PD-1 and CTLA-4 can play an important role in addressing the issue of autoimmune diseases. PD-1 is a transmembrane glycoprotein expressed on T, B, and Dentric cells. This molecule functions as a checkpoint in T cell proliferation. Ligation of PD-1 with its ligands inhibits the production of IL-2, IL-7, IL-10, and IL-12 as well as other cytokines by macrophages, natural killer (NK) cells, and T cells, which can suppress cell proliferation and inflammation. Today, scientists attempt to protect against autoimmune diseases by PD-1 inhibitory signals. In this review, we discuss the structure, expression, and signaling pathway of PD-1. In addition, we discuss the importance of PD-1 in regulating several autoimmune diseases, reflecting how manipulating this molecule can be an effective method in the immunotherapy of some autoimmune diseases.
Sin3 associated protein 18 (SAP18) is an evolutionary conserved protein, originally discovered in a complex with the transcriptional regulatory protein, Sin3. Subsequent investigations revealed SAP18 as an integral splicing component of the exon junction complex (EJC)-associated apoptosis-and splicing-associated protein (ASAP)/PNN-RNPS1-SAP18 (PSAP) complex. In association with Sin3, SAP18 contributes toward transcriptional repression of genes implicated in embryonic development, stress response, human immunodeficiency virus type 1 replication, and tumorigenesis. As a part of EJC, SAP18 mediates alternative splicing events and suppresses the cryptic splice sites present within flanking regions of exon–exon junctions. In this review, we provide a thorough discussion on SAP18, focussing on its conserved dual role in transcriptional regulation and messenger RNA splicing. Recent research on the involvement of SAP18 in the emergence of cancer and human disorders has also been highlighted. The potential of SAP18 as a therapeutic target is also discussed in these recent studies, particularly related to malignancies of the myeloid lineage.
MicroRNAs (miRNAs) are a class of noncoding RNAs that occupy a significant role in biological processes as important regulators of intracellular homeostasis. First, we will discuss the biological genesis and functions of the miR-302/367 cluster, including miR-302a, miR-302b, miR-302c, miR-302d, and miR-367, as well as their roles in physiologically healthy tissues. The second section of this study reviews the progress of the miR-302/367 cluster in the treatment of cancer, inflammation, and diseases associated with aging. This cluster's aberrant expression in cells and/or tissues exhibits similar or different effects in various diseases through molecular mechanisms such as proliferation, apoptosis, cycling, drug resistance, and invasion. This article also discusses the upstream and downstream regulatory networks of miR-302/367 clusters and their related mechanisms. Particularly because studies on the upstream regulatory molecules of miR-302/367 clusters, which include age-related macular degeneration, myocardial infarction, and cancer, have become more prevalent in recent years. MiR-302/367 cluster can be an important therapeutic target and the use of miRNAs in combination with other molecular markers may improve diagnostic or therapeutic capabilities, providing unique insights and a more dynamic view of various diseases. It is noted that miRNAs can be an important bio-diagnostic target and offer a promising method for illness diagnosis, prevention, and treatment.
Noncoding RNAs (ncRNAs) are active regulators of a wide range of biological and physiological processes, including the majority of mammalian reproductive events. Knowledge of the biological activities of ncRNAs in the context of mammalian reproduction will allow for a more comprehensive and comparative understanding of male sterility and fertility. In this review, we describe recent advances in ncRNA-mediated control of mammalian reproduction and emphasize the importance of ncRNAs in several aspects of mammalian reproduction, such as germ cell biogenesis and reproductive organ activity. Furthermore, we focus on gene expression regulatory feedback loops including hormones and ncRNA expression to better understand germ cell commitment and reproductive organ function. Finally, this study shows the role of ncRNAs in male reproductive failure and provides suggestions for further research.
Multiple sclerosis (MS) is a life-threading disease that poses a great threat to the human being lifestyle. Having said extensive research in the realm of underlying mechanisms and treatment procedures, no definite remedy has been found. Over the past decades, many medicines have been disclosed to alleviate the symptoms and marking of MS. Meanwhile, the substantial efficacy of herbal medicines including curcumin must be underscored. Accumulated documents demonstrated the fundamental role of curcumin in the induction of the various signaling pathways. According to evidence, curcumin can play a role in mitochondrial dysfunction and apoptosis, autophagy, and mitophagy. Also, by targeting the signaling pathways AMPK, PGC-1α/PPARγ, and PI3K/Akt/mTOR, curcumin interferes with the metabolism of MS. The anti-inflammatory, antioxidant, and immune regulatory effects of this herbal compound are involved in its effectiveness against MS. Thus, the present review indicates the molecular and metabolic pathways associated with curcumin's various pharmacological actions on MS, as well as setting into context the many investigations that have noted curcumin-mediated regulatory effects in MS.
The metastatic behavior of melanoma has accentuated the need for specific therapy targets. Compounds, namely l-kynurenine ( l-kyn), quinolinic acid (Quin), and kynurenic acid (KA) previously displayed antiproliferative and cytotoxic effects in vitro against cancer cells. Despite the growing interest in these compounds there are limited studies examining the in vitro effects on melanoma. In B16 F10 melanoma cells, RAW 264.7 macrophage cells, and HaCat keratinocyte cells, postexposure to the compounds, crystal violet staining was used to determine the half-maximal inhibitory concentration (IC50), whereas polarization-optical transmitted light differential interference contrast and light microscopy after hematoxylin and eosin (H&E) staining was used to assess morphological changes. l-kyn, Quin, and KA-induced cytotoxicity in all cell lines, with l-kyn being the most cytotoxic compound. l-kyn and KA at IC50-induced morphological changes in B16 F10, RAW 264.7, and HaCat cell lines, whereas Quin had effects on B16 F10 and RAW 264.7 cells but did not affect HaCat cells. l-kyn, Quin, and KA each display different levels of cytotoxicity, which were cell line specific. l-kyn was shown to be the most potent compound against all cell lines and may offer future treatment strategies when combined with other viable treatments against melanoma.
The prevalence of breast cancer (BC) continues to increase and is the leading cause of cancer deaths in many countries. Numerous in vitro and in vivo studies have demonstrated that 2-methoxyestradiol (2-ME) has antiproliferative and antiangiogenic effects in BC, thereby inhibiting tumour growth and metastasis. We compared the effect of 2-ME in early- and late-stage BC using a transgenic mouse model—FVB/N-Tg(MMTV-PyVT)—of spontaneously development of aggressive mammary carcinoma with lung metastasis. Mice received 100 mg/kg 2-ME treatment immediately when palpable mammary tumours were identified (early-stage BC; Experimental group 1) and 28 days after palpable mammary tumours were detected (late-stage BC; Experimental group 2). 2-ME was administered via oral gavage three times a week for 28 days after initiation of treatment, whereas control mice received the vehicle containing 10% dimethyl sulfoxide and 90% sunflower oil for the same duration as the treatment group. Mammary tumours were measured weekly over the 28 days and at termination, blood, mammary and lung tissue were collected for analysis. Mice with a tumour volume threshold of 4000 mm3 were killed before the treatment regime was completed. 2-ME treatment of early-stage BC led to lower levels of mammary tumour necrosis, whereas tumour mass and volume were increased. Additionally, necrotic lesions and anti-inflammatory CD163-expressing cells were more frequent in pulmonary metastatic tumours in this group. In contrast, 2-ME treatment of late-stage BC inhibited tumour growth over the 28-day period and resulted in increased CD3+ cell number and tumour necrosis. Furthermore, 2-ME treatment slowed down pulmonary metastasis but did not increase survival of late-stage BC mice. Besides late-stage tumour necrosis, none of the other results were statistically significant. This study demonstrates that 2-ME treatment has an antitumour effect on late-stage BC, however, with no increase in survival rate, whereas the treatment failed to demonstrate any benefit in early-stage BC.
Choosing fusion tags to enhance the recombinant protein levels in the cytoplasm of Bacillus subtilis has been limited. Our previous study demonstrated that His-tag at the N-terminus could increase the expression levels of the low-expression gene egfp, while significantly reducing the high-expression genes gfp+ and bgaB in the cytoplasm of B. subtilis. In this study, we aimed to prove the potential of a fusion tag, the combination of the N-terminal domain of B. subtilis lysyl tRNA synthetase (LysSN) and His-tag with varying numbers of histidine (6xHis, 8xHis, 10xHis) by investigating their effects on the expression levels of egfp, gfp+ and bgaB in B. subtilis. For the low-expression gene, LysSN-xHis-tag could enhance the fluorescent intensity of EGFP 23.5 times higher than EGFP without a fusion tag, and 1.5 times higher than that fused with only His-tag. For high-expression genes, the expression level of BgaB and GFP+ was 2.9 and 12.5 times higher than that of His-tag, respectively. The number of histidines in LysSN-xHis-tag did not influence the expression levels of the high-expression genes but affected the expression levels of the low-expression gene.
Diabetes is one of the major health issues globally. Type 1 diabetes mellitus develops due to the destruction of pancreatic β cells. Mesenchymal stem cells (MSCs) having remarkable self-renewal and differentiation potential, can regenerate β cells. MSCs preconditioned with bioactive small molecules possess enhanced biological features and therapeutic potential under in vivo environment. Interestingly, compounds of naphthoquinone class possess antidiabetic and anti-inflammatory properties, and can be explored as potential candidates for preconditioning MSCs. This study analyzed the effect of lawsone-preconditioned human umbilical cord MSCs (hUMSCs) on the regeneration of β cells in the streptozotocin (STZ)-induced Type 1 diabetes (T1D) rats. hUMSCs were isolated and characterized for the presence of surface markers. MSCs were preconditioned with optimized concentration of lawsone. T1D rat model was established by injecting 50 mg/kg of STZ intraperitoneally. Untreated and lawsone-preconditioned hUMSCs were transplanted into the diabetic rats via tail vein. Fasting blood sugar and body weight were monitored regularly for 4 weeks. Pancreas was harvested and β cell regeneration was evaluated by hematoxylin and eosin staining, and gene expression analysis. Immunohistochemistry was also done to assess the insulin expression. Lawsone-preconditioned hUMSCs showed better anti-hyperglycemic effect in comparison with untreated hUMSCs. Histological analysis presented the regeneration of islets of Langerhans with upregulated expression of βcell genes and reduced expression of inflammatory markers. Immunohistochemistry revealed strong insulin expression in the preconditioned hUMSCs compared with the untreated hUMSCs. It is concluded from the present study that lawsone-preconditioned hMSCs were able to exhibit pronounced anti-hyperglycemic effect in vivo compared with hUMSCs alone.