AIM: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of same epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferator-activa...AIM: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of same epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferator-activated receptor γ (PPARγ), the mechanism by which TZD exert their anticancer effect is presently unclear. In this study, we analyzed the mechanism by which TZD inhibit growth of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma. METHODS: The effects of TZD in pancreatic cancer cells were assessed in anchorage-independent growth assay. Expression of PPARy was measured by reverse-transcription polymerase chain reaction and confirmed by Western blot analysis. PPARy activity was evaluated by transient reporter gene assay. Flow cytometry and DMA fragmentation,assay were used to determine the effect of TZD on cell cycle progression and apoptosis respectively. The effect of TZD on ductal differentiation markers was performed by Western blot. RESULTS: Exposure to TZD inhibited colony formation in a PPARγ-dependent manner. Growth inhibition was linked to G1 phase cell cycle arrest through induction of the ductal differentiation program without any increase of the apoptotic rate. CONCLUSION: TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth by a PPAR-dependent induction of pacreatic ductal differentiation.展开更多
Objective: Osteoporosis and type 2 diabetes mellitus (DM) two of the most common chronic conditions and represent major public health burdens. Epidemiological and observational studies indicate that thiazolidinedione ...Objective: Osteoporosis and type 2 diabetes mellitus (DM) two of the most common chronic conditions and represent major public health burdens. Epidemiological and observational studies indicate that thiazolidinedione (TZD) therapy with rosiglitazone and pioglitazone is associated with an increased risk of fractures and decreased bone mineral density (BMD). To our knowledge, no data are available to evaluate bisphosphonate therapy in thiazolidinedione-treated patients. The aim of this study was to investigate the benefit of bisphosphonates to improve changes in BMD in subjects with DM associated with TZDs. Methods: In a cross-sectional observational study using a retrospective review of electronic medical records, the changes in BMD in subjects with type 2 DM. The study subjects were divided into four groups. First group with DM receiving both TZDs and BPs;second group neither;third group receiving only TZDs and the fourth only BPs. The comparison of annual percent changes in BMD between the groups were carried out. Results: Decreased BMD noted in subjects with DM on TZDs. Bisphosphonates improved BMD in subjects with DM on TZDs. BMD improved in subjects with DM in those not receiving TZDs also. Conclusion: We conclude that concomitant treatment with bisphosphonates improves BMD in subjects with diabetes and on TZDs.展开更多
A facile preparation of ZnO nanobelts by chemical precipitation technique and its utility as catalyst in Knoevenagel condensation of 2,4-thiazolidinedione/rhodanine has been described. X-ray diffraction and transmissi...A facile preparation of ZnO nanobelts by chemical precipitation technique and its utility as catalyst in Knoevenagel condensation of 2,4-thiazolidinedione/rhodanine has been described. X-ray diffraction and transmission electron microscopy techniques revealed the formation ZnO nanobelts. Scanning electron microscopic observations indicate that the lengths of nanobelts are ranging from a few hundreds of micrometers to a few millimeters. Its use for the condensation of aldehydes and active methylene compounds under solvent free reaction condition at 90℃ afforded the corresponding products in excellent yields in minute time.展开更多
BACKGROUND Chiglitazar is an emerging pan-agonist of all peroxisome proliferator activated receptors(PPAR)-α,δandγ,and has therapeutic potential for type 2 diabetes(T2D).However,to date,no clinical studies or meta-...BACKGROUND Chiglitazar is an emerging pan-agonist of all peroxisome proliferator activated receptors(PPAR)-α,δandγ,and has therapeutic potential for type 2 diabetes(T2D).However,to date,no clinical studies or meta-analyses have compared the efficacy and safety of chiglitazar and traditional PPAR-γagonist thiazolidinediones(TZDs).A meta-analysis concerning this topic is therefore required.AIM To compare the efficacy and safety of chiglitazar and TZD in patients with T2D.METHODS PubMed,Medline,Embase,the Cochrane Central Register of Controlled Trials,Reference Citation Analysis and Clinicaltrial.gov websites were searched from August 1994 to March 2022.Randomized controlled trials(RCTs)of chiglitazar or TZD vs placebo in patients with T2D were included.Indirect comparisons and sensitivity analyses were implemented to evaluate multiple efficacy and safety endpoints of interest.RESULTS We included 93 RCTs that compared TZD with placebo and one that compared chiglitazar with placebo.For efficacy endpoints,the augmented dose of chiglitazar resulted in greater reductions in hemoglobin(Hb)A1c[weighted mean difference(WMD)=-0.15%,95%confidence interval(CI):-0.27 to-0.04%],triglycerides(WMD=-0.17 mmol/L,95%CI:-0.24 to-0.11 mmol/L)and alanine aminotransferase(WMD=-5.25 U/L,95%CI:-8.50 to-1.99 U/L),and a greater increase in homeostasis model assessment-β(HOMA-β)(WMD=17.75,95%CI:10.73-24.77)when compared with TZD treatment.For safety endpoints,the risks of hypoglycemia,edema,bone fractures,upper respiratory tract infection,urinary tract infection,and weight gain were all comparable between the augmented dose of chiglitazar and TZD.In patients with baseline HbA1c≥8.5%,body mass index≥30 kg/m^(2)or diabetes duration<10 years,the HbA1c reduction and HOMA-βincrease were more conspicuous for the augmented dose of chiglitazar compared with TZD.CONCLUSION Augmented dose of chiglitazar,a pan-activator of PPARs,may serve as an antidiabetic agent with preferable glycemic and lipid control,betterβ-cell function preserving capacity,and does not increase the risk of safety concerns when compared with TZD.展开更多
The metabolic syndrome is strongly associated with insulin resistance and consists of a constellation of factors such as hypertension and hyperlipidemia that raise the risk for cardiovascular disease (CVD) and diabete...The metabolic syndrome is strongly associated with insulin resistance and consists of a constellation of factors such as hypertension and hyperlipidemia that raise the risk for cardiovascular disease (CVD) and diabetes mellitus. Emerging data suggest that peroxisome proliferator-activated receptor-γ (PPARγ) is a critical determinant that may provide functional links between diabetes and CVD.展开更多
The peroxisome proliferator activator receptor-<em>γ</em> (PPAR-<em>γ</em>) remained the most effective target for management of diabetes mellitus. The present work endeavors rational designi...The peroxisome proliferator activator receptor-<em>γ</em> (PPAR-<em>γ</em>) remained the most effective target for management of diabetes mellitus. The present work endeavors rational designing new PPAR-<em>γ</em> agonist bearing cyclotriphosphazene and thiazolidine-2,4-dione scaffolds. Thiazolidinedione (TZD) derivatives are the novel class of oral antidiabetic drugs which are selective agonist for the nuclear PPAR<em>γ</em> that enhances the transcription of several insulin responsive genes but TZDs are known to cause weight gain, hepatotoxicity and fluid retention. So, cyclotriphosphazene containing thiazolidine-2,4-dione was designed, synthesized as PPAR<em>γ</em> agonist. The <em>in-vitro</em> antidiabetic activity showed that compound <strong>8</strong> has similar activity and exhibited higher glucose uptake in comparison to pioglitazone as reference drugs. This research opened new avenues for smart designing of molecules with high efficiency towards the management of hyperglycemia.展开更多
Thiazolidinediones （TZDs）, pharmacological activa-tors of peroxisome-proliferator-activated receptors γ （PPARγ）, significantly improve insulin resistance and lower plasma glucose concentrations. However, the us...Thiazolidinediones （TZDs）, pharmacological activa-tors of peroxisome-proliferator-activated receptors γ （PPARγ）, significantly improve insulin resistance and lower plasma glucose concentrations. However, the use of TZDs is associated with plasma volume expansion, the mechanism of which has been a matter of contro-versy. Originally, PPARγ-mediated enhanced transcrip-tion of the epithelial Na channel （ENaC） γ subunit was thought to play a central role in TZD-induced volume expansion. However, later studies suggested that the activation of ENaC alone could not explain TZD-induced volume expansion. We have recently shown that TZDs rapidly stimulate sodium-coupled bicarbonate absorp-tion from renal proximal tubule （PT） in vitro and in vivo. TZD-induced transport stimulation was dependent on PPARγ/Src/EGFR/ERK, and observed in rat, rabbit and human. However, this stimulation was not observed in mouse PTs where Src/EGFR is constitutively activated. Analysis in mouse embryonic fbroblast cells confrmed the existence of PPARγ/Src-dependent non-genomic signaling, which requires the ligand binding ability but not the transcriptional activity of PPARγ. The TZD-in-duced enhancement of association between PPARγ and Src supports an obligatory role for Src in this signal-ing. These results support the view that TZD-induced volume expansion is multifactorial. In addition to the PPARγ-dependent enhanced expression of the sodium transport system（s） in distal nephrons, the PPARγ-dependent non-genomic stimulation of renal proximal transport may be also involved in TZD-induced volume expansion.展开更多
基金Supported by Ministero dell'Università,della Ricerca Scientifica e Tecnologica, (MURST)
文摘AIM: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of same epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferator-activated receptor γ (PPARγ), the mechanism by which TZD exert their anticancer effect is presently unclear. In this study, we analyzed the mechanism by which TZD inhibit growth of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma. METHODS: The effects of TZD in pancreatic cancer cells were assessed in anchorage-independent growth assay. Expression of PPARy was measured by reverse-transcription polymerase chain reaction and confirmed by Western blot analysis. PPARy activity was evaluated by transient reporter gene assay. Flow cytometry and DMA fragmentation,assay were used to determine the effect of TZD on cell cycle progression and apoptosis respectively. The effect of TZD on ductal differentiation markers was performed by Western blot. RESULTS: Exposure to TZD inhibited colony formation in a PPARγ-dependent manner. Growth inhibition was linked to G1 phase cell cycle arrest through induction of the ductal differentiation program without any increase of the apoptotic rate. CONCLUSION: TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth by a PPAR-dependent induction of pacreatic ductal differentiation.
文摘Objective: Osteoporosis and type 2 diabetes mellitus (DM) two of the most common chronic conditions and represent major public health burdens. Epidemiological and observational studies indicate that thiazolidinedione (TZD) therapy with rosiglitazone and pioglitazone is associated with an increased risk of fractures and decreased bone mineral density (BMD). To our knowledge, no data are available to evaluate bisphosphonate therapy in thiazolidinedione-treated patients. The aim of this study was to investigate the benefit of bisphosphonates to improve changes in BMD in subjects with DM associated with TZDs. Methods: In a cross-sectional observational study using a retrospective review of electronic medical records, the changes in BMD in subjects with type 2 DM. The study subjects were divided into four groups. First group with DM receiving both TZDs and BPs;second group neither;third group receiving only TZDs and the fourth only BPs. The comparison of annual percent changes in BMD between the groups were carried out. Results: Decreased BMD noted in subjects with DM on TZDs. Bisphosphonates improved BMD in subjects with DM on TZDs. BMD improved in subjects with DM in those not receiving TZDs also. Conclusion: We conclude that concomitant treatment with bisphosphonates improves BMD in subjects with diabetes and on TZDs.
文摘A facile preparation of ZnO nanobelts by chemical precipitation technique and its utility as catalyst in Knoevenagel condensation of 2,4-thiazolidinedione/rhodanine has been described. X-ray diffraction and transmission electron microscopy techniques revealed the formation ZnO nanobelts. Scanning electron microscopic observations indicate that the lengths of nanobelts are ranging from a few hundreds of micrometers to a few millimeters. Its use for the condensation of aldehydes and active methylene compounds under solvent free reaction condition at 90℃ afforded the corresponding products in excellent yields in minute time.
基金Beijing Natural Science Foundation,No.7202216National Natural Science Foundation of China,No.81970698 and No.81970708.
文摘BACKGROUND Chiglitazar is an emerging pan-agonist of all peroxisome proliferator activated receptors(PPAR)-α,δandγ,and has therapeutic potential for type 2 diabetes(T2D).However,to date,no clinical studies or meta-analyses have compared the efficacy and safety of chiglitazar and traditional PPAR-γagonist thiazolidinediones(TZDs).A meta-analysis concerning this topic is therefore required.AIM To compare the efficacy and safety of chiglitazar and TZD in patients with T2D.METHODS PubMed,Medline,Embase,the Cochrane Central Register of Controlled Trials,Reference Citation Analysis and Clinicaltrial.gov websites were searched from August 1994 to March 2022.Randomized controlled trials(RCTs)of chiglitazar or TZD vs placebo in patients with T2D were included.Indirect comparisons and sensitivity analyses were implemented to evaluate multiple efficacy and safety endpoints of interest.RESULTS We included 93 RCTs that compared TZD with placebo and one that compared chiglitazar with placebo.For efficacy endpoints,the augmented dose of chiglitazar resulted in greater reductions in hemoglobin(Hb)A1c[weighted mean difference(WMD)=-0.15%,95%confidence interval(CI):-0.27 to-0.04%],triglycerides(WMD=-0.17 mmol/L,95%CI:-0.24 to-0.11 mmol/L)and alanine aminotransferase(WMD=-5.25 U/L,95%CI:-8.50 to-1.99 U/L),and a greater increase in homeostasis model assessment-β(HOMA-β)(WMD=17.75,95%CI:10.73-24.77)when compared with TZD treatment.For safety endpoints,the risks of hypoglycemia,edema,bone fractures,upper respiratory tract infection,urinary tract infection,and weight gain were all comparable between the augmented dose of chiglitazar and TZD.In patients with baseline HbA1c≥8.5%,body mass index≥30 kg/m^(2)or diabetes duration<10 years,the HbA1c reduction and HOMA-βincrease were more conspicuous for the augmented dose of chiglitazar compared with TZD.CONCLUSION Augmented dose of chiglitazar,a pan-activator of PPARs,may serve as an antidiabetic agent with preferable glycemic and lipid control,betterβ-cell function preserving capacity,and does not increase the risk of safety concerns when compared with TZD.
文摘The metabolic syndrome is strongly associated with insulin resistance and consists of a constellation of factors such as hypertension and hyperlipidemia that raise the risk for cardiovascular disease (CVD) and diabetes mellitus. Emerging data suggest that peroxisome proliferator-activated receptor-γ (PPARγ) is a critical determinant that may provide functional links between diabetes and CVD.
文摘The peroxisome proliferator activator receptor-<em>γ</em> (PPAR-<em>γ</em>) remained the most effective target for management of diabetes mellitus. The present work endeavors rational designing new PPAR-<em>γ</em> agonist bearing cyclotriphosphazene and thiazolidine-2,4-dione scaffolds. Thiazolidinedione (TZD) derivatives are the novel class of oral antidiabetic drugs which are selective agonist for the nuclear PPAR<em>γ</em> that enhances the transcription of several insulin responsive genes but TZDs are known to cause weight gain, hepatotoxicity and fluid retention. So, cyclotriphosphazene containing thiazolidine-2,4-dione was designed, synthesized as PPAR<em>γ</em> agonist. The <em>in-vitro</em> antidiabetic activity showed that compound <strong>8</strong> has similar activity and exhibited higher glucose uptake in comparison to pioglitazone as reference drugs. This research opened new avenues for smart designing of molecules with high efficiency towards the management of hyperglycemia.
文摘Thiazolidinediones （TZDs）, pharmacological activa-tors of peroxisome-proliferator-activated receptors γ （PPARγ）, significantly improve insulin resistance and lower plasma glucose concentrations. However, the use of TZDs is associated with plasma volume expansion, the mechanism of which has been a matter of contro-versy. Originally, PPARγ-mediated enhanced transcrip-tion of the epithelial Na channel （ENaC） γ subunit was thought to play a central role in TZD-induced volume expansion. However, later studies suggested that the activation of ENaC alone could not explain TZD-induced volume expansion. We have recently shown that TZDs rapidly stimulate sodium-coupled bicarbonate absorp-tion from renal proximal tubule （PT） in vitro and in vivo. TZD-induced transport stimulation was dependent on PPARγ/Src/EGFR/ERK, and observed in rat, rabbit and human. However, this stimulation was not observed in mouse PTs where Src/EGFR is constitutively activated. Analysis in mouse embryonic fbroblast cells confrmed the existence of PPARγ/Src-dependent non-genomic signaling, which requires the ligand binding ability but not the transcriptional activity of PPARγ. The TZD-in-duced enhancement of association between PPARγ and Src supports an obligatory role for Src in this signal-ing. These results support the view that TZD-induced volume expansion is multifactorial. In addition to the PPARγ-dependent enhanced expression of the sodium transport system（s） in distal nephrons, the PPARγ-dependent non-genomic stimulation of renal proximal transport may be also involved in TZD-induced volume expansion.
