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The Future We Need
In The Future We Need
, Erica Smiley and Sarita Gupta bring a novel perspective
to building worker power and what labor organizing could look like
in the future, suggesting ways to evolve collective bargaining to
match the needs of modern people-not only changing their wages and
working conditions, but being able to govern over more aspects of
their lives.
Weaving together stories of real working people, Smiley and
Gupta position the struggle to build collective bargaining power as
a central element in the effort to build a healthy democracy and
explore both existing levers of power and new ones we must build
for workers to have the ability to negotiate in today and
tomorrow's contexts. The Future We Need illustrates the
necessity of centralizing the fight against white supremacy and
gender discrimination, while offering paths forward to harness the
power of collective bargaining in every area for a new era.
eBook
Insulin resistance: an additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes
Sedentary life style and high calorie dietary habits are prominent leading cause of metabolic syndrome in modern world. Obesity plays a central role in occurrence of various diseases like hyperinsulinemia, hyperglycemia and hyperlipidemia, which lead to insulin resistance and metabolic derangements like cardiovascular diseases (CVDs) mediated by oxidative stress. The mortality rate due to CVDs is on the rise in developing countries. Insulin resistance (IR) leads to micro or macro angiopathy, peripheral arterial dysfunction, hampered blood flow, hypertension, as well as the cardiomyocyte and the endothelial cell dysfunctions, thus increasing risk factors for coronary artery blockage, stroke and heart failure suggesting that there is a strong association between IR and CVDs. The plausible linkages between these two pathophysiological conditions are altered levels of insulin signaling proteins such as IR-β, IRS-1, PI3K, Akt, Glut4 and PGC-1α that hamper insulin-mediated glucose uptake as well as other functions of insulin in the cardiomyocytes and the endothelial cells of the heart. Reduced AMPK, PFK-2 and elevated levels of NADP(H)-dependent oxidases produced by activated M1 macrophages of the adipose tissue and elevated levels of circulating angiotensin are also cause of CVD in diabetes mellitus condition. Insulin sensitizers, angiotensin blockers, superoxide scavengers are used as therapeutics in the amelioration of CVD. It evidently becomes important to unravel the mechanisms of the association between IR and CVDs in order to formulate novel efficient drugs to treat patients suffering from insulin resistance-mediated cardiovascular diseases. The possible associations between insulin resistance and cardiovascular diseases are reviewed here.
Journal Article
Investigating the potential role of swertiamarin on insulin resistant and non-insulin resistant granulosa cells of poly cystic ovarian syndrome patients
Background and aim
Conventional drugs have limitations due to prevalence of contraindications in PCOS patients. To explore the potential effects of swertiamarin, on abrupted insulin and steroidogenic signaling in human luteinized granulosa cells from PCOS patients with or without insulin resistance.
Experimental procedure
hLGCs from 8 controls and 16 PCOS patients were classified for insulin resistance based on down regulation of protein expression of insulin receptor-β (INSR- β) as shown in our previous paper. Cells were grouped as control, PCOS-IR and PCOS-NIR, treated with swertiamarin (66 µM) and metformin (1 mM). Expression of key molecules involved in insulin signaling, fat metabolism, IGF system and steroidogenesis were compared between groups.
Results
Swertiamarin significantly (
P
< 0.05) reversed the expression of INSR-β, PI(3)K, p-Akt, PKC-ζ, PPARγ, (
P
< 0.01) IRS (Ser 307) and IGF system in PCOS-IR group and was equally potent to metformin. In the same group, candidate genes viz SREBP1c, FAS, ACC-1 and CPT-1 were down regulated by swertiamarin (
P
< 0.001) and metformin (
P
< 0.001). Significant upregulation was demonstrated in expression of StAR, CYP19A1, 17β-HSD and 3β-HSD when treated with swertiamarin (
P
< 0.01) and metformin (
P
< 0.01) in PCOS-IR followed by increase in 17β-HSD and 3β-HSD enzyme activity along with estradiol and progesterone secretions. However, swertiamarin did not reveal any effect on PCOS-NIR group as compared to metformin that significantly (
P
< 0.01) reversed all the parameters related to steroidogenesis and down regulated basal expression of insulin signaling genes.
Conclusion
Swertiamarin, presents itself as a potential fertility drug in hLGCs from PCOS-IR patients.
Journal Article
Role of poly(ADP-ribose) polymerase-1 in regulating human islet cell differentiation
Poly(ADP-ribose) polymerase-1 (PARP1), a fundamental DNA repair enzyme, is known to regulate β cell death, replication, and insulin secretion. PARP1 knockout (KO) mice are resistant to diabetes, while PARP1 overactivation contributes to β cell death. Additionally, PARP1 inhibition (PARPi) improves diabetes complications in patients with type-2 diabetes. Despite these beneficial effects, the use of PARP1 modulating agents in diabetes treatment is largely neglected, primarily due to the poorly studied mechanistic action of PARP1 catalytic function in human β cell development. In the present study, we evaluated PARP1 regulatory action in human β cell differentiation using the human pancreatic progenitor cell line, PANC-1. We surveyed islet census and histology from PARP1 wild-type versus KO mice pancreas in a head-to-head comparison with PARP1 regulatory action for in-vitro β cell differentiation following either PARP1 depletion or its pharmacological inhibition in PANC-1-differentiated islet cells. shRNA mediated PARP1 depleted (SiP) and shRNA control (U6) PANC-1 cells were differentiated into islet-like clusters using established protocols. We observed complete abrogation of new β cell formation with absolute PARP1 depletion while its inhibition using the potent inhibitor, PJ34, promoted the endocrine β cell differentiation and maturation. Immunohistochemistry and immunoblotting for key endocrine differentiation players along with β cell maturation markers highlighted the potential regulatory action of PARP1 and augmented β cell differentiation due to direct interaction of unmodified PARP1 protein elicited p38 MAPK phosphorylation and Neurogenin-3 (Ngn3) re-activation. In summary, our study suggests that PARP1 is required for the proper development and differentiation of human islets. Selective inhibition with PARPi can be an advantage in pushing more insulin-producing cells under pathological conditions and delivers a potential for pilot clinical testing for β cell replacement cell therapies for diabetes.
Journal Article
Direct lineage tracing reveals Activin-a potential for improved pancreatic homing of bone marrow mesenchymal stem cells and efficient ß-cell regeneration in vivo
Background
Despite the potential, bone marrow-derived mesenchymal stem cells (BMSCs) show limitations for beta (ß)-cell replacement therapy due to inefficient methods to deliver BMSCs into pancreatic lineage. In this study, we report TGF-ß family member protein, Activin-a potential to stimulate efficient pancreatic migration, enhanced homing and accelerated ß-cell differentiation.
Methods
Lineage tracing of permanent green fluorescent protein (GFP)- tagged donor murine BMSCs transplanted either alone or in combination with Activin-a in diabetic mice displayed potential ß-cell regeneration and reversed diabetes.
Results
Pancreatic histology of Activin-a treated recipient mice reflected high GFP
+
BMSC infiltration into damaged pancreas with normalized fasting blood glucose and elevated serum insulin. Whole pancreas FACS profiling of GFP
+
cells displayed significant homing of GFP
+
BMSC with Activin-a treatment (6%) compared to BMSCs alone transplanted controls (0.5%). Within islets, approximately 5% GFP+ cells attain ß-cell signature (GFP
+
Ins
+
) with Activin-a treatment versus controls. Further, double immunostaining for mesenchymal stem cell markers CD44
+
/GFP
+
in infiltrated GFP
+
BMSC deciphers substantial endocrine reprogramming and ß-cell differentiation (6.4% Ins
+
/GFP
+
) within 15 days.
Conclusion
Our investigation thus presents a novel pharmacological approach for stimulating direct migration and homing of therapeutic BMSCs that re-validates BMSC potential for autologous stem cell transplantation therapy in diabetes.
Journal Article
Dexamethasone Alters the Appetite Regulation via Induction of Hypothalamic Insulin Resistance in Rat Brain
Elevated levels of glucocorticoid, a steroid hormone released in response to stress, have been implicated in the pathophysiology of diabetes, which is now known to extend its effect on brain functions. Hence, we aimed to investigate the status of brain insulin signaling in response to dexamethasone (a synthetic glucocorticoid) treatment in female Charles Foster rat. This model exhibited pronounced hyperinsulinemia and glucose intolerance with loss in appetite and body weight. Immunoblotting of insulin receptor (INSR)-PI3kinase-AKT demonstrated reduced insulin signaling in hypothalamus but no change in hippocampus, cortex, and cerebellum in dexamethasone-treated rats as compared to vehicle-treated rats, signifying the diversity of distribution and function of insulin in different brain regions. These results also correlated with appetite change, a key function governed by hypothalamus. Hence, we further explored the hypothalamic feeding circuit and found altered levels of neuropeptide genes (
Agrp
,
Npy
,
Pomc
) and candidate nutrient sensors (GLUT1, SirT1, and PPARγ). There was also a considerable reduction in glycogen content and appetite-regulating neurotransmitters (GABA, glutamate, dopamine) in dexamethasone-treated rats. Thus, concluding that dexamethasone not only induces peripheral insulin resistance but also impairs hypothalamic function of appetite regulation via the interwoven cascade of insulin signaling, neurotransmitters, and neuropeptides.
Graphical Abstract
Reduced insulin signaling as well as elevated glucocorticoid levels in hypothalamus modulates the key appetite regulating neuropeptides, neurotransmitters, and nutrient sensors resulting into reduced appetite and bodyweight
Journal Article
Swertisin an Anti-Diabetic Compound Facilitate Islet Neogenesis from Pancreatic Stem/Progenitor Cells via p-38 MAP Kinase-SMAD Pathway: An In-Vitro and In-Vivo Study
Transplanting islets serves best option for restoring lost beta cell mass and function. Small bio-chemical agents do have the potential to generate new islets mass, however lack of understanding about mechanistic action of these small molecules eventually restricts their use in cell-based therapies for diabetes. We recently reported \"Swertisin\" as a novel islet differentiation inducer, generating new beta cells mass more effectively. Henceforth, in the present study we attempted to investigate the molecular signals that Swertisin generate for promoting differentiation of pancreatic progenitors into islet cells. To begin with, both human pancreatic progenitors (PANC-1 cells) and primary cultured mouse intra-islet progenitor cells (mIPC) were used and tested for Swertisin induced islet neogenesis mechanism, by monitoring immunoblot profile of key transcription factors in time dependent manner. We observed Swertisin follow Activin-A mediated MEPK-TKK pathway involving role of p38 MAPK via activating Neurogenin-3 (Ngn-3) and Smad Proteins cascade. This MAP Kinase intervention in differentiation of cells was confirmed using strong pharmacological inhibitor of p38 MAPK (SB203580), which effectively abrogated this process. We further confirmed this mechanism in-vivo in partial pancreatectomised (PPx) mice model, where we could show Swertisin exerted potential increase in insulin transcript levels with persistent down-regulation of progenitor markers like Nestin, Ngn-3 and Pancreatic Duodenal Homeobox Gene-1 (PDX-1) expression, within three days post PPx. With detailed molecular investigations here in, we first time report the molecular mode of action of Swertisin for islet neogenesis mediated through MAP Kinase (MEPK-TKK) pathway involving Ngn-3 and Smad transcriptional regulation. These findings held importance for developing Swertisin as potent pharmacological drug candidate for effective and endogenous differentiation of islets in cell based therapy for diabetes.
Journal Article
Identification of Novel Mutations in HEXA Gene in Children Affected with Tay Sachs Disease from India
Tay Sachs disease (TSD) is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients). Total leukocyte hexosaminidase activity was assayed by 4-methylumbelliferyl-N-acetyl-β-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N-acetyl-β-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K), c.964 G>A (p.D322N), c.964 G>T (p.D322Y), c.1178C>G (p.R393P) and c.1385A>T (p.E462V), c.1432 G>A (p.G478R) and two previously reported mutations. c.1277_1278insTATC and c.508C>T (p.R170W). The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V.
Journal Article
Lead and Cadmium Co-exposure Mediated Toxic Insults on Hepatic Steroid Metabolism and Antioxidant System of Adult Male Rats
The redox status and steroid metabolism of liver of adult male rat exposed to lead (Pb) and cadmium (Cd) either alone or in co-exposure (0.025 mg/kg body weight intraperitoneally/15 days) was studied. Pb and Cd significantly accumulated in the liver. The activity of steroid metabolizing enzymes 17-βhydroxysteroid oxidoreductase and uridine diphosphate-glucuronyltransferase were decreased in experimental animals. 17-β-Hydroxysteroid dehydrogenase was reduced to 33%, 38%, and 24% on treatment of Pb, Cd, and co-exposure (Pb + Cd). Furthermore, the activity of uridine diphosphate-glucuronosyltransferase was significantly reduced to 27% (Pb exposure), 36% (Cd exposure), and 25% (co-exposure of Pb + Cd). Cd exposure exhibited more toxic effect than Pb, while co-exposure demonstrated the least. The activities of antioxidant enzymes, superoxide dismutase, catalase, glutathione reductase, and glucose-6-phosphate dehydrogenase decreased and glutathione peroxidase increased in mitochondrial and post-mitochondrial fractions. The level of lipid peroxidation increased, and cellular glutathione concentration decreased. Hepatic DNA was decreased, whereas RNA content and the activity of alanine transaminase remained unchanged. Histological studies revealed that only Cd-exposed groups exhibited cytotoxic effect. These results suggest that when Pb and Cd are present together in similar concentrations, they exhibited relatively decreased toxic effect when compared to lead and cadmium in isolation with regard to decreased steroid metabolizing and antioxidant enzyme activities. This seems that the toxic effect of these metals is antagonized by co-exposure due to possible competition amongst Pb and Cd for hepatic accumulation.
Journal Article