Gene Expression Analysis in T2DM and Its Associated Microvascular Diabetic Complications: Focus on Risk Factor and RAAS Pathway.

Prolonged hyperglycemic conditions in type 2 diabetes mellitus (T2DM) cause pathological and functional damage to many organs and tissues, including the kidneys, retina, skin, and neuronal tissues, resulting in the development of microvascular diabetic complications. The altered renin angiotensin aldosterone system (RAAS) pathway has been reported to play an important role in the development of insulin resistance in T2DM and associated complications. The current study was carried out to evaluate the association of risk factors and altered expression of RAAS genes in T2DM patients without complications and T2DM patients with complications (retinopathy, nephropathy, and neuropathy). Four hundred and twenty subjects including 140 healthy controls, 140 T2DM patients with diabetic complications, and 140 T2DM patients without diabetic complications were included in the study. Risk factors associated with the development of T2DM and diabetic complications were evaluated. Further, expression analysis of RAAS genes (AGT, ACE, ACE2, and AGT1R) was carried out using qRTPCR in healthy controls, T2DM patients with complications, and T2DM patients without complications. Various risk factors like urban background, higher BMI, alcoholism, smoking, and family history of diabetes among others were found to be associated with the development of T2DM as well as diabetic complications. The expression level of AGT, ACE, and AGT1R was found to be upregulated whereas ACE2 was found to be downregulated in T2DM patients with complications and T2DM patients without complications as compared to controls. Altered expression of the studied genes of RAAS pathway is associated with the development of microvascular diabetic complications.

Trehalose and its Diverse Biological Potential.

Trehalose, a disaccharide molecule of natural origin, is known for its diverse biological applications, like in drug development, research application, natural scaffold, stem cell preservation, food, and various other industries. This review has discussed one such diverse molecule 'trehalose aka mycose', and its diverse biological applications with respect to therapeutics. Due to its inertness and higher stability at variable temperatures, it has been developed as a preservative to store stem cells, and later, it has been found to have anticancer properties. Trehalose has recently been associated with modulating cancer cell metabolism, diverse molecular processes, neuroprotective effect, and so on. This article describes the development of trehalose as a cryoprotectant and protein stabilizer as well as a dietary component and therapeutic agent against various diseases. The article discusses its role in diseases via modulation of autophagy, various anticancer pathways, metabolism, inflammation, aging and oxidative stress, cancer metastasis and apoptosis, thus highlighting its diverse biological potential.

Comprehensive analysis of culture conditions governing differentiation of MSCs into articular chondrocytes.

Treatment of osteoarthritic patients requires the development of morphologically and mechanically complex hyaline cartilage at the injury site. A tissue engineering approach toward differentiating mesenchymal stem cells into articular chondrocytes has been developed to overcome the drawbacks of conventional therapeutic and surgical procedures. To imitate the native micro and macro environment of articular chondrocytes, cell culture parameters such as oxygen concentration, mechanical stress, scaffold design, and growth factor signalling cascade regulation must be addressed. This review aims to illuminate the path toward developing tissue engineering approaches, accommodating these various parameters and the role these parameters play in regulating chondrogenesis for better articular cartilage development to treat osteoarthritis effectively.

Osteoarthritis is a common problem where the protective layer of cartilage on the joints wears away. It's difficult to treat with current methods. However, stem cell therapy is a promising alternative that has been researched a lot recently. Stem cells are special cells that can change into different types of tissue, including cartilage. Scientists are trying to figure out how to get these stem cells to grow into cartilage effectively. They are also trying to understand how stem cells find the right place in the body to go and do their job. By modifying the genes of stem cells and using special materials and growth factors, scientists hope to improve the effectiveness of stem cell therapy for osteoarthritis.

Oncogenic metabolic reprogramming in breast cancer: focus on signaling pathways and mitochondrial genes.

Oncogenic metabolic reprogramming impacts the abundance of key metabolites that regulate signaling and epigenetics. Metabolic vulnerability in the cancer cell is evident from the Warburg effect. The research on metabolism in the progression and survival of breast cancer (BC) is under focus. Oncogenic signal activation and loss of tumor suppressor are important regulators of tumor cell metabolism. Several intrinsic and extrinsic factors contribute to metabolic reprogramming. The molecular mechanisms underpinning metabolic reprogramming in BC are extensive and only partially defined. Various signaling pathways involved in the metabolism play a significant role in the modulation of BC. Notably, PI3K/AKT/mTOR pathway, lactate-ERK/STAT3 signaling, loss of the tumor suppressor Ras, Myc, oxidative stress, activation of the cellular hypoxic response and acidosis contribute to different metabolic reprogramming phenotypes linked to enhanced glycolysis. The alterations in mitochondrial genes have also been elaborated upon along with their functional implications. The outcome of these active research areas might contribute to the development of novel therapeutic interventions and the remodeling of known drugs.

In Vivo Anticancer Evaluation of 6b, a Non-Covalent Imidazo[1,2-a]quinoxaline-Based Epidermal Growth Factor Receptor Inhibitor against Human Xenograft Tumor in Nude Mice.

Tyrosine kinase inhibitors are validated therapeutic agents against EGFR-mutated non-small cell lung cancer (NSCLC). However, the associated critical side effects of these agents are inevitable, demanding more specific and efficient targeting agents. Recently, we have developed and reported a non-covalent imidazo[1,2-a]quinoxaline-based EGFR inhibitor (6b), which showed promising inhibitory activity against the gefitinib-resistant H1975(L858R/T790M) lung cancer cell line. In the present study, we further explored the 6b compound in vivo by employing the A549-induced xenograft model in nude mice. The results indicate that the administration of the 6b compound significantly abolished the growth of the tumor in the A549 xenograft nude mice. Whereas the control mice bearing tumors displayed a declining trend in the survival curve, treatment with the 6b compound improved the survival profile of mice. Moreover, the histological examination showed the cancer cell cytotoxicity of the 6b compound was characterized by cytoplasmic destruction observed in the stained section of the tumor tissues of treated mice. The immunoblotting and qPCR results further signified that 6b inhibited EGFR in tissue samples and consequently altered the downstream pathways mediated by EGFR, leading to a reduction in cancer growth. Therefore, the in vivo findings were in corroboration with the in vitro results, suggesting that 6b possessed potential anticancer activity against EGFR-dependent lung cancer. 6b also exhibited good stability in human and mouse liver microsomes.

Differential molecular mechanistic behavior of HDACs in cancer progression.

Genetic aberration including mutation in oncogenes and tumor suppressor genes transforms normal cells into tumor cells. Epigenetic modifications work concertedly with genetic factors in controlling cancer development. Histone acetyltransferases (HATs), histone deacetylases (HDACs), DNA methyltransferases (DNMTs) and chromatin structure modifier are prospective epigenetic regulators. Specifically, HDACs are histone modifiers regulating the expression of genes implicated in cell survival, growth, apoptosis, and metabolism. The majority of HDACs are highly upregulated in cancer, whereas some have a varied function and expression in cancer progression. Distinct HDACs have a positive and negative role in controlling cancer progression. HDACs are also significantly involved in tumor cells acquiring metastatic and angiogenic potential in order to withstand the anti-tumor microenvironment. HDACs' role in modulating metabolic genes has also been associated with tumor development and survival. This review highlights and discusses the molecular mechanisms of HDACs by which they regulate cell survival, apoptosis, metastasis, invasion, stemness potential, angiogenesis, and epithelial to mesenchymal transitions (EMT) in tumor cells. HDACs are the potential target for anti-cancer drug development and various inhibitors have been developed and FDA approved for a variety of cancers. The primary HDAC inhibitors with proven anti-cancer efficacy have also been highlighted in this review.

Design, synthesis and anticancer activity of 2-arylimidazo[1,2-a]pyridinyl-3-amines.

A series of imido-heterocycle compounds were designed, synthesized, characterized, and evaluated for the anticancer potential using breast (MCF-7 and MDA-MB-231), pancreatic (PANC-1), and colon (HCT-116 and HT-29) cancer cell lines and normal cells, while normal cells showed no toxicity. Among the screened compounds, 4h exhibited the best anticancer potential with IC50 values ranging from 1 to 5.5 µM. Compound 4h caused G2/M phase arrest and apoptosis in all the cell lines except MDA-MB-231 mammosphere formation was inhibited. In-vitro enzyme assay showed selective topoisomerase IIα inhibition by compound 4h, leading to DNA damage as observed by fluorescent staining. Cell signalling studies showed decreased expression of cell cycle promoting related proteins while apoptotic proteins were upregulated. Interestingly MDA-MB-231 cells showed only cytostatic effects upon treatment with compound 4h due to defective p53 status. Toxicity study using overexpression of dominant-negative mutant p53 in MCF-7 cells (which have wild type functional p53) showed that anticancer potential of compound 4h is positively correlated with p53 expression.

Design and Synthesis of Non-Covalent Imidazo[1,2-a]quinoxaline-Based Inhibitors of EGFR and Their Anti-Cancer Assessment.

A series of 30 non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of epidermal growth factor receptor (EGFR) were designed and synthesized. EGFR inhibitory assessment (against wild type) data of compounds revealed 6b, 7h, 7j, 9a and 9c as potent EGFRWT inhibitors with IC50 values of 211.22, 222.21, 193.18, 223.32 and 221.53 nM, respectively, which were comparable to erlotinib (221.03 nM), a positive control. Furthermore, compounds exhibited excellent antiproliferative activity when tested against cancer cell lines harboring EGFRWT; A549, a non-small cell lung cancer (NSCLC), HCT-116 (colon), MDA-MB-231 (breast) and gefitinib-resistant NSCLC cell line H1975 harboring EGFRL858R/T790M. In particular, compound 6b demonstrated significant inhibitory potential against gefitinib-resistant H1975 cells (IC50 = 3.65 µM) as compared to gefitinib (IC50 > 20 µM). Moreover, molecular docking disclosed the binding mode of the 6b to the domain of EGFR (wild type and mutant type), indicating the basis of inhibition. Furthermore, its effects on redox modulation, mitochondrial membrane potential, cell cycle analysis and cell death mode in A549 lung cancer cells were also reported.

Metabolic Adaptations in Cancer Stem Cells.

Cancer stem cells (CSCs) are a small and elusive subpopulation of self-renewing cancer cells with remarkable ability to initiate, propagate, and spread the malignant disease. In addition, they exhibit increased resistance to anticancer therapies, thereby contributing to disease relapse. CSCs are reported to be present in many tumor types such as melanoma, sarcoma, mammary tumors, colon cancer and other solid tumors. These cells from different tumors show unique energetic and metabolic pathways. For example, CSCs from one type of tumor may predominantly use aerobic glycolysis, while from another tumor type may utilize oxidative phosphorylation. Most commonly these cells use fatty acid oxidation and ketone bodies as the main source of energy production. CSCs have a remarkable ability to reprogram their metabolism in order to survive under adverse conditions such as hypoxia, acidosis, and starvation. There is increasing interest to identify molecular targets that can be utilized to kill CSCs and to control their growth. In this review, we discuss how an understanding of the unique metabolism of CSCs from different tumors can offer promising strategies for targeting CSCs and hence to prevent disease relapse and to treat the metastatic disease.