Cucurbitacin E reduces obesity and related metabolic dysfunction in mice by targeting JAK-STAT5 signaling pathway

Murtaza, Munazza; Khan, Gulnaz; Aftab, Meha Fatima; Afridi, Shabbir Khan; Ghaffar, Safina; Ahmed, Ayaz; Hafizur, Rahman M.; Waraich, Rizwana Sanaullah

doi:10.1371/journal.pone.0178910

Cited by 32 publications

(27 citation statements)

References 41 publications

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“…Our study was positively compared with the previous study associated with cucurbitacin and expression of PPARγ in skeletal muscle and adipose tissue. [18,21] In conclusion, our present findings suggest that administration of cucurbitacin shows authoritative antioxidant potential and elevated insulin secretion through signal transduction in rats. In addition, cucurbitacin also exerts antihyperglycemic effect by enhancing glucose uptake into skeletal muscle via PI3K-Akt signaling pathway.…”

Section: Discussionsupporting

confidence: 56%

“…[15] Further, the studies indicated that cucurbitacins has cytotoxic effects on various cancer cells, including bladder, pancreas, liver, mammary gland and blood. [16][17][18] In addition, the study further reported that cucurbitacins inhibit JAK-STAT signaling in various cancer cell lines. [19,20] Furthermore, the recent study showed inhibitory role of cucurbitacin on adipocytes in vitro.…”

Section: Banu World Journal Of Pharmaceutical Researchmentioning

confidence: 94%

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Cucurbitacin Augments Insulin Sensitivity and Glucose Uptake Through Translocation and Activation of Glut4 in Pi3k/Akt Signaling Pathway

Banu¹

2017

WJPR

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Vegetables that are generally consumed in India as one of the main components of the diet have been proven for their antidiabetic potential. Cucurbitacin is an important member of the Cucurbitaceae family and exhibit potential effects in various metabolic disorders and cancer. The aim of the present study is to investigate the effect and the mechanism of cucurbitacin on glucose uptake in an insulin target skeletal muscle and activation of PI3k/Akt signaling pathways in STZ induced diabetic animal model. STZ induced diabetic rats showed significantly elevated levels of plasma glucose, TBARS, and lipid hydroperoxides, and decreased levels of plasma insulin and enzymatic (superoxide dismutase, catalase, glutathione peroxidase) and non -enzymatic antioxidants (vitamin C, E and GSH), and impairment in insulin signaling proteins including IR, IRS-1/2, Akt, PI3K, GLUT4, and PPAR-γ proteins. The administration of cucurbitacin (5 mg/kg b.w/p.o) showed near-normalized levels of plasma glucose, lipid peroxidation products, enzymatic and non-enzymatic antioxidants and improved insulin signaling proteins. Based on the present findings, cucurbitacin improves glucose uptake by enhancing GLUT4 protein activities in skeletal muscle through PI3K/Akt and antioxidant defense in plasma and it also maintains blood glucose homeostasis.

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Section: Discussionsupporting

confidence: 56%

Section: Banu World Journal Of Pharmaceutical Researchmentioning

confidence: 94%

Cucurbitacin Augments Insulin Sensitivity and Glucose Uptake Through Translocation and Activation of Glut4 in Pi3k/Akt Signaling Pathway

Banu¹

2017

WJPR

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“…Additionally, the extracellular signal-regulated kinase 1/2 (ERK1/2) is known to promote adipocyte differentiation and hypertrophy [10, 11]. Importantly, pharmacological treatment to reduce adipocyte hypertrophy has been shown to improve IR and resolve adipose inflammation [10, 12, 13]. Identifying factors contributing to these adipose tissue expansion and inflammatory signal pathways is important for managing obesity and associated metabolic diseases.…”

Section: Introductionmentioning

confidence: 99%

Cellular retinoic acid binding protein 1 protects mice from high-fat diet-induced obesity by decreasing adipocyte hypertrophy

et al. 2019

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Objectives Obesity, an emerging global health issue, involves numerous factors; understanding its underlying mechanisms for prevention and therapeutics is urgently needed. Cellular retinoic acid binding protein 1 (Crabp1) knockout (CKO) mice exhibit an obese phenotype under normal diet feedings, which prompted us to propose that Crabp1 could play a role in modulating adipose tissue development/homeostasis. Studies were designed to elucidate the underlying mechanism of Crabp1’s action in reducing obesity. Subjects/methods In animal studies, 6 weeks old male wild type and CKO mice were fed with normal diet (ND) or high fat diet (HFD) for 10 weeks. Body weight and food intake were regularly monitored. Glucose tolerance test and biological parameters of plasma (glucose and insulin levels) were measured after 10 weeks of ND vs. HFD feedings. Visceral adipose tissues were collected for histological and molecular analyses to determine affected signaling pathways. In cell culture studies, the 3T3L1 adipocyte differentiation model was used to examine and validate relevant signaling pathways. Results CKO mice, compared to WT mice, gained more body weight, exhibited more elevated fasting plasma glucose levels, and developed more severe impaired glucose tolerance under both ND and HFD. Histological examination revealed readily increased adipocyte hypertrophy and adipose tissue inflammation under HFD feedings. In 3T3L1 adipocytes, Crabp1 silencing enhanced extracellular signal-regulated kinase 1/2 (ERK1/2) activation, accompanied by elevated markers and signaling pathways of lipid accumulation and adipocyte hypertrophy. Conclusions This study identifies Crabp1’s physiological role against the development of obesity. The protective function of CRABP1 is likely attributed to its classically proposed (canonical) activity as a trap for RA, which will reduce RA availability, thereby dampening RA-stimulated ERK1/2 activation and adipocyte hypertrophy. The results suggest Crabp1 as a potentially new therapeutic target in managing obesity and metabolic diseases.

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“…Previous studies have shown that curcurbitacin I can inhibit STAT3 in SeAx cells and primary Sz cells [ 32 ]. Moreover, cucurbitacin B and E have been shown to inhibit STAT5 activation in other cell types [ 45 , 46 ]. To investigate the role of STAT3 and STAT5 activation in SeAx cells treated with cucurbitacin E and I, levels of total and phosphorylated protein were measured ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Van Kester et al [ 32 ] previously showed that STAT3 activation and total STAT3 levels are affected by cucurbitacin I treatment in Sz. Furthermore, several cucurbitacins have been shown to inhibit STAT5 activation in other diseases [ 45 , 46 ]. This is interesting, since it has been suggested that STAT5, not STAT3, has an important role in promoting survival in lymphoid tumors [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Cucurbitacin E and I target the JAK/STAT pathway and induce apoptosis in Sézary cells

Brouwer

Out-Luiting

Vermeer

et al. 2020

Biochemistry and Biophysics Reports

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Cutaneous T-cell lymphomas and leukemias (CTCLs) are a heterogeneous group of extranodal non-Hodgkin's lymphomas. These are characterized by an accumulation of malignant CD4 + T-lymphocytes in the skin, lymph nodes, and peripheral blood. Novel treatment options are needed for patients who progress to advanced stage disease. Cucurbitacin I has previously shown promising results in Sézary syndrome (Sz). A plethora of cucurbitacins, however, have not yet been tested in CTCL. Herein, we investigated the effect of cucurbitacin E and I in two CTCL cell lines. We show that both cucurbitacins decrease viability and cause apoptosis in these cell lines, although HuT-78 was more affected than SeAx (IC 50 of 17.38 versus 22.01 μM for cucurbitacin E and 13.36 versus 24.47 μM for cucurbitacin I). Moreover, both cucurbitacins decrease viability of primary cells of a Sz patient (56.46% for cucurbitacin E and 59.07% for cucurbitacin I). Furthermore, while JAK2 inhibition leads to decreased viability in SeAx cells (IC 50 of 9.98 and 29.15 μM for AZD1480 and ruxolitinib respectively), both JAK1 and JAK3 do not. This suggests that JAK2 has a preferential role in promoting survival. Western blotting in SeAx cells revealed that both cucurbitacins inhibit STAT3 activation (P < 0.0001), while only cucurbitacin I inhibits STAT5 activation (P = 0.05). This suggests that STAT3 plays a preferential role in the mechanism of action of these cucurbitacins. Nevertheless, a role of STAT5 and JAK2 cannot be excluded and should be explored further. This knowledge could contribute to the development of effective therapies for CTCL and other malignancies involving dysfunction of the JAK/STAT pathway.

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Cucurbitacin E reduces obesity and related metabolic dysfunction in mice by targeting JAK-STAT5 signaling pathway

Cited by 32 publications

References 41 publications

Cucurbitacin Augments Insulin Sensitivity and Glucose Uptake Through Translocation and Activation of Glut4 in Pi3k/Akt Signaling Pathway

Cucurbitacin Augments Insulin Sensitivity and Glucose Uptake Through Translocation and Activation of Glut4 in Pi3k/Akt Signaling Pathway

Cellular retinoic acid binding protein 1 protects mice from high-fat diet-induced obesity by decreasing adipocyte hypertrophy

Cucurbitacin E and I target the JAK/STAT pathway and induce apoptosis in Sézary cells

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