each study was assessed according to the Newcastle-Ottawa Scale. Subgroup and meta-regression analysis were also performed. RESULTS: A total of 47 case-control studies were included in this meta-analysis. The overall population results revealed a significant association between FokI, and BsmI (heterozygote model) polymorphisms and T2D in the overall analysis. However, no association was found with the TaqI and ApaI polymorphisms. Moreover, the pooled results of subgroup analysis by ethnicity suggested significant association between FokI, TaqI, and BsmI polymorphisms and T2D in some subgroups. Meta-regression analyses indicated that none of the publication year, ethnicity, and genotyping method were the source of heterogenicity in all four polymorphisms. CONCLUSIONS: This meta-analysis suggested a significant association between VDR gene FokI, and BsmI (heterozygote model) polymorphisms and T2D susceptibility in overall population and ethnic-specific analysis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-020-00704-z.

A deep insight into CRISPR/Cas9 application in CAR-T cell-based tumor immunotherapies.

To date, two chimeric antigen receptors (CAR)-T cell products from autologous T cells have been approved by The United States Food and Drug Administration (FDA). The case-by-case autologous T cell generation setting is largely considered as a pivotal restraining cause for its large-scale clinical use because of the costly and prolonged manufacturing procedure. Further, activated CAR-T cells mainly express immune checkpoint molecules, including CTLA4, PD1, LAG3, abrogating CAR-T anti-tumor activity. In addition, CAR-T cell therapy potently results in some toxicity, such as cytokine releases syndrome (CRS). Therefore, the development of the universal allogeneic T cells with higher anti-tumor effects is of paramount importance. Thus, genome-editing technologies, in particular, clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 are currently being used to establish "off-the-shelf" CAR-T cells with robust resistance to immune cell-suppressive molecules. In fact, that simultaneous ablation of PD-1, T cell receptor alpha constant (TRAC or TCR), and also ß-2 microglobulin (B2M) by CRISPR-Cas9 technique can support the manufacture of universal CAR-T cells with robust resistance to PD-L1. . Indeed, the ablation of ß2M or TARC can severely hinder swift elimination of allogeneic T cells those express foreign HLA-I molecules, and thereby enables the generation of CAR-T cells from allogeneic healthy donors T cells with higher persistence in vivo. Herein, we will deliver a brief overview of the CAR-T cell application in the context of tumor immunotherapy. More importantly, we will discuss recent finding concerning the application of genome editing technologies for preparing universal CAR-T cells or cells that can effectively counter tumor escape, with a special focus on CRISPR-Cas9 technology.

The effects of oxygen-ozone therapy on regulatory T-cell responses in multiple sclerosis patients.

Multiple sclerosis (MS) is a common degenerative disorder of the central nervous system. The decreased frequency and dysfunction of Treg cells cause inflammation and disease progression. Ozone autohemotherapy can be used as a potential therapeutic approach to regulate the immune system responses and inflammation in MS. For this purpose, 20 relapsing-remitting multiple sclerosis patients were under treatment with ozone twice weekly for 6 months. The frequency of Treg cell, the expression levels of the Treg cell-related factors (FoxP3, IL-10, TGF-ß, miR-17, miR-27, and miR-146A), and the secretion levels of IL-10 and TGF-ß were assessed. We found a significant increase in the number of Treg cells, expression levels of FoxP3, miRNAs (miR-17 and miR-27), IL-10, and TGF-ß factors in patients after oxygen-ozone (O2 -O3 ) therapy compared to before treatment. In contrast, oxygen-ozone therapy notably decreased the expression level of miR-146a in treated patients. Interestingly, the secretion levels of both IL-10 and TGF-ß cytokines were considerably increased in both serum and supernatant of cultured peripheral blood mononuclear cells in posttreatment condition compared to pretreatment condition. According to results, oxygen-ozone therapy raised the frequency of Treg cell and its relevant factors in treated MS patients. Oxygen-ozone therapy would contribute to improving the MS patients by elevating the Treg cell responses.

Mesenchymal stem/stromal cells as a valuable source for the treatment of immune-mediated disorders.

Over recent years, mesenchymal stem/stromal cells (MSCs) and their potential biomedical applications have received much attention from the global scientific community in an increasing manner. Firstly, MSCs were successfully isolated from human bone marrow (BM), but in the next steps, they were also extracted from other sources, mostly from the umbilical cord (UC) and adipose tissue (AT). The International Society for Cellular Therapy (ISCT) has suggested minimum criteria to identify and characterize MSCs as follows: plastic adherence, surface expression of CD73, D90, CD105 in the lack of expression of CD14, CD34, CD45, and human leucocyte antigen-DR (HLA-DR), and also the capability to differentiate to multiple cell types including adipocyte, chondrocyte, or osteoblast in vitro depends on culture conditions. However, these distinct properties, including self-renewability, multipotency, and easy accessibility are just one side of the coin; another side is their huge secretome which is comprised of hundreds of mediators, cytokines, and signaling molecules and can effectively modulate the inflammatory responses and control the infiltration process that finally leads to a regulated tissue repair/healing or regeneration process. MSC-mediated immunomodulation is a direct result of a harmonic synergy of MSC-released signaling molecules (i.e., mediators, cytokines, and chemokines), the reaction of immune cells and other target cells to those molecules, and also feedback in the MSC-molecule-target cell axis. These features make MSCs a respectable and eligible therapeutic candidate to be evaluated in immune-mediated disorders, such as graft versus host diseases (GVHD), multiple sclerosis (MS), Crohn's disease (CD), and osteoarthritis (OA), and even in immune-dysregulating infectious diseases such as the novel coronavirus disease 2019 (COVID-19). This paper discussed the therapeutic applications of MSC secretome and its biomedical aspects related to immune-mediated conditions. Sources for MSC extraction, their migration and homing properties, therapeutic molecules released by MSCs, and the pathways and molecular mechanisms possibly involved in the exceptional immunoregulatory competence of MSCs were discussed. Besides, the novel discoveries and recent findings on immunomodulatory plasticity of MSCs, clinical applications, and the methods required for their use as an effective therapeutic option in patients with immune-mediated/immune-dysregulating diseases were highlighted.

P53 long noncoding RNA regulatory network in cancer development.

The protein p53 as a transcription factor with strong tumor-suppressive activities is known to trigger apoptosis via multiple pathways and is directly involved in the recognition of DNA damage and DNA repair processes. P53 alteration is now recognized as a common event in the pathogenesis of many types of human malignancies. Deregulation of tumor suppressor p53 pathways plays an important role in the activation of cell proliferation or inactivation of apoptotic cell death during carcinogenesis and tumor progression. Mounting evidence indicates that the p53 status of tumors and also the regulatory functions of p53 may be relevant to the long noncoding RNAs (lncRNA)-dependent gene regulation programs. Besides coding genes, lncRNAs that do not encode for proteins are induced or suppressed by p53 transcriptional response and thus control cancer progression. LncRNAs also have emerged as key regulators that impinge on the p53 signaling network orchestrating global gene-expression profile. Studies have suggested that aberrant expression of lncRNAs as a molecular-genomic signature may play important roles in cancer biology. Accordingly, it is important to elucidate the mechanisms by which the crosstalk between lncRNAs and p53 occurs in the development of numerous cancers. Here, we review how several classes of lncRNAs and p53 pathways are linked together in controlling the cell cycle and apoptosis in various cancer cells in both human and mouse model systems.

Mesenchymal stem cells and cancer therapy: insights into targeting the tumour vasculature.

A crosstalk established between tumor microenvironment and tumor cells leads to contribution or inhibition of tumor progression. Mesenchymal stem cells (MSCs) are critical cells that fundamentally participate in modulation of the tumor microenvironment, and have been reported to be able to regulate and determine the final destination of tumor cell. Conflicting functions have been attributed to the activity of MSCs in the tumor microenvironment; they can confer a tumorigenic or anti-tumor potential to the tumor cells. Nonetheless, MSCs have been associated with a potential to modulate the tumor microenvironment in favouring the suppression of cancer cells, and promising results have been reported from the preclinical as well as clinical studies. Among the favourable behaviours of MSCs, are releasing mediators (like exosomes) and their natural migrative potential to tumor sites, allowing efficient drug delivering and, thereby, efficient targeting of migrating tumor cells. Additionally, angiogenesis of tumor tissue has been characterized as a key feature of tumors for growth and metastasis. Upon introduction of first anti-angiogenic therapy by a monoclonal antibody, attentions have been drawn toward manipulation of angiogenesis as an attractive strategy for cancer therapy. After that, a wide effort has been put on improving the approaches for cancer therapy through interfering with tumor angiogenesis. In this article, we attempted to have an overview on recent findings with respect to promising potential of MSCs in cancer therapy and had emphasis on the implementing MSCs to improve them against the suppression of angiogenesis in tumor tissue, hence, impeding the tumor progression.

Shedding more light on the role of Midkine in hepatocellular carcinoma: New perspectives on diagnosis and therapy.

One of the most common malignant tumors is hepatocellular carcinoma (HCC). Progression of HCC mainly results from highly complex molecular and pathological pathways. Midkine (MDK) is a growth factor that impacts viability, migration, and other cell activities. Since MDK has been involved in the inflammatory responses, it has been claimed that MDK has a crucial role in HCC. MDK acts as an anti-apoptotic factor, which mediates tumor cell viability. In addition, MDK blocks anoikis to promote metastasis. There is also evidence that MDK is involved in angiogenesis. It has been shown that the application of anti-MDK approaches might be promising in the treatment of HCC. Besides, due to the elevated expression in HCC, MDK has been proposed as a biomarker in the prognosis and diagnosis of HCC. In this review, we will discuss the role of MDK in HCC. It is hoped that the development of new strategies concerning MDK-based therapies will be promising in HCC management.

Codelivery of STAT3 and PD-L1 siRNA by hyaluronate-TAT trimethyl/thiolated chitosan nanoparticles suppresses cancer progression in tumor-bearing mice.

Immunotherapy methods using potential tumor microenvironment modulators have elicited durable therapeutic responses in cancer treatment. Immune checkpoint molecule programmed cell death-ligand 1 (PD-L1) and oncogenic transcription factor STAT3 (signal transducer and activator of transcription-3) assigned as inhibitory targets of our study and particular delivery system designed to deliver small interfering RNAs (siRNAs) to silence the targeted genes. Generated trimethyl chitosan (TMC) and thiolated chitosan (TC) nanoparticles (NPs) conjugated with HIV-1-derived TAT peptide and HA (hyaluronic acid) exhibited eligible physicochemical characteristics, notable siRNA encapsulation, serum stability, non-toxicity, controlled siRNA release, and extensive cellular uptake by cancer cells. Dual inhibition with STAT3/PD-L1 siRNA-loaded HA-TAT-TMC-TC NPs led to promising results, including significant downregulation of PD-L1 and STAT3 genes, striking suppressive effects on proliferation, migration, and angiogenesis of breast and melanoma cancer cell lines, and restrained tumor growth in vivo. These findings infer the capability of HA-TAT-TMC-TC NPs containing STAT3/PD-L1 siRNAs as a novel tumor-suppressive candidate in cancer treatment.