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International Journal of Molecular... May 2024Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by diffuse hepatocellular steatosis due to fatty deposits in hepatocytes,...
Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by diffuse hepatocellular steatosis due to fatty deposits in hepatocytes, excluding alcohol and other known liver injury factors. However, there are no specific drugs for the clinical treatment of NAFLD. Therefore, research on the pathogenesis of NAFLD at the cellular and molecular levels is a promising approach to finding therapeutic targets and developing targeted drugs for NAFLD. Pin1 is highly expressed during adipogenesis and contributes to adipose differentiation, but its specific mechanism of action in NAFLD is unclear. In this study, we investigated the role of Pin1 in promoting the development of NAFLD and its potential mechanisms in vitro and in vivo. First, Pin1 was verified in the NAFLD model in vitro using MCD diet-fed mice by Western Blot, RT-qPCR and immunohistochemistry (IHC) assays. In the in vitro study, we used the oleic acid (OA) stimulation-induced lipid accumulation model and examined the lipid accumulation in each group of cells by oil red O staining as well as BODIPY staining. The results showed that knockdown of Pin1 inhibited lipid accumulation in hepatocytes in an in vitro lipid accumulation model and improved lipid indices and liver injury levels. Moreover, in vivo, WT and Pin1-KO mice were fed a methionine-choline deficient (MCD) diet for 4 weeks to induce the NAFLD model. The effects of Pin1 on lipid accumulation, hepatic fibrosis, and oxidative stress were evaluated by biochemical analysis, glucose and insulin tolerance tests, histological analysis, IHC, RT-qPCR and Western blot assays. The results indicate that Pin1 knockdown significantly alleviated hepatic steatosis, fibrosis and inflammation in MCD-induced NAFLD mice, improved glucose tolerance and alleviated insulin resistance in mice. Further studies showed that the AMPK/ACC1 signalling pathway might take part in the process by which Pin1 regulates NAFLD, as evidenced by the inhibition of the AMPK/ACC1 pathway. In addition, immunofluorescence (IF), coimmunoprecipitation (Co-IP) and GST pull-down experiments also showed that Pin1 interacts directly with ACC1 and inhibits ACC1 phosphorylation levels. Our study suggests that Pin1 promotes NAFLD progression by inhibiting the activation of the AMPK/ACC1 signalling pathway, and it is possible that this effect is achieved by Pin1 interacting with ACC1 and inhibiting the phosphorylation of ACC1.
Topics: Animals; NIMA-Interacting Peptidylprolyl Isomerase; Non-alcoholic Fatty Liver Disease; Mice; Male; Mice, Knockout; Hepatocytes; Humans; Lipid Metabolism; Mice, Inbred C57BL; Disease Models, Animal; Protein Binding; Acetyl-CoA Carboxylase
PubMed: 38892011
DOI: 10.3390/ijms25115822 -
Cells May 2024The bone marrow (BM) stromal cell microenvironment contains non-hematopoietic stromal cells called mesenchymal stromal cells (MSCs). MSCs are plastic adherent, form... (Review)
Review
The bone marrow (BM) stromal cell microenvironment contains non-hematopoietic stromal cells called mesenchymal stromal cells (MSCs). MSCs are plastic adherent, form CFU-Fs, and give rise to osteogenic, adipogenic, chondrogenic progenitors, and most importantly provide HSC niche factor chemokine C-X-C motif ligand 12 (CXCL12) and stem cell factor (SCF). Different authors have defined different markers for mouse MSC identification like PDGFRSca-1 subsets, Nestin, or LepR cells. Of these, the LepR cells are the major source of SCF and CXCL12 in the BM microenvironment and play a major role in HSC maintenance and hematopoiesis. LepR cells give rise to most of the bones and BM adipocytes, further regulating the microenvironment. In adult BM, LepR cells are quiescent but after fracture or irradiation, they proliferate and differentiate into mesenchymal lineage osteogenic, adipogenic and/or chondrogenic cells. They also play a crucial role in the steady-state hematopoiesis process, as well as hematopoietic regeneration and the homing of hematopoietic stem cells (HSCs) after myeloablative injury and/or HSC transplantation. They line the sinusoidal cavities, maintain the trabeculae formation, and provide the space for HSC homing and retention. However, the LepR cell subset is heterogeneous; some subsets have higher adipogenic potential, while others express osteollineage-biased genes. Different transcription factors like Early B cell factor 3 (EBF3) or RunX2 help maintain this balance between the self-renewing and committed states, whether osteogenic or adipogenic. The study of LepR MSCs holds immense promise for advancing our understanding of HSC biology, tissue regeneration, metabolic disorders, and immune responses. In this review, we will discuss the origin of the BM resident LepR cells, different subtypes, and the role of LepR cells in maintaining hematopoiesis, osteogenesis, and BM adipogenesis following their multifaceted impact.
Topics: Mesenchymal Stem Cells; Animals; Humans; Receptors, Leptin; Bone Marrow Cells; Bone and Bones; Hematopoiesis; Bone Marrow; Cell Differentiation
PubMed: 38891042
DOI: 10.3390/cells13110910 -
Cancer Research Communications Jun 2024Obesity is a modifiable predisposition factor for postmenopausal breast cancer. This suggests a localized, reciprocal interaction between breast cancer cells and the...
Obesity is a modifiable predisposition factor for postmenopausal breast cancer. This suggests a localized, reciprocal interaction between breast cancer cells and the surrounding mammary white adipose tissue. To investigate how breast cancer cells alter the composition and function of adipose tissue, we screened the secretomes of ten human breast cancer cell lines for the ability to modulate the differentiation of adipocyte stem and progenitor cells. The screen identified an adipogenic modulator, Zinc Alpha-2-Glycoprotein (ZAG/AZGP1) that is secreted by triple-negative breast cancer (TNBC) cells. TNBC-secreted ZAG inhibits adipogenesis and instead induces the expression of fibrotic genes. Accordingly, depletion of ZAG in TNBC cells attenuates fibrosis in white adipose tissue and inhibits tumor growth. Further, high expression of ZAG is linked to poor prognosis in TNBC patients, but not in patients with other clinical subtypes of breast cancer. Our findings suggest a role of TNBC-secreted ZAG in promoting the transdifferentiation of adipocyte stem and progenitor cells into cancer-associated fibroblasts to support tumorigenesis.
PubMed: 38888911
DOI: 10.1158/2767-9764.CRC-24-0218 -
SAGE Open Medicine 2024Dolutegravir is an integrase inhibitor and is recommended by the World Health Organization as the preferred first-line and second-line human immunodeficiency virus... (Review)
Review
Dolutegravir is an integrase inhibitor and is recommended by the World Health Organization as the preferred first-line and second-line human immunodeficiency virus treatment in all populations. Excessive weight gain associated with dolutegravir-based regimens is an emerging issue; however, the long-term metabolic consequences of this effect have not been fully understood. Growing evidence shows that this leads to a higher incidence of hyperglycemia, hypertension, and metabolic syndrome, along with elevated cardiovascular risk. Dolutegravir-based regimens, also associated with greater adipocyte differentiation and greater expression of markers associated with lipid storage, continue to be a problem among patients living with human immunodeficiency virus. The mechanisms by which certain antiretroviral therapy agents differentially contribute to weight gain remain unknown. Some clinical investigators speculate that dolutegravir could interfere with central nervous system appetite regulation (melanocortin-4 receptor) and insulin signaling, or may have better penetration of adipose tissue where they could exert a direct impact on adipose tissue adipogenesis, fibrosis, and insulin resistance. This review summarizes our current understanding of weight gain and fat changes associated with dolutegravir and its possible secondary metabolic comorbidities.
PubMed: 38881592
DOI: 10.1177/20503121241260613 -
The American Journal of Chinese Medicine Jun 2024Osteoporosis (OP) represents a substantial public health issue and is associated with increasing rates of morbidity and mortality. It is characterized by reduced bone...
Osteoporosis (OP) represents a substantial public health issue and is associated with increasing rates of morbidity and mortality. It is characterized by reduced bone mineral density, deterioration of bone tissue quality, disruption of the microarchitecture of bones, and compromised bone strength. These changes may be attributed to the following factors: intercellular communication between osteoblasts and osteoclasts; imbalanced bone remodeling; imbalances between osteogenesis and adipogenesis; imbalances in hormonal regulation; angiogenesis; chronic inflammation; oxidative stress; and intestinal microbiota imbalances. Treating a single aspect of the disease is insufficient to address its multifaceted nature. In recent decades, traditional Chinese medicine (TCM) has shown great potential in the treatment of OP, and the therapeutic effects of Chinese patent drugs and Chinese medicinal herbs have been scientifically proven. TCMs, which contain multiple components, can target the diverse pathogeneses of OP through a multitargeted approach. Herbs such as XLGB, JTG, GSB, Yinyanghuo, Gusuibu, Buguzhi, and Nvzhenzi are among the TCMs that can be used to treat OP and have demonstrated promising effects in this context. They exert their therapeutic effects by targeting various pathways involved in bone metabolism. These TCMs balance the activity of osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells), and they exhibit anti-inflammatory, immunomodulatory, anti-oxidative, and estrogen-like functions. These multifaceted mechanisms underlie the efficacy of these herbs in the management and treatment of OP. Herein, we examine the efficacy of various Chinese herbs and Chinese patent drugs in treating OP by reviewing previous clinical trials and basic experiments, and we examine the potential mechanism of these therapies to provide evidence regarding the use of TCM for treating OP.
PubMed: 38879748
DOI: 10.1142/S0192415X24500393 -
Journal of Ethnopharmacology Jun 2024Murraya koenigii commonly known as curry leaf, is traditionally used in India to manage various ailments including diabetes mellitus. Curry leaves are well documented in...
ETHNOPHARMACOLOGICAL RELEVANCE
Murraya koenigii commonly known as curry leaf, is traditionally used in India to manage various ailments including diabetes mellitus. Curry leaves are well documented in Indian Ayurvedic system of medicine for beneficial effects in skin eruptions, dysentery, emesis, poisonous bites and bruises. The anti-hyperglycemic and anti-hyperlipidemic effects of curry leaf extracts have been demonstrated through several in vitro and in vivo experiments previously.
AIM OF THE STUDY
To prepare an alkaloid enriched fraction (AEF) from M. koenigii and its evaluation on i) in vitro adipogenesis process and ii) in vivo high fat diet-induced obesity in C57BL/6J mice.
MATERIALS AND METHODS
MKME and AEF were prepared from M. koenigii leaves. The four carbazole alkaloids (bioactive markers) isolated from AEF were quantitatively determined in the leaves by RP-HPLC method. MKME and AEF were studied for anti-obesogenic activity in adipocytes in vitro and in HFD-induced C57BL/6J obese mice in vivo. At the termination of the in vivo study, lipid profile, hepatic and renal injury and glucose levels were analyzed in the blood samples. Animal tissues were examined histopathologically to determine any signs of damage. Repeated dose oral toxicity study for 28 days on Sprague-Dawley rats was also performed to determine the safety profile of AEF.
RESULTS
Both MKME and AEF displayed anti-obesogenic activity at 25 μg/ml concentration in vitro and showed 54.06 ± 3.86% and 37.46 ± 3.17% lipid accumulation, respectively compared to control. Further, supplementation of AEF and MKME in HFD-fed C57BL/6J mice helped in controlling weight gain, improved dyslipidemia and glucose intolerance significantly. AEF showed better anti-obesity activity than MKME both in vitro and in vivo study. Repeated administration of AEF up to 1 g/kg dose for 28 days showed no pathological tissue damage. Both MKME and AEF were standardized using a simple and validated RP-HPLC method.
CONCLUSION
Present study was aimed at preparation of a novel alkaloid-enriched fraction from methanolic extract of M. koenigii leaf and its evaluation for anti-diabesity effect. Our results demonstrated AEF to be a promising plant-based therapy for ameliorating obesity and related metabolic complications in HFD-fed C57BL/6J mice.
PubMed: 38878841
DOI: 10.1016/j.jep.2024.118423 -
Cellular and Molecular Life Sciences :... Jun 2024The pathological advancement of osteoporosis is caused by the uneven development of bone marrow-derived mesenchymal stem cells (BMSCs) in terms of osteogenesis and...
The pathological advancement of osteoporosis is caused by the uneven development of bone marrow-derived mesenchymal stem cells (BMSCs) in terms of osteogenesis and adipogenesis. While the role of EEF1B2 in intellectual disability and tumorigenesis is well established, its function in the bone-fat switch of BMSCs is still largely unexplored. During the process of osteogenic differentiation, we observed an increase in the expression of EEF1B2, while a decrease in its expression was noted during adipogenesis. Suppression of EEF1B2 hindered the process of osteogenic differentiation and mineralization while promoting adipogenic differentiation. On the contrary, overexpression of EEF1B2 enhanced osteogenesis and strongly inhibited adipogenesis. Furthermore, the excessive expression of EEF1B2 in the tibias has the potential to mitigate bone loss and decrease marrow adiposity in mice with osteoporosis. In terms of mechanism, the suppression of β-catenin activity occurred when EEF1B2 function was suppressed during osteogenesis. Our collective findings indicate that EEF1B2 functions as a regulator, influencing the differentiation of BMSCs and maintaining a balance between bone and fat. Our finding highlights its potential as a therapeutic target for diseases related to bone metabolism.
Topics: Animals; Male; Mice; Adipogenesis; beta Catenin; Bone Marrow Cells; Cell Differentiation; Cells, Cultured; Mesenchymal Stem Cells; Mice, Inbred C57BL; Osteogenesis; Osteoporosis; Wnt Signaling Pathway; Peptide Elongation Factor 1; Guanine Nucleotide Exchange Factors
PubMed: 38878096
DOI: 10.1007/s00018-024-05297-x -
Biochimica Et Biophysica Acta.... Jun 2024The functional differences between preadipocytes and fully differentiated mature adipocytes derived from stromal vascular fraction stem cells, as well as primary...
The functional differences between preadipocytes and fully differentiated mature adipocytes derived from stromal vascular fraction stem cells, as well as primary adipocytes have been analysed by evaluating their response to the obesogenic factor (a saturated fatty acid) and TNF-triggered inflammation. The analysis of single adipocytes shows that the saturated fatty acid (palmitic acid) accumulation is accompanied by inflammation and considerably dependent on the stage of the adipogenesis. In particular, preadipocytes show the exceptional potential for palmitic acid uptake resulting in their hypertrophy and the elevated cellular expression of the inflammation marker (ICAM-1). Our research provides new information on the impact of obesogenic factors on preadipocytes that is important in the light of childhood obesity prevention.
PubMed: 38876269
DOI: 10.1016/j.bbalip.2024.159525 -
Journal of Molecular Medicine (Berlin,... Jun 2024Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that promotes adipogenesis, lipid uptake and storage, insulin sensitivity, and...
Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that promotes adipogenesis, lipid uptake and storage, insulin sensitivity, and glucose metabolism. Hence, defects in PPARγ have been associated to the development of metabolic disorders. Sex hormone-binding globulin (SHBG) is a glycoprotein primarily produced in the liver that regulates the bioavailability of sex hormones. Alike PPARγ, low SHBG levels have been correlated with insulin resistance and associated endocrine abnormalities. Therefore, this study aimed to verify whether SHBG may restore depleted PPARγ functions and thus serve as a new candidate for the management of metabolic conditions. A model of equine adipose-derived stromal cells (EqASCs) has been used, in which a PPARγ silencing and SHBG treatment have been achieved to determine the changes in cell viability, premature senescence, oxidative stress, and mitochondrial functions. Obtained data demonstrated that loss in PPARγ triggers cell apoptosis which is not reversed by SHBG application. Moreover, PPARγ knockdown cells exhibited premature senescence, which has been substantially alleviated by SHBG concomitantly to increased BAX/BCL2 ratio, suggesting a possible effect on senescence-induced apoptosis resistance. Interestingly, PPARγ silencing induced a significant alteration in mitochondrial membrane potential as well as the expression of dynamics and metabolism-related markers. SHBG treatment enabled to ameliorate the transmembrane potential, to normalize the expression levels of key dynamics and metabolism mediators, and to restore the protein levels of PINK, which is critically involved in mitochondria recycling machinery. Presented data suggest that SHBG may provide new mechanistic insights into the regulation of PPARγ functions, and thus offers a preliminary picture on a possible SHBG-PPARγ metabolic crosstalk. KEY MESSAGES : PPARγ is a transcription factor that tightly regulates cell metabolism. Low SHBG levels correlate with insulin resistance and associated endocrine abnormalities. PPARγ silencing reduces cell viability, triggers premature senescence and profound mitochondrial failure in equine ASCs. SHBG protein reverses senescent phenotype and apoptosis resistance of PPARγ- ASCs. SHBG improves mitochondrial dynamics and metabolism following PPARγ knockdown. SHBG might serve as a PPARγ potential mimicking agent for the modulation of ASCs metabolic processes.
PubMed: 38874666
DOI: 10.1007/s00109-024-02459-z -
Biochemistry and Biophysics Reports Jul 2024The estrogen-synthesizing enzyme aromatase is expressed in adipose tissue where it controls the local concentration of estrogen. It has been suggested that the organic...
The estrogen-synthesizing enzyme aromatase is expressed in adipose tissue where it controls the local concentration of estrogen. It has been suggested that the organic solvents ethanol and ethylene glycol can induce estrogen synthesis by inhibiting PPARγ activity. Since elevated estrogen synthesis in adipose tissue is a risk factor for breast cancer development, it is of interest to further characterize the mechanisms regulating aromatase expression. Here, we explored the mechanisms by which ethanol and ethylene glycol modulate aromatase mRNA expression and the ultimate conversion of androgens into estrogens. NMR spectroscopy revealed that ethanol and ethylene glycol influence the active state of PPARγ. An inhibitory effect on PPARγ was confirmed by adipogenesis assays and PPARγ target gene expression analysis in adipocytes. However, only ethanol increased aromatase mRNA in differentiated human adipocytes. In contrast, ethylene glycol downregulated aromatase in a PPARγ-independent manner. An animal study using female Wistar rats was conducted to assess the acute effects of ethanol and ethylene glycol on aromatase expression in adipose tissue within a physiological context. No changes in aromatase or PPARγ target gene ( and ) levels were observed in adipose tissue or ovary in response to the chemical exposures, suggesting an absence of acute PPARγ-mediated effects in these organs. The results suggest that ethanol and ethylene glycol are weak PPARγ antagonists in mouse and human adipocytes as well as in cell-free NMR spectroscopy. Both compounds seem to affect adipocyte aromatase expression , where ethanol increased aromatase expression PPARγ-dependently and ethylene glycol decreased aromatase expression independently of PPARγ. No acute effects on aromatase expression or PPARγ activity were observed in adipose tissue or ovary in rats in this study design.
PubMed: 38873224
DOI: 10.1016/j.bbrep.2024.101742