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This study investigated the effects of Lycium chinense Mill (LCM) extract on obesity and diabetes, using both in vitro and high-fat diet (HFD)-induced obesity mouse models. We found that LCM notably enhanced glucagon-like peptide-1 (GLP-1) secretion in NCI-h716 cells from 411.4 ± 10.75 pg/mL to 411.4 ± 10.75 pg/mL compared to NT (78.0 ± 0.67 pg/mL) without causing cytotoxicity, implying the involvement of Protein Kinase A C (PKA C) and AMP-activated protein kinase (AMPK) in its action mechanism. LCM also decreased lipid droplets and lowered the expression of adipogenic and lipogenic indicators, such as Fatty Acid Synthase (FAS), Fatty Acid-Binding Protein 4 (FABP4), and Sterol Regulatory Element-Binding Protein 1c (SREBP1c), indicating the suppression of adipocyte differentiation and lipid accumulation. LCM administration to HFD mice resulted in significant weight loss (41.5 ± 3.3 g) compared to the HFD group (45.1 ± 1.8 g). In addition, improved glucose tolerance and serum lipid profiles demonstrated the ability to counteract obesity-related metabolic issues. Additionally, LCM exhibited hepatoprotective properties by reducing hepatic lipid accumulation and diminishing white adipose tissue mass and adipocyte size, thereby demonstrating its effectiveness against hepatic steatosis and adipocyte hypertrophy. These findings show that LCM can be efficiently used as a natural material to treat obesity and diabetes, providing a new approach for remedial and therapeutic purposes.
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Fármacos Antiobesidad , Dieta Alta en Grasa , Hipoglucemiantes , Lycium , Obesidad , Extractos Vegetales , Animales , Ratones , Lycium/química , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Dieta Alta en Grasa/efectos adversos , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/uso terapéutico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Masculino , Humanos , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Péptido 1 Similar al Glucagón/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Ratones Endogámicos C57BL , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismoRESUMEN
Obesity is a serious global health challenge, closely associated with numerous chronic conditions including type 2 diabetes. Anemarrhena asphodeloides Bunge (AA) known as Jimo has been used to address conditions associated with pathogenic heat such as wasting-thirst in Korean Medicine. Timosaponin A3 (TA3), a natural compound extracted from AA, has demonstrated potential therapeutic effects in various disease models. However, its effects on diabetes and obesity remain largely unexplored. We investigated the anti-obesity and anti-diabetic properties of TA3 using in vitro and in vivo models. TA3 treatment in NCI-H716 cells stimulated the secretion of glucagon-like peptide 1 (GLP-1) through the activation of phosphorylation of protein kinase A catalytic subunit (PKAc) and 5'-AMP-activated protein kinase (AMPK). In 3T3-L1 adipocytes, TA3 effectively inhibited lipid accumulation by regulating adipogenesis and lipogenesis. In a high-fat diet (HFD)-induced mice model, TA3 administration significantly reduced body weight gain and food intake. Furthermore, TA3 improved glucose tolerance, lipid profiles, and mitigated hepatic steatosis in HFD-fed mice. Histological analysis revealed that TA3 reduced the size of white adipocytes and inhibited adipose tissue generation. Notably, TA3 downregulated the expression of lipogenic factor, including fatty-acid synthase (FAS) and sterol regulatory element-binding protein 1c (SREBP1c), emphasizing its potential as an anti-obesity agent. These findings revealed that TA3 may be efficiently used as a natural compound for tackling obesity, diabetes, and associated metabolic disorders, providing a novel approach for therapeutic intervention.
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Fármacos Antiobesidad , Diabetes Mellitus Tipo 2 , Saponinas , Animales , Ratones , Obesidad/metabolismo , Esteroides/farmacología , Fármacos Antiobesidad/farmacología , Adipogénesis , Proteínas Quinasas Activadas por AMP/metabolismo , Lípidos/farmacología , Células 3T3-L1 , Dieta Alta en Grasa , Ratones Endogámicos C57BLRESUMEN
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, and despite advances in treatment, survival rates are still low; therefore, the development of novel drugs is imperative. Acetylcorynoline (ACN) is derived from Corydalis ambigua Cham. et Schltdl tubers. The effect of ACN on colon cancer is still unknown. Therefore, we investigated its potential effects. Our data showed that ACN inhibited cell viability and proliferation. Moreover, ACN induced apoptosis and cell cycle arrest by inhibiting cell growth. In the present study, we hypothesized that ACN regulates c-Myc through CNOT2 or MID1IP1. ACN reduced the protein expression of oncogenic genes, decreased c-Myc half-life, and rapidly inhibited the serum stimulation response. Moreover, knockdown of CNOT2 and MID1IP1 with ACN increased apoptosis and further reduced the expression of oncogenes. In addition, ACN exhibited a synergistic effect with low-dose 5-fluorouracil (5-FU) and doxorubicin (Dox). Collectively, our data demonstrate that ACN inhibited c-Myc expression through CNOT2 and MID1IP1, and induced apoptosis. These findings indicate the potential of ACN as a therapeutic agent against colon cancer.
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Neoplasias del Colon , Transducción de Señal , Humanos , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Puntos de Control del Ciclo Celular , Apoptosis , Fluorouracilo/farmacología , Mitosis , Proliferación Celular , Línea Celular Tumoral , Proteínas Represoras/genéticaRESUMEN
Research indicates that Chunghyul-dan (CHD), a herbal medicine, has an inhibitory effect on stroke recurrence in small vessel disease. Recent studies have suggested that CHD might also act on large arteries. This study aimed to verify the preventive effect of CHD on strokes of all the Trial of Org 10172 in Acute Stroke Treatment (TOAST) causative classifications. We retrospectively analyzed 2 years of medical records of patients with ischemic stroke treated with CHD, 600 mg once daily, in combination with antiplatelet or anticoagulant agents. The prevalence of stroke recurrence in 2 years was analyzed. Stroke recurrence was defined as new neurological symptoms with corresponding brain imaging results. Nine of the 202 patients (4.46%) had recurrent ischemic stroke. Four occurred within 180 days, 3 between 180 and 365 days, and 2 between 365 and 730 days. All had only 1 recurrence. The recurrence rates were 1.12%, 5%, and 5.48% for small vessel occlusion, cardioembolism, and large vessel atherosclerosis, respectively. There were no adverse effects. These results suggest that CHD could inhibit ischemic stroke recurrence of all TOAST causative categories. A randomized controlled trial is needed to confirm this hypothesis.
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Aterosclerosis , Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular Isquémico/complicaciones , Estudios Retrospectivos , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Aterosclerosis/complicaciones , Extractos Vegetales , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/prevención & control , Isquemia Encefálica/complicaciones , Recurrencia , Factores de RiesgoRESUMEN
In this study, we investigated the potential anticancer effects of Viscum album, a parasitic plant that grows on Malus domestica (VaM) on breast cancer cells, and explored the underlying mechanisms. VaM significantly inhibited cell viability and proliferation and induced apoptosis in a dose-dependent manner. VaM also regulated cell cycle progression and effectively inhibited activation of the STAT3 signaling pathway through SHP-1. Combining VaM with low-dose doxorubicin produced a synergistic effect, highlighting its potential as a promising therapeutic. In vivo, VaM administration inhibited tumor growth and modulated key molecular markers associated with breast cancer progression. Overall, our findings provide strong evidence for the therapeutic potential of VaM in breast cancer treatment and support further studies exploring clinical applications.
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Neoplasias de la Mama , Viscum album , Humanos , Femenino , Viscum album/metabolismo , Neoplasias de la Mama/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Apoptosis , Transducción de Señal , Proliferación Celular , Línea Celular Tumoral , Factor de Transcripción STAT3/metabolismoRESUMEN
Pancreatic cancer(PC) is less common than other cancers; however, it has a poor prognosis. Therefore, studying novel target signaling and anticancer agents is necessary. Momordicae Semen (MS), the seed of Momordica sochinensis Spreng, mainly found in South-East Asia, including China and Bangladesh, is used to treat various diseases because of its anticancer, antioxidant, anti-inflammatory, and antibacterial properties. However, the effect of the MS extract on pancreatic cancer cells remains unknown. In this study investigated whether the MS extract exerted an anti-cancer effect by regulating c-Myc through CNOT2. Cytotoxicity and proliferation were investigated using MTT and colony formation assays. The levels of apoptotic, oncogenic, and migration-associated factors were confirmed using immunoblotting and immunofluorescence. Wound closure was analyzed using a wound healing assay. The chemical composition of the MS methanol extracts was analyzed using liquid chromatography-mass spectrometry. We confirmed that the MS extract regulated apoptotic factors and attenuated the stability of c-Myc and its sensitivity to fetal bovine serum. Furthermore, the MS extract increased apoptosis by regulating c-Myc and CNOT2 expression and enhanced the sensitivity of 5-FU in pancreatic cancer. This study showed that the MS extract is a promising new drug for PC.
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Antineoplásicos , Neoplasias Pancreáticas , Humanos , Línea Celular Tumoral , Semillas , Apoptosis , Antineoplásicos/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Extractos Vegetales/química , Proliferación Celular , Proteínas Represoras/farmacología , Neoplasias PancreáticasRESUMEN
We hypothesized that Euonymus sachalinensis (ES) induces apoptosis by inhibiting the expression of c-Myc in colon cancer cells, and this study proved that the methanol extract of ES has anticancer effects in colon cancer cells. ES belongs to the Celastraceae family and is well known for its medicinal properties. Extracts of species belonging to this family have been used to treat diverse diseases, including rheumatoid arthritis, chronic nephritis, allergic conjunctivitis, rhinitis, and asthma. However, ES has been targeted because there are currently few studies on the efficacy of ES for various diseases, including cancer. ES lowers cell viability in colon cancer cells and reduces the expression of c-Myc protein. We confirm that the protein level of apoptotic factors such as PARP and Caspase 3 decrease when ES is treated with Western blot, and confirm that DNA fragments occur through TUNEL assay. In addition, it is confirmed that the protein level of oncogenes CNOT2 and MID1IP1 decrease when ES is treated. We have also found that ES enhances the chemo-sensitivity of 5-FU in 5-FU-resistant cells. Therefore, we confirm that ES has anticancer effects by inducing apoptotic cell death and regulating the oncogenes CNOT2 and MID1IP1, suggesting its potential for use in the treatment of colon cancer.
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Neoplasias del Colon , Euonymus , Humanos , Neoplasias del Colon/metabolismo , Apoptosis , Línea Celular Tumoral , Fluorouracilo/farmacología , Proliferación Celular , Proteínas RepresorasRESUMEN
Bitter taste receptors (TAS2Rs) are G protein-coupled receptors localized in the taste buds of the tongue. They may also be present in non-lingual organs, including the brain, lung, kidney, and gastrointestinal (GI) tract. Recent studies on bitter taste receptor functions have suggested TAS2Rs as potential therapeutic targets. The human bitter taste receptor subtype hTAS2R50 responds to its agonist isosinensetin (ISS). Here, we demonstrated that, unlike other TAS2R agonists, isosinensetin activated hTAS2R50 as well as increased Glucagon-like peptide 1 (GLP-1) secretion through the Gßγ-mediated pathway in NCI-H716 cells. To confirm this mechanism, we showed that ISS increased intracellular Ca2+ and was suppressed by the IP3R inhibitor 2-APB as well as the PLC inhibitor U73122, suggesting that TAS2Rs alters the physiological state of enteroendocrine L cells in a PLC-dependent manner. Furthermore, we demonstrated that ISS upregulated proglucagon mRNA and stimulated GLP-1 secretion. ISS-mediated GLP-1 secretion was suppressed in response to small interfering RNA-mediated silencing of Gα-gust and hTAS2R50 as well as 2-APB and U73122. Our findings improved the understanding of how ISS modulates GLP-1 secretion and indicates the possibility of using ISS as a therapeutic agent in the treatment of diabetes mellitus.
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Péptido 1 Similar al Glucagón , Receptores Acoplados a Proteínas G , Transducción de Señal , Humanos , Células Enteroendocrinas/metabolismo , Tracto Gastrointestinal/metabolismo , Péptido 1 Similar al Glucagón/efectos de los fármacos , Péptido 1 Similar al Glucagón/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Inflammation causes a protective immune response, which can be observed by examining the inflammatory responses of macrophages. Macrophages release various immunostimulatory factors when destroying external pathogens. We induced lipopolysaccharides (LPS) in RAW 264.7 cells, a macrophage cell line, to determine whether Helixor-M can cause immuno-suppression. Helixor-M is known to have anticancer and immune effects. However, an indicator that regulates immunity has not been clearly confirmed. To this end, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was conducted to confirm Helixor-M was not cytotoxic. Western blotting and real-time polymerase chain reaction (RT-PCR) confirmed the anti-inflammatory effects. Additionally, immunofluorescence assay confirmed the translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65, a representative inflammatory pathway. Helixor-M was found to be non-cytotoxic, induce the NF-κB pathway, and reduce the levels of pro-inflammatory cytokine and mitogen-activated protein kinase (MAPK). We found Helixor-M affected the PI3K/AKT/JNK pathway. Therefore, we confirmed Helixor-M acts as an anti-inflammatory agent through NF-κB, TLR4 and PI3K inhibition and that it could be an effective immunosuppressive drug.
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CONTEXT.: Although several neuroendocrine cell types constitute gastroenteropancreatic neuroendocrine tumors (NETs), the clinical and prognostic implications of the expression of multiple peptide hormones have not been comprehensively evaluated in rectal NETs. OBJECTIVE.: To identify the clinicopathologic characteristics and prognostic impact of peptide hormone expression. DESIGN.: We evaluated the expression of peptide YY (PYY), glucagon, somatostatin, serotonin, insulin, and gastrin using immunolabeling in 446 endoscopically or surgically resected rectal NETs. RESULTS.: PYY, glucagon, serotonin, somatostatin, insulin, and gastrin were expressed in 261 of 389 (67.1%), 205 of 446 (46.0%), 36 of 446 (8.1%), 33 of 446 (7.4%), 2 of 446 (0.4%), and 1 of 446 cases (0.2%), respectively. Immunoreactivity to any peptide hormone was present in 345 of 446 cases (77.4%). Tumors expressing serotonin or somatostatin were associated with lymphovascular invasion, chromogranin A expression, and shorter disease-free survival (DFS). Rectal NETs were classified as L-cell, enterochromaffin-cell, D-cell, null-expression, or mixed-expression type based on peptide hormonal expression status. Patients with D-cell NET had the shortest DFS (10-year DFS, 54.5%), followed by those with enterochromaffin-cell NET (89.5%), null expression (97.0%), L-cell NET (99.6%), and mixed-expression NET (100%; P < .001). Multivariable analyses revealed that somatostatin expression was an independent indicator of poor prognosis with respect to DFS in rectal NETs (P = .001). CONCLUSIONS.: Somatostatin expression is a poor prognostic indicator in patients with rectal NETs. Therefore, additional peptide hormonal immunolabeling, including somatostatin, serotonin, and PYY, in rectal NETs can provide more information regarding DFS.
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Tumores Neuroendocrinos , Neoplasias del Recto , Humanos , Tumores Neuroendocrinos/patología , Glucagón , Gastrinas , Serotonina , Somatostatina/metabolismo , InsulinaRESUMEN
Ophiopogonin D (OP-D), which is extracted from the root tuber of Ophiopogon japonicus, is well known for its anti-inflammatory, anti-oxidant, and anti-cancer effects. It is also therapeutic for various diseases such as diabetic myocardial injuries, obesity, atopic dermatitis, and osteoporosis. However, there are insufficient reports on the anti-cancer effects and molecular mechanisms of OP-D in colorectal cancer. Therefore, this study aimed to investigate the anti-cancer-modulating effect of OP-D on colorectal cancer. The study proved that OP-D (20-40 uM) has significant cell viability inhibition and anti-proliferative effects in Cell Counting Kit-8 (CCK-8) assay and colony formation assay. In addition, our immunofluorescence analysis data showed that OP-D (40 uM) inhibited the expression of Ki67, a cell proliferation marker, and confirmed that OP-D could induce nucleolar stress by depletion of IPO7 and XPO1. Furthermore, our western blot data showed that OP-D induced p53 expression via ribosomal protein (RP) L5 or L11 and inhibited c-Myc expression through CNOT2 in a dose-dependent manner. Additionally, OP-D regulated cyclin D1 and CDK4, which are well known as cell cycle regulatory proteins. OP-D consistently inhibited the phosphorylation of AKT expression in a dose-dependent manner. Furthermore, OP-D shortened c-Myc's half-life in a time-dependent manner. Furthermore, CNOT2 knockdown enhanced the inhibitory effect of OP-D on c-Myc in colon cancer cells. Besides that, we confirmed that OP-D has a combinational anti-cancer effect of 5-FU or doxorubicin to reduce cell viability and induce apoptosis through p53 and c-Myc regulation. Altogether, our results suggest that OP-D regulates colon cancer cell proliferation and induces apoptosis by inhibiting c-Myc expression via activation of p53 and CNOT2 regulation. The study demonstrated that OP-D may be a promising natural anti-cancer agent for the treatment of colorectal cancer.
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Colorectal cancer cell (CRC) is the fourth most common cancer in the world. There are several chemotherapy drugs available for its treatment, though they have side effects. Cycloastragenol (CY) is a compound from Astragalus membranaceus (Fisch.) Bge known to be effective in aging, anti-inflammatory, anticancer, and anti-heart failure treatments. Although many studies have demonstrated the functions of CY in cancer cells, no studies have shown the effects of p53 in colon cancer cells. In this study, we found that CY reduces the viability of colon cancer cells in p53 wild-type cells compared to p53 null cells and HT29. Furthermore, CY induces apoptosis by p53 activation in a dose- and time-dependent manner. And it was confirmed that it affects the L5 gene related to p53. Additionally, CY enhanced p53 expression compared to when either doxorubicin or 5-FU was used alone. Altogether, our findings suggest that CY induces apoptosis via p53 activation and inhibits the proliferation of colon cancer cells. In addition, apoptosis occurs in colon cancer cells due to other factors. Moreover, CY is expected to have a combined effect when used together with existing treatments for colon cancer in the future.
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Neoplasias del Colon , Proteína p53 Supresora de Tumor , Humanos , Apoptosis , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Células HCT116 , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Antineoplásicos/farmacologíaRESUMEN
Timosaponin A3 (TA3), extracted from the rhizome of Anemarrhenaasphodeloides Bunge, has been reported to affect various diseases, such as cancer, Alzheimer's disease, and allergies. However, the underlying molecular mechanisms and impacts are largely unknown. In the present study, we hypothesized that TA3 induces apoptosis through the inhibition of c-Myc expression via CNOT2 or MID1IP1 in HCT116. An MTT assay and colony formation assay were used to measure cell viability and proliferation. The protein expression of apoptotic markers and oncogenes was measured using immunoblotting and immunofluorescence assays. The interaction between MID1IP1 and c-Myc was confirmed by performing an immunoprecipitation assay. TA3 markedly inhibited colon cancer cell proliferation. Consistently, TA3 regulated the apoptotic proteins pro-PARP and caspase 3. TA3 inhibited the half-life of c-Myc and suppressed its expression in response to serum stimulation. In addition, TA3 enhanced the apoptotic effects of doxorubicin and 5-FU in colon cancer cells. Altogether, our results reveal a mechanism by which TA3 induces apoptosis through inhibiting c-Myc expression via CNOT2 or MID1IP1 in HCT116, which may help in the development of new therapies for colon cancer based on TA3 in the future.
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Neoplasias del Colon , Neoplasias Colorrectales , Apoptosis , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular , Neoplasias del Colon/patología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Células HCT116 , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Proteínas Represoras , Saponinas , EsteroidesRESUMEN
Exposure to water-soluble particulate matter (WPM) containing heavy metals can cause severe inflammatory responses and trigger and exacerbate the onset of asthma. As a follow-up study of Rosa laevigata (RL), this study analyzed the therapeutic effects and mechanisms of oral and intratracheal administration of RL and demonstrated anti-inflammatory effects in asthma models. Worse T-helper cell type 2 (Th2)-related inflammatory and pro-inflammatory responses were observed after simultaneous challenge with ovalbumin (OVA) and WPM. To establish a model of asthma exacerbated by WPM, BALB/c mice were sensitized with OVA + aluminum hydroxide and challenged with OVA + WPM. To confirm the therapeutic efficacy of RL, it was administered both orally and intratracheally. Histopathological analysis of H&E staining confirmed that oral and intratracheal administration of RL alleviated inflammatory cell infiltration in the airways aggravated by OVA + WPM. RL effectively reduced the number of inflammatory cells obtained from the bronchoalveolar lavage fluid. In addition, enzyme-linked immunosorbent assay (ELISA) and multiplex analysis of serum samples confirmed that the administration of RL reduced the levels of immuno-globulin E (IgE), Th2-related cytokines, and pro-inflammatory cytokines. Furthermore, real-time PCR analysis of lung tissue samples confirmed that the release of MUC5AC (Mucin 5AC, Oligomeric Mucus/Gel-Forming) and pro-inflammatory cytokines was reduced by RL, and western blotting confirmed that the administration of RL reduced the phosphorylation of ERK and p38 in the MAPK pathway. In conclusion, oral and intratracheal administration of RL appears to have an anti-asthmatic effect by reducing the secretion of Th2-related cytokines, pro-inflammatory cytokines, and IgE by downregulating the MAPK pathway. Thus, RL has further demonstrated potential for development as an oral and inhaled therapeutic for asthma symptoms exacerbated by WPM exposure.
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Timosaponin A3 (TA3) was demonstrated as a potent anticancer chemical by several studies. Although the effects of inhibiting growth, metastasis, and angiogenesis in various cancer cells were demonstrated through multiple mechanisms, the pharmacological mechanism of TA3 shown in pancreatic cancer (PC) is insufficient compared to other cancers. In this study, we aimed to explore the key molecular mechanisms underlying the growth inhibitory effects of TA3 using PC cells and a xenograft model. First, from the microarray results, we found that TA3 regulated INSIG-1 and HMGCR in BxPC-3 cells. Furthermore, we showed that inhibition of sterol regulatory element-binding protein-1 (SREBP-1) by TA3 reduced the fatty acid synthases FASN and ACC, thereby controlling the growth of BxPC-3 cells. We also tried to find mechanisms involved with SREBP-1, such as Akt, Gsk3ß, mTOR, and AMPK, but these were not related to SREBP-1 inhibition by TA3. In the BxPC-3 xenograft model, the TA3 group had more reduced tumor formation and lower toxicity than the gemcitabine group. Interestingly, the level of the fatty acid metabolites palmitate and stearate were significantly reduced in the tumor tissue in the TA3 group. Overall, our study demonstrated that SREBP-1 was a key transcription factor involved in pancreatic cancer growth and it remained a precursor form due to TA3, reducing the adipogenesis and growth in BxPC-3 cells. Our results improve our understanding of novel mechanisms of TA3 for the regulation of lipogenesis and provide a new approach to the prevention and treatment of PC.
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CCR4-NOT transcription complex subunit 2 (CNOT2), a subunit of the CCR4-NOT complex, has been described in cancer progression. The CNOT complex plays an important role in multiple cellular functions. Recent studies in our laboratory showed that CNOT2 promotes breast cancer cell proliferation and angiogenesis. In addition, CNOT2 signals are critically related to apoptosis induced by atorvastatin in lung cancer cells. Furthermore, depletion of CNOT2 was shown to enhance the antitumor effect of midline 1 interacting protein 1 (MID1IP1) depletion, thus inhibiting c-Myc expression in liver cancer cells. However, the molecular mechanisms related to its oncogenic role remain unclear. Herein, for the first time, we report that CNOT2 inhibition can induce apoptosis in colorectal cancer cells by activating p53. Inhibition of CNOT2 markedly induced apoptosis in various cancer cells like that of the wild-type p53. Furthermore, inhibition of CNOT2 elongated p53 s half-life. Previously, our laboratory demonstrated that MID1IP1 promoted colocalization with c-Myc mediated by CNOT2. Interestingly, inhibition of CNOT2 cannot induce p53 expression without MID1IP1 or apoptosis in cancer cells. In conclusion, our results demonstrate that CNOT2 inhibition induces apoptosis through MID1IP1 by activating p53.
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Apoptosis , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Proteínas del Citoesqueleto/metabolismo , Proteínas Represoras/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Daño del ADN , Doxorrubicina/farmacología , Técnicas de Silenciamiento del Gen , Humanos , Modelos Biológicos , Estabilidad Proteica , Proteínas Represoras/metabolismoRESUMEN
Obesity is a risk factor for metabolic diseases including type 2 diabetes, nonalcoholic steatohepatitis (NASH), heart diseases, and cancer. This study aimed to investigate the anti-obesity effect of Polygalin C (PC) isolated from Polygala japonica Houtt. in 3T3-L1 adipocytes. Based on Oil Red O assay results, PC significantly decreased lipid accumulation compared to the control. We found that PC suppressed adipogenesis transcription factors including peroxisome proliferator-activated receptor γ (PPAR γ) and CCAAT/enhancer-binding protein (C/EBP) α, and lipogenic factors such as sterol regulatory element-binding protein 1c (SREBP 1c) and fatty acid synthase (FAS), in 3T3-L1 adipocytes using Western blotting and real-time polymerase chain reaction (PCR). Moreover, PC inhibited the differentiation of 3T3-L1 cells by regulating the AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) and mitogen-activated protein kinase/protein kinase B (MAPK/Akt) signaling pathways. Additionally, we confirmed that PC inhibited early adipogenesis factors C/EBP ß and C/EBP δ. Therefore, PC inhibited adipogenesis and lipogenesis in vitro. Thus, PC appears to exert potential therapeutic effects on obesity by suppressing lipid metabolism.
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Adipogénesis/efectos de los fármacos , Flavonoles/farmacología , Lipogénesis/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Obesidad , Polygala/química , Células 3T3-L1 , Animales , Acido Graso Sintasa Tipo I/biosíntesis , Flavonoles/química , Flavonoles/aislamiento & purificación , Ratones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Obesidad/patología , PPAR gamma/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismoRESUMEN
Acute pneumonia is an inflammatory disease caused by several pathogens, with symptoms such as fever and chest pain, to which children are particularly vulnerable. Gancaonin N is a prenylated isoflavone of Glycyrrhiza uralensis that has been used in the treatment of various diseases in oriental medicine. There are little data on the anti-inflammatory efficacy of Gancaonin N, and its effects and mechanisms on acute pneumonia are unknown. Therefore, this study was conducted as a preliminary analysis of the anti-inflammatory effect of Gancaonin N in lipopolysaccharide (LPS)-induced RAW264.7 cells, and to identify its preventive effect on the lung inflammatory response and the molecular mechanisms underlying it. In this study, Gancaonin N inhibited the production of NO and PGE2 in LPS-induced RAW264.7 cells and significantly reduced the expression of iNOS and COX-2 proteins at non-cytotoxic concentrations. In addition, in LPS-induced A549 cells, Gancaonin N significantly reduced the expression of COX-2 and pro-inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6. Moreover, Gancaonin N reduced MAPK signaling pathway phosphorylation and NF-κB nuclear translocation. Therefore, Gancaonin N relieved the inflammatory response by inactivating the MAPK and NF-κB signaling pathways; thus, it is a potential natural anti-inflammatory agent that can be used in the treatment of acute pneumonia.
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One of the recent advances in nanotechnology within the medical field is the development of a nanoformulation of anticancer drugs or photosensitizers. Cancer cell-specific drug delivery and upregulation of the endogenous level of reactive oxygen species (ROS) are important in precision anticancer treatment. Within our article, we report a new therapeutic nanoformulation of cancer cell targeting using endogenous ROS self-generation without an external initiator and a switch-on drug release (ROS-induced cascade nanoparticle degradation and anticancer drug generation). We found a substantial cellular ROS generation by treating an isothiocyanate-containing chemical and functionalizing it onto the surface of porous silicon nanoparticles (pSiNPs) that are biodegradable and ROS-responsive nanocarriers. Simultaneously, we loaded an ROS-responsive prodrug (JS-11) that could be converted to the original anticancer drug, SN-38, and conducted further surface functionalization with a cancer-targeting peptide, CGKRK. We demonstrated the feasibility as a cancer-targeting and self-activating therapeutic nanoparticle in a pancreatic cancer xenograft mouse model, and it showed a superior therapeutic efficacy through ROS-induced therapy and drug-induced cell death. The work presented is a new concept of a nanotherapeutic and provides a more feasible clinical translational pathway.
Asunto(s)
Antineoplásicos/uso terapéutico , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Liberación de Fármacos , Femenino , Humanos , Irinotecán/farmacocinética , Irinotecán/uso terapéutico , Isotiocianatos/química , Isotiocianatos/farmacocinética , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Oligopéptidos/química , Oligopéptidos/farmacocinética , Fármacos Fotosensibilizantes/farmacocinética , Medicina de Precisión , Profármacos/farmacocinética , Profármacos/uso terapéutico , Silanos/química , Silanos/farmacocinética , Silicio/química , Silicio/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Injured tissue triggers complex interactions through biological process associated with keratins. Rapid recovery is most important for protection against secondary infection and inflammatory pain. For rapid wound healing with minimal pain and side effects, shilajit has been used as an ayurvedic medicine. However, the mechanisms of rapid wound closure are unknown. Here, we found that shilajit induced wound closure in an acute wound model and induced migration in skin explant cultures through evaluation of transcriptomics via microarray testing. In addition, ferulic acid (FA), as a bioactive compound, induced migration via modulation of keratin 6α (K6α) and inhibition of ß-catenin in primary keratinocytes of skin explant culture and injured full-thickness skin, because accumulation of ß-catenin into the nucleus acts as a negative regulator and disturbs migration in human epidermal keratinocytes. Furthermore, FA alleviated wound-induced inflammation via activation of nuclear factor erythroid-2-related factor 2 (Nrf2) at the wound edge. These findings show that FA is a novel therapeutic agent for wound healing that acts via inhibition of ß-catenin in keratinocytes and by activation of Nrf2 in wound-induced inflammation.