Inflammatory β-Cell Stress and Immune Surveillance in Type 1 Diabetes.

Recent years have seen increased recognition for the role of β-cell stress as a contributing factor to the autoimmune destruction process that ultimately results in symptomatic type 1 diabetes (T1D). Preclinical studies have discovered a variety of stress responses in the β-cell that occur at presymptomatic stages and contribute to disease progression, but unifying explanations of how these mechanisms operate to promote disease progression remain incomplete. We propose that stressed β-cells transition into β-cells expressing inflammatory molecules that provoke an immune response to restore homeostasis by coordinating islet repair and the removal of stressed cells.

Trilliumosides K and L, two novel steroidal saponins from rhizomes of , as potent anti-cancer agents targeting apoptosis in the A-549 cancer cell line.

Two novel steroidal saponins, trilliumosides K () and L (), were isolated from the rhizomes of led by bioactivity-guided phytochemical investigation along with seven known compounds: govanoside D (), protodioscin (), borassoside E (), 20-hydroxyecdysone (), 5,20-hydroxyecdysone (), govanic acid (), and diosgenin (). The structure of novel compounds 1-2 was established using analysis of spectroscopic data including 1D and 2D nuclear magnetic resonance (NMR) and high resolution mass spectrometry (HR-ESI-MS) data. All isolated compounds were evaluated for cytotoxic activity against a panel of human cancer cell lines.

Costunosides A-C: cytotoxic sesquiterpene lactones from the rhizomes of Falc.

Three new eudesmane type rare sesquiterpene lactone galactosides, costunosides A-C ( were isolated from the rhizomes of along with ten known compounds (). Costunosides A-C ( are the first example of naturally eudesmane glycosides containing a -galactopyranoside moiety. The structure and relative configurations of these compounds were established by comprehensive analysis of MS and, in particular 1D/2D NMR spectroscopic data.

Apoptotic Potential and Antitumor Efficacy of Trilliumoside A: A New Steroidal Saponin Isolated from Rhizomes of .

Natural product-derived molecules exhibit potential as anticancer agents. Trilliumoside A, a new steroidal saponin, was obtained from rhizomes of , and its anticancer activity was investigated in the presented study. Trilliumoside A was investigated in a panel of cell lines, and it exhibited promising cytotoxic activity on the A549 cells (human lung cancer cells) with an IC of 1.

HPLC-PDA Method for Quantification of Bioactive Compounds in Crude Extract and Fractions of Falc. and Cytotoxicity Studies against Cancer Cells.

Falc. (Synonym: Saussurea costus (Falc.) Lipsch.

anti-sickling potential of baicalin and naringenin isolated from and on human sickle red blood cells.

Sickle cell disease (SCD) is a rare inherited disorder in which red blood cells (RBCs) under oxidative stress have altered sickle shape resulting in clinical complications. In this study, a library of pure natural products were screened to see their effectiveness in preventing sickling induced in blood samples of SCA patients. The results indicated that baicalin () and naringenin (), reduced sickling by 46.

The Transcription Factor YY1 Is Essential for Normal DNA Repair and Cell Cycle in Human and Mouse β-Cells.

Identifying the mechanisms behind the β-cell adaptation to failure is important to develop strategies to manage type 2 diabetes (T2D). Using db/db mice at early stages of the disease process, we took advantage of unbiased RNA sequencing to identify genes/pathways regulated by insulin resistance in β-cells. We demonstrate herein that islets from 4-week-old nonobese and nondiabetic leptin receptor-deficient db/db mice exhibited downregulation of several genes involved in cell cycle regulation and DNA repair.

Uncovering immune and senescent cell interactions in disease.

In this backstory, Anil Bhushan explains how recent work from his group investigating the immune-mediated clearance of senescent cells may offer a unique route to the development of senolytic therapies. These findings appeared in the May 2021 issue of Med (https://www.cell.

Biotransformation of eugenol by an endophytic fungus IIIMF4010 isolated from .

Natural value-added compounds produced from biological sources have attained immense significance in medicinal, food, flavourings, and agrochemical industries. Further, biotransformation is a powerful tool used to produce value-added compounds cost-effectively and selectively. In the present study, biotransformation of eugenol using an endophytic fungus IIIMF4010 isolated from the fresh leaves of the plant leads to the production of two known value-added compounds.

Comparative morpho-anatomical standardization and chemical profiling of root drugs for distinction of fourteen species of family Apocynaceae.

Background: The root drugs of the family Apocynaceae are medicinally important and used in Indian Systems of Medicine (ISM). There is often a problem of misidentification and adulteration of genuine samples with other samples in the market trade. Keeping in view the adulteration problem of raw drug material, comparative macroscopic and microscopic (qualitative and quantitative) characterisation and chemical analysis (TLC and LC-MS profiling) of a total of 14 economically important root drugs of family Apocynaceae were done for practical and rapid identification.

and Symbiosis: A Natural Mine of Bioactive Compounds.

Phylum Nematoda is of great economic importance. It has been a focused area for various research activities in distinct domains across the globe. Among nematodes, there is a group called entomopathogenic nematodes, which has two families that live in symbiotic association with bacteria of genus and , respectively.

Invariant Natural Killer T cells coordinate removal of senescent cells.

Background: The failure of immune surveillance to remove senescent cells drive age-related diseases. Here, we target an endogenous immune surveillance mechanism that can promote elimination of senescent cells and reverse disease progression.

Methods: We identify a class of lipid-activated T cells, invariant natural killer T cells (iNKTs) are involved in the removal of pathologic senescent cells.

BET Proteins Are Required for Transcriptional Activation of the Senescent Islet Cell Secretome in Type 1 Diabetes.

Type 1 diabetes (T1D) results from the progressive loss of pancreatic beta cells as a result of autoimmune destruction. We recently reported that during the natural history of T1D in humans and the female nonobese diabetic (NOD) mouse model, beta cells acquire a senescence-associated secretory phenotype (SASP) that is a major driver of disease onset and progression, but the mechanisms that activate SASP in beta cells were not explored. Here, we show that the SASP in islet cells is transcriptionally controlled by Bromodomain ExtraTerminal (BET) proteins, including Bromodomain containing protein 4 (BRD4).

mTORC1 to AMPK switching underlies β-cell metabolic plasticity during maturation and diabetes.

Pancreatic beta cells (β-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). How this happens is not clear. In exploring what molecular mechanisms drive the maturation of β-cell function, we found that the control of cellular signaling in β-cells fundamentally switched from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this was critical for functional maturation.

The Pdx1-Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet β-Cell Function.

Transcription factors positively and/or negatively impact gene expression by recruiting coregulatory factors, which interact through protein-protein binding. Here we demonstrate that mouse pancreas size and islet β-cell function are controlled by the ATP-dependent Swi/Snf chromatin remodeling coregulatory complex that physically associates with Pdx1, a diabetes-linked transcription factor essential to pancreatic morphogenesis and adult islet cell function and maintenance. Early embryonic deletion of just the Swi/Snf Brg1 ATPase subunit reduced multipotent pancreatic progenitor cell proliferation and resulted in pancreas hypoplasia.

Author Correction: Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived β cells.

In the version of this article originally published, the Gene Expression Omnibus (GEO) accession number listed in the data availability section was incorrectly given as GSE10979 instead of GSE109795. The sentence should read "RNA-seq data that support the findings of this study have been deposited in the Gene Expression Omnibus (GEO) under accession code GSE109795," and the code should link to https://www.ncbi.

Targeted Elimination of Senescent Beta Cells Prevents Type 1 Diabetes.

Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by hyperglycemia due to progressive loss of pancreatic beta cells. Immune-mediated beta cell destruction drives the disease, but whether beta cells actively participate in the pathogenesis remains unclear. Here, we show that during the natural history of T1D in humans and the non-obese diabetic (NOD) mouse model, a subset of beta cells acquires a senescence-associated secretory phenotype (SASP).

Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived β cells.

Despite advances in the differentiation of insulin-producing cells from human embryonic stem cells, the generation of mature functional β cells in vitro has remained elusive. To accomplish this goal, we have developed cell culture conditions to closely mimic events occurring during pancreatic islet organogenesis and β cell maturation. In particular, we have focused on recapitulating endocrine cell clustering by isolating and reaggregating immature β-like cells to form islet-sized enriched β-clusters (eBCs).

Examining How the MAFB Transcription Factor Affects Islet β-Cell Function Postnatally.

The sustained expression of the MAFB transcription factor in human islet β-cells represents a distinct difference in mice. Moreover, mRNA expression of closely related and islet β-cell-enriched MAFA does not peak in humans until after 9 years of age. We show that the MAFA protein also is weakly produced within the juvenile human islet β-cell population and that expression is postnatally restricted in mouse β-cells by de novo DNA methylation.

Cyclin D2 is sufficient to drive β cell self-renewal and regeneration.

Diabetes results from an inadequate mass of functional β cells, due to either β cell loss caused by autoimmune destruction (type I diabetes) or β cell failure in response to insulin resistance (type II diabetes). Elucidating the mechanisms that regulate β cell mass may be key to developing new techniques that foster β cell regeneration as a cellular therapy to treat diabetes. While previous studies concluded that cyclin D2 is required for postnatal β cell self-renewal in mice, it is not clear if cyclin D2 is sufficient to drive β cell self-renewal.

β Cells led astray by transcription factors and the company they keep.

Pancreatic β cells have one of the highest protein secretion burdens in the body, as these cells must synthesize and secrete insulin in proportion to postprandial rises in blood glucose. Remarkably, it is now becoming clear that adult β cells retain plasticity and can dedifferentiate into embryonic fates or adopt alternate islet endocrine cell identities. This property is especially important, because changes in cell fate alter β cell function and could form the basis for defects in insulin secretion that occur early in the pathogenesis of the most prevalent form of β cell dysfunction, type 2 diabetes.

Inhibition of TGF-β Signaling Promotes Human Pancreatic β-Cell Replication.

Diabetes is associated with loss of functional pancreatic β-cells, and restoration of β-cells is a major goal for regenerative therapies. Endogenous regeneration of β-cells via β-cell replication has the potential to restore cellular mass; however, pharmacological agents that promote regeneration or expansion of endogenous β-cells have been elusive. The regenerative capacity of β-cells declines rapidly with age, due to accumulation of p16(INK4a), resulting in limited capacity for adult endocrine pancreas regeneration.

DNA methylation directs functional maturation of pancreatic β cells.

Pancreatic β cells secrete insulin in response to postprandial increases in glucose levels to prevent hyperglycemia and inhibit insulin secretion under fasting conditions to protect against hypoglycemia. β cells lack this functional capability at birth and acquire glucose-stimulated insulin secretion (GSIS) during neonatal life. Here, we have shown that during postnatal life, the de novo DNA methyltransferase DNMT3A initiates a metabolic program by repressing key genes, thereby enabling the coupling of insulin secretion to glucose levels.

Human β-cell proliferation and intracellular signaling: part 3.

This is the third in a series of Perspectives on intracellular signaling pathways coupled to proliferation in pancreatic β-cells. We contrast the large knowledge base in rodent β-cells with the more limited human database. With the increasing incidence of type 1 diabetes and the recognition that type 2 diabetes is also due in part to a deficiency of functioning β-cells, there is great urgency to identify therapeutic approaches to expand human β-cell numbers.

Combined modulation of polycomb and trithorax genes rejuvenates β cell replication.

Inadequate functional β cell mass underlies both type 1 and type 2 diabetes. β Cell growth and regeneration also decrease with age through mechanisms that are not fully understood. Age-dependent loss of enhancer of zeste homolog 2 (EZH2) prevents adult β cell replication through derepression of the gene encoding cyclin-dependent kinase inhibitor 2a (INK4a).