Jose Guzman‑Esquivel, Janet Diaz‑Martinez, Jose Ortega‑Ortiz, Efren Murillo‑Zamora, Valery Melnikov, Hector Tejeda‑Luna, Vanessa Cosio‑Medina, Karla Llerenas‑Aguirre, Jose Guzman‑Solorzano, Gustavo Hernandez‑Fuentes, Maria Ochoa‑Castro, Martha Cardenas‑Rojas, Fabian Rojas‑Larios, Ivan Delgado‑Enciso
There are contradictory results regarding changes in estimated glomerular filtration rate (eGFR) in coronavirus disease 2019 (COVID‑19) survivors. An analysis of eGFR changes and clinical characteristics associated with those changes was conducted among COVID‑19 survivors. eGFR values were compared at different time points (before and 4‑, 8‑ and 12‑months after COVID‑19 infection). A multivariate generalized linear mixed model (GENLINMIXED procedure) with a binary logistic regression link was used to determine factors associated with eGFR reduction of ≥10 ml/min/1.73 m2. Being hospitalized (RR=2.90, 95% CI=1.10‑7.68, P=0.032), treated with Ivermectin (RR=14.02, 95% CI=4.11‑47.80, P<0.001) or anticoagulants (RR=6.51, 95% CI=2.69‑15.73, P<0.001) are risk factors for a reduced eGFR. Having a low eGFR (<90 ml/min/1.73 m2) before COVID‑19 infection, having B‑positive blood type, diabetes, taking vitamin C during the acute phase of COVID‑19 or suffering from chronic COVID‑19 symptoms, were identified as protective factors. Analysis involving a two‑way interaction (A x B, where A and B are factors) demonstrated that the combination of patients with a normal eGFR value before COVID‑19 infection without diabetes (RR=58.60, 95% CI=11.62‑295.38, P<0.001), or a normal eGFR value with being hospitalized for COVID‑19 (RR=38.07, 95% CI=8.68‑167.00, P<0.001), increased the probability of a reduced eGFR. The changes in eGFR in COVID‑19 survivors varied depending on patient characteristics. Furthermore, the principal risk factors for post‑COVID‑19 eGFR reduction were analyzed in separate models.
{"title":"Interactions between the principal risk factors for reduction of the eGFR in unvaccinated COVID‑19 survivors: Normal pre-COVID‑19 eGFR, not having diabetes and being hospitalized","authors":"Jose Guzman‑Esquivel, Janet Diaz‑Martinez, Jose Ortega‑Ortiz, Efren Murillo‑Zamora, Valery Melnikov, Hector Tejeda‑Luna, Vanessa Cosio‑Medina, Karla Llerenas‑Aguirre, Jose Guzman‑Solorzano, Gustavo Hernandez‑Fuentes, Maria Ochoa‑Castro, Martha Cardenas‑Rojas, Fabian Rojas‑Larios, Ivan Delgado‑Enciso","doi":"10.3892/etm.2023.12279","DOIUrl":"https://doi.org/10.3892/etm.2023.12279","url":null,"abstract":"There are contradictory results regarding changes in estimated glomerular filtration rate (eGFR) in coronavirus disease 2019 (COVID‑19) survivors. An analysis of eGFR changes and clinical characteristics associated with those changes was conducted among COVID‑19 survivors. eGFR values were compared at different time points (before and 4‑, 8‑ and 12‑months after COVID‑19 infection). A multivariate generalized linear mixed model (GENLINMIXED procedure) with a binary logistic regression link was used to determine factors associated with eGFR reduction of ≥10 ml/min/1.73 m2. Being hospitalized (RR=2.90, 95% CI=1.10‑7.68, P=0.032), treated with Ivermectin (RR=14.02, 95% CI=4.11‑47.80, P<0.001) or anticoagulants (RR=6.51, 95% CI=2.69‑15.73, P<0.001) are risk factors for a reduced eGFR. Having a low eGFR (<90 ml/min/1.73 m2) before COVID‑19 infection, having B‑positive blood type, diabetes, taking vitamin C during the acute phase of COVID‑19 or suffering from chronic COVID‑19 symptoms, were identified as protective factors. Analysis involving a two‑way interaction (A x B, where A and B are factors) demonstrated that the combination of patients with a normal eGFR value before COVID‑19 infection without diabetes (RR=58.60, 95% CI=11.62‑295.38, P<0.001), or a normal eGFR value with being hospitalized for COVID‑19 (RR=38.07, 95% CI=8.68‑167.00, P<0.001), increased the probability of a reduced eGFR. The changes in eGFR in COVID‑19 survivors varied depending on patient characteristics. Furthermore, the principal risk factors for post‑COVID‑19 eGFR reduction were analyzed in separate models.","PeriodicalId":12285,"journal":{"name":"Experimental and therapeutic medicine","volume":"45 2","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136067786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Apoptosis is a main characteristic of seawater aspiration‑induced acute lung injury (ALI). The local angiotensin (ANG) system angiotensin converting enzyme (ACE)‑2/ANG1‑7/Mas axis and ANGII/angiotensin II receptor type 1 (AT1) play an important role in apoptosis. MicroRNA (miR)‑200c‑3p is involved in the regulation of the ACE‑2 pathway, but its role and mechanism in seawater‑induced ALI remain to be elucidated. In the present study, seawater‑ALI lung tissue and cell model was established and apoptosis‑related proteins, ACE2, ANGII, ANG1‑7 were detected by western blotting following downregulation of miR‑200c‑3p. In addition, miR‑200c‑3p was detected by reverse transcription‑quantitative PCR. The target relationship between miR‑200c‑3p and ACE2 was confirmed by dual‑luciferase reporter assay. Seawater stimulation increased the expression of miR‑200c‑3p, ANGII and decreased ACE‑2/ANG1‑7 expression and induced changes of apoptosis‑related protein expression. Apoptosis can be inhibited by AT1 blocker and abrogated by addition of ANG1‑7 following seawater stimulation. In addition, inhibition of miR‑200c‑3p suppressed apoptosis and decreased the expression of ANGII, but increased the ACE‑2/ANG1‑7 expression. These results suggested that increased expression of miR‑200c‑3p was an important cause in seawater‑induced ALI and this phenomenon was through inhibition of ACE2/ANG1‑7 pathway.
{"title":"MicroRNA‑200c‑3p regulates seawater‑induced acute lung injury via ANGII and ACE2/ANG1‑7 pathways","authors":"Minlong Zhang, Lixin Xie","doi":"10.3892/etm.2023.12281","DOIUrl":"https://doi.org/10.3892/etm.2023.12281","url":null,"abstract":"Apoptosis is a main characteristic of seawater aspiration‑induced acute lung injury (ALI). The local angiotensin (ANG) system angiotensin converting enzyme (ACE)‑2/ANG1‑7/Mas axis and ANGII/angiotensin II receptor type 1 (AT1) play an important role in apoptosis. MicroRNA (miR)‑200c‑3p is involved in the regulation of the ACE‑2 pathway, but its role and mechanism in seawater‑induced ALI remain to be elucidated. In the present study, seawater‑ALI lung tissue and cell model was established and apoptosis‑related proteins, ACE2, ANGII, ANG1‑7 were detected by western blotting following downregulation of miR‑200c‑3p. In addition, miR‑200c‑3p was detected by reverse transcription‑quantitative PCR. The target relationship between miR‑200c‑3p and ACE2 was confirmed by dual‑luciferase reporter assay. Seawater stimulation increased the expression of miR‑200c‑3p, ANGII and decreased ACE‑2/ANG1‑7 expression and induced changes of apoptosis‑related protein expression. Apoptosis can be inhibited by AT1 blocker and abrogated by addition of ANG1‑7 following seawater stimulation. In addition, inhibition of miR‑200c‑3p suppressed apoptosis and decreased the expression of ANGII, but increased the ACE‑2/ANG1‑7 expression. These results suggested that increased expression of miR‑200c‑3p was an important cause in seawater‑induced ALI and this phenomenon was through inhibition of ACE2/ANG1‑7 pathway.","PeriodicalId":12285,"journal":{"name":"Experimental and therapeutic medicine","volume":"36 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136022855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Following the publication of this paper, the authors personally requested that the article be retracted on account of their subsequent realization that they had used improper experimental methods, combined with general concerns about the published data and the fact that a large number of the experimental findings were found to be irreproducible. Independently of the authors’ request, it was drawn to the Editor’s attention by a concerned reader that the immunohistochemical data shown in the various data panels in Fig. 1 on p. 599 were overlapping, such that data which had been included in the figure to represent different experimental conditions may have been derived from the same original source(s). In addition, control western blotting data shown in Fig. 3 on p. 600 were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes, which had either already been published or were under consideration for publication at around the same time. Owing to the fact that contentious data in the above article had already been published prior to its submission to Experimental and Therapeutic Medicine, and also based on an overall lack of confidence in the presented data, the Editor has accepted the request of the authors to retract this paper from the Journal. The Editor apologizes to the readership for any inconvenience caused. [Experimental and Therapeutic Medicine 19: 597‑602, 2020; DOI: 10.3892/etm.2019.8270]
{"title":"[Retracted] Imatinib inhibits oxidative stress response in spinal cord injury rats by activating Nrf2/HO‑1 signaling pathway","authors":"Limin Liu, Jingyuan Zhou, Yufeng Wang, Tengmin Qi, Zengshun Wang, Linxu Chen, Nananxiu Suo","doi":"10.3892/etm.2023.12280","DOIUrl":"https://doi.org/10.3892/etm.2023.12280","url":null,"abstract":"Following the publication of this paper, the authors personally requested that the article be retracted on account of their subsequent realization that they had used improper experimental methods, combined with general concerns about the published data and the fact that a large number of the experimental findings were found to be irreproducible. Independently of the authors’ request, it was drawn to the Editor’s attention by a concerned reader that the immunohistochemical data shown in the various data panels in Fig. 1 on p. 599 were overlapping, such that data which had been included in the figure to represent different experimental conditions may have been derived from the same original source(s). In addition, control western blotting data shown in Fig. 3 on p. 600 were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes, which had either already been published or were under consideration for publication at around the same time. Owing to the fact that contentious data in the above article had already been published prior to its submission to <em>Experimental and Therapeutic Medicine</em>, and also based on an overall lack of confidence in the presented data, the Editor has accepted the request of the authors to retract this paper from the Journal. The Editor apologizes to the readership for any inconvenience caused. [Experimental and Therapeutic Medicine 19: 597‑602, 2020; DOI: 10.3892/etm.2019.8270]","PeriodicalId":12285,"journal":{"name":"Experimental and therapeutic medicine","volume":"13 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136068219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hyperforin is a type of bicyclic tetraketone with four isoprenoid chains extracted from Hypericum perforatum L. that has multiple biological activities such as anti‑diabetes, antitumor and anti‑inflammation. However, the role and potential mechanism of hyperforin in allergic rhinitis (AR) remains to be clarified. In the present study, cell viability was analyzed using Cell Counting Kit‑8 assay, while inflammation was detected using ELISA and reverse transcription‑quantitative PCR. Epithelial cell barrier damage was measured using western blotting and immunofluorescence staining. The expression levels of B‑cell lymphoma 6 (BCL6) and the p38 MAPK/C‑C motif chemokine 11 (CCL11) pathway were detected using western blotting. In addition, the association between hyperforin and BCL6 was analyzed by SWISS TargetPrediction, DisGeNET, Gene Ontology and Pathway databases. Molecular docking was performed using AutoDockTools 1.5.6 and Discovery Studio 4.5 software. The data demonstrated that there were 16 interlinking target genes of hyperforin with AR, in which BCL6 was the most relevant one with hyperforin in AR. The binding between hyperforin and BCL6 was verified, and molecular docking was modeled. The results revealed that hyperforin inhibited IL‑13‑induced nasal epithelial inflammatory cytokine release and repressed the damage to the cellular barrier from IL‑13 stimulation. In addition, hyperforin activated BCL6 expression and significantly suppressed the expression of p38 MAPK/CCL11. Silencing of BCL6 reversed the effects of hyperforin on IL‑13‑induced inflammation and barrier damage. In summary, the present results revealed that hyperforin suppressed IL‑13‑induced nasal epithelial cell inflammation and barrier damage by targeting BCL6/p38 MAPK/CCL11, which may provide promising therapeutic targets for AR.
{"title":"Hyperforin modulates MAPK/CCL11 signaling to reduce the inflammatory response of nasal mucosal epithelial cells caused by allergic rhinitis by targeting BCL6","authors":"Chen Xu, Wen Su","doi":"10.3892/etm.2023.12278","DOIUrl":"https://doi.org/10.3892/etm.2023.12278","url":null,"abstract":"Hyperforin is a type of bicyclic tetraketone with four isoprenoid chains extracted from <em>Hypericum perforatum</em> L. that has multiple biological activities such as anti‑diabetes, antitumor and anti‑inflammation. However, the role and potential mechanism of hyperforin in allergic rhinitis (AR) remains to be clarified. In the present study, cell viability was analyzed using Cell Counting Kit‑8 assay, while inflammation was detected using ELISA and reverse transcription‑quantitative PCR. Epithelial cell barrier damage was measured using western blotting and immunofluorescence staining. The expression levels of B‑cell lymphoma 6 (BCL6) and the p38 MAPK/C‑C motif chemokine 11 (CCL11) pathway were detected using western blotting. In addition, the association between hyperforin and BCL6 was analyzed by SWISS TargetPrediction, DisGeNET, Gene Ontology and Pathway databases. Molecular docking was performed using AutoDockTools 1.5.6 and Discovery Studio 4.5 software. The data demonstrated that there were 16 interlinking target genes of hyperforin with AR, in which BCL6 was the most relevant one with hyperforin in AR. The binding between hyperforin and BCL6 was verified, and molecular docking was modeled. The results revealed that hyperforin inhibited IL‑13‑induced nasal epithelial inflammatory cytokine release and repressed the damage to the cellular barrier from IL‑13 stimulation. In addition, hyperforin activated BCL6 expression and significantly suppressed the expression of p38 MAPK/CCL11. Silencing of BCL6 reversed the effects of hyperforin on IL‑13‑induced inflammation and barrier damage. In summary, the present results revealed that hyperforin suppressed IL‑13‑induced nasal epithelial cell inflammation and barrier damage by targeting BCL6/p38 MAPK/CCL11, which may provide promising therapeutic targets for AR.","PeriodicalId":12285,"journal":{"name":"Experimental and therapeutic medicine","volume":"17 9","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136262642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaobo Wang, Lihua Yuan, Bo Lu, Dongjun Lin, Xiaojun Xu
Azacitidine is a DNA methyltransferase inhibitor that has been used as a singular agent for the treatment of myelodysplastic syndrome‑refractory anemia with excess blast‑1 and ‑2 (MDS‑RAEB I/II). However, recurrence and overall response rates following this treatment remain unsatisfactory. The combination of azacitidine and venetoclax has been used for the clinical treatment of a variety of hematological diseases due to the synergistic killing effect of the two drugs. Venetoclax is a BCL‑2 inhibitor that can inhibit mitochondrial metabolism. In addition, azacitidine has been shown to reduce the levels of myeloid cell leukemia 1 (MCL‑1) in acute myeloid leukemia cells. MCL‑1 is an anti‑apoptotic protein and a potential source of resistance to venetoclax. However, the mechanism underlying the effects of combined venetoclax and azacitidine treatment remains to be fully elucidated. In the present study, the molecular mechanism underlying the impact of venetoclax on the efficacy of azacitidine was investigated by examining its effects on cell cycle progression. SKM‑1 cell lines were treated in vitro with 0‑2 µM venetoclax and 0‑4 µM azacytidine. After 24, 48 and 72 h of treatment, the impact of the drugs on the cell cycle was assessed by flow cytometry. Following drug treatment, changes in cellular glutamine metabolism pathways was analyzed using western blotting (ATF4, CHOP, ASCT2, IDH2 and RB), quantitative PCR (ASCT2 and IDH2), liquid chromatography‑mass spectrometry (α‑KG, succinate and glutathione) and ELISA (glutamine and glutaminase). Venetoclax was found to inhibit mitochondrial activity though the alanine‑serine‑cysteine transporter 2 (ASCT2) pathway, which decreased glutamine uptake. Furthermore, venetoclax partially antagonized the action of azacitidine through this ASCT2 pathway, which was reversed by glutathione (GSH) treatment. These results suggest that GSH treatment can potentiate the synergistic therapeutic effects of venetoclax and azacitidine combined treatment on a myelodysplastic syndrome‑refractory anemia cell line at lower concentrations.
{"title":"Glutathione promotes the synergistic effects of venetoclax and azacytidine against myelodysplastic syndrome‑refractory anemia by regulating the cell cycle","authors":"Xiaobo Wang, Lihua Yuan, Bo Lu, Dongjun Lin, Xiaojun Xu","doi":"10.3892/etm.2023.12274","DOIUrl":"https://doi.org/10.3892/etm.2023.12274","url":null,"abstract":"Azacitidine is a DNA methyltransferase inhibitor that has been used as a singular agent for the treatment of myelodysplastic syndrome‑refractory anemia with excess blast‑1 and ‑2 (MDS‑RAEB I/II). However, recurrence and overall response rates following this treatment remain unsatisfactory. The combination of azacitidine and venetoclax has been used for the clinical treatment of a variety of hematological diseases due to the synergistic killing effect of the two drugs. Venetoclax is a BCL‑2 inhibitor that can inhibit mitochondrial metabolism. In addition, azacitidine has been shown to reduce the levels of myeloid cell leukemia 1 (MCL‑1) in acute myeloid leukemia cells. MCL‑1 is an anti‑apoptotic protein and a potential source of resistance to venetoclax. However, the mechanism underlying the effects of combined venetoclax and azacitidine treatment remains to be fully elucidated. In the present study, the molecular mechanism underlying the impact of venetoclax on the efficacy of azacitidine was investigated by examining its effects on cell cycle progression. SKM‑1 cell lines were treated <em>in vitro</em> with 0‑2 µM venetoclax and 0‑4 µM azacytidine. After 24, 48 and 72 h of treatment, the impact of the drugs on the cell cycle was assessed by flow cytometry. Following drug treatment, changes in cellular glutamine metabolism pathways was analyzed using western blotting (ATF4, CHOP, ASCT2, IDH2 and RB), quantitative PCR (<em>ASCT2</em> and <em>IDH2</em>), liquid chromatography‑mass spectrometry (α‑KG, succinate and glutathione) and ELISA (glutamine and glutaminase). Venetoclax was found to inhibit mitochondrial activity though the alanine‑serine‑cysteine transporter 2 (ASCT2) pathway, which decreased glutamine uptake. Furthermore, venetoclax partially antagonized the action of azacitidine through this ASCT2 pathway, which was reversed by glutathione (GSH) treatment. These results suggest that GSH treatment can potentiate the synergistic therapeutic effects of venetoclax and azacitidine combined treatment on a myelodysplastic syndrome‑refractory anemia cell line at lower concentrations.","PeriodicalId":12285,"journal":{"name":"Experimental and therapeutic medicine","volume":"8 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134905840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alendronate (ALN) is an anti-bone-resorptive drug with inflammatory side effects. ALN upregulates lipid A-induced interleukin (IL)-1α and IL-1β release by J774.1 cells via apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) activation. The present study examined whether ALN augmented lipid A-induced proinflammatory cytokine production using ASC-deficient mouse macrophage-like RAW264 cells. Pretreatment of RAW264 cells with ALN significantly augmented lipid A-induced IL-1β release, although ALN did not upregulate the expression of Toll-like receptor 4, myeloid differentiation factor 88 (MyD88) and caspase-11. Moreover, pretreatment of caspase-11-deficient RAW264.7 cells with ALN significantly augmented lipid A-induced IL-1β release. Notably, ALN upregulated the activation of FosB, c-Jun or JunD, but not c-Fos or NF-κB in RAW264 cells. Furthermore, pretreatment with the activator protein 1 (AP-1) inhibitor SR11302, but not the c-Fos inhibitor T-5224, before addition of ALN inhibited ALN-augmented IL-1β release by lipid A-treated RAW264 cells. SR11302 also reduced ALN-augmented lactate dehydrogenase release by the cells. These findings collectively suggested that ALN augmented lipid A-induced IL-1β release and cell membrane damage in ASC-deficient RAW264 cells via activation of AP-1, but not NF-κB.
{"title":"Alendronate augments lipid A‑induced IL‑1β release by ASC‑deficient RAW264 cells via AP‑1 activation","authors":"Noriyuki Watanabe, Riyoko Tamai, Yusuke Kiyoura","doi":"10.3892/etm.2023.12276","DOIUrl":"https://doi.org/10.3892/etm.2023.12276","url":null,"abstract":"Alendronate (ALN) is an anti-bone-resorptive drug with inflammatory side effects. ALN upregulates lipid A-induced interleukin (IL)-1α and IL-1β release by J774.1 cells via apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) activation. The present study examined whether ALN augmented lipid A-induced proinflammatory cytokine production using ASC-deficient mouse macrophage-like RAW264 cells. Pretreatment of RAW264 cells with ALN significantly augmented lipid A-induced IL-1β release, although ALN did not upregulate the expression of Toll-like receptor 4, myeloid differentiation factor 88 (MyD88) and caspase-11. Moreover, pretreatment of caspase-11-deficient RAW264.7 cells with ALN significantly augmented lipid A-induced IL-1β release. Notably, ALN upregulated the activation of FosB, c-Jun or JunD, but not c-Fos or NF-κB in RAW264 cells. Furthermore, pretreatment with the activator protein 1 (AP-1) inhibitor SR11302, but not the c-Fos inhibitor T-5224, before addition of ALN inhibited ALN-augmented IL-1β release by lipid A-treated RAW264 cells. SR11302 also reduced ALN-augmented lactate dehydrogenase release by the cells. These findings collectively suggested that ALN augmented lipid A-induced IL-1β release and cell membrane damage in ASC-deficient RAW264 cells via activation of AP-1, but not NF-κB.","PeriodicalId":12285,"journal":{"name":"Experimental and therapeutic medicine","volume":"5 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134909307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Idiopathic membranous nephropathy (IMN) is a common glomerular disease, in which 50‑60% of patients can progress to end‑stage renal disease within 10‑20 years, seriously endangering human health. Podocyte injury is the direct cause of IMN. Sublytic C5b‑9 complement complex induces damage in podocytes' structure and function. In sublytic C5b‑9 treated podocytes, the expression of canonical transient receptor potential 6 (TRPC6) is increased. However, the specific mechanism of TRPC6 in sublytic C5b‑9 treated podocytes is unclear. The present study aimed to reveal the effect and mechanism of TRPC6 on sublytic C5b‑9‑induced podocytes. Normal human serum was stimulated using zymosan to form C5b‑9. A lactate dehydrogenase release assay was used to examine C5b‑9 cytotoxicity in podocytes. The RNA and protein expression levels were analyzed using reverse transcription‑quantitative PCR, western blotting and immunofluorescent assay, respectively. Cell Counting Kit‑8 assay and flow cytometry were carried out to test the viability and apoptosis of podocytes, respectively. Transmission electron microscopy was used to observe autophagic vacuole. F‑actin was tested through phalloidin staining. Sublytic C5b‑9 was deposited and TRPC6 expression was boosted in podocytes stimulated through zymosan activation serum. Knockdown of TRPC6 raised the viability and reduced the apoptosis rate of sublytic C5b‑9‑induced podocytes. Meanwhile, transfection of small‑interfering (si)TRPC6 facilitated autophagy progression and enhanced the activation of cathepsin B/L in sublytic C5b‑9‑induced podocytes. The phosphorylation level of ERK1/2 was receded in siTRPC6 and sublytic C5b‑9 co‑treated podocytes. Moreover, the addition of the ERK1/2 activator partially reversed the effect of TRPC6 inhibition on sublytic C5b‑9‑induced podocytes. TRPC6 knockdown reduced the damage of sublytic C5b‑9 to podocytes by weakening the ERK1/2 phosphorylation level to activate autophagy. These results indicated that targeting TRPC6 reduced the injury of sublytic C5b‑9 on podocytes.
{"title":"Downregulation of TRPC6 regulates ERK1/2 to prevent sublytic C5b‑9 complement complex‑induced podocyte injury through activating autophagy","authors":"Yuanyuan Li, Youfu Fang, Jing Liu","doi":"10.3892/etm.2023.12275","DOIUrl":"https://doi.org/10.3892/etm.2023.12275","url":null,"abstract":"Idiopathic membranous nephropathy (IMN) is a common glomerular disease, in which 50‑60% of patients can progress to end‑stage renal disease within 10‑20 years, seriously endangering human health. Podocyte injury is the direct cause of IMN. Sublytic C5b‑9 complement complex induces damage in podocytes' structure and function. In sublytic C5b‑9 treated podocytes, the expression of canonical transient receptor potential 6 (TRPC6) is increased. However, the specific mechanism of TRPC6 in sublytic C5b‑9 treated podocytes is unclear. The present study aimed to reveal the effect and mechanism of TRPC6 on sublytic C5b‑9‑induced podocytes. Normal human serum was stimulated using zymosan to form C5b‑9. A lactate dehydrogenase release assay was used to examine C5b‑9 cytotoxicity in podocytes. The RNA and protein expression levels were analyzed using reverse transcription‑quantitative PCR, western blotting and immunofluorescent assay, respectively. Cell Counting Kit‑8 assay and flow cytometry were carried out to test the viability and apoptosis of podocytes, respectively. Transmission electron microscopy was used to observe autophagic vacuole. F‑actin was tested through phalloidin staining. Sublytic C5b‑9 was deposited and TRPC6 expression was boosted in podocytes stimulated through zymosan activation serum. Knockdown of TRPC6 raised the viability and reduced the apoptosis rate of sublytic C5b‑9‑induced podocytes. Meanwhile, transfection of small‑interfering (si)TRPC6 facilitated autophagy progression and enhanced the activation of cathepsin B/L in sublytic C5b‑9‑induced podocytes. The phosphorylation level of ERK1/2 was receded in siTRPC6 and sublytic C5b‑9 co‑treated podocytes. Moreover, the addition of the ERK1/2 activator partially reversed the effect of TRPC6 inhibition on sublytic C5b‑9‑induced podocytes. TRPC6 knockdown reduced the damage of sublytic C5b‑9 to podocytes by weakening the ERK1/2 phosphorylation level to activate autophagy. These results indicated that targeting TRPC6 reduced the injury of sublytic C5b‑9 on podocytes.","PeriodicalId":12285,"journal":{"name":"Experimental and therapeutic medicine","volume":"563 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136381718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wei Zhou, Qigang Dai, Ning Su, Zhihui Liu, Jinxing Hu
Pneumonia is a disease caused by inflammation and has high morbidity and mortality rates. Stromal interaction molecule 1 (STIM1) is involved in the regulation of inflammatory processes. However, to the best of the authors' knowledge, the role of STIM1 in pneumonia has not yet been reported. In the present study, lipopolysaccharide (LPS) was administered to A549 cells to construct a cell damage model. The expression of STIM1 in the model cells was detected by western blotting and reverse transcription-quantitative PCR. Then, STIM1 expression was inhibited and cell survival was detected by Cell Counting Kit-8 and flow cytometry. The expression of inflammatory factors was detected by enzyme-linked immunosorbent assay and endoplasmic reticulum stress (ERS)-related proteins were detected by immunofluorescence and western blotting. Subsequently, the relationship between insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) and STIM1 was verified by RNA-binding protein immunoprecipitation assay and actinomycin D treatment. Finally, the regulatory mechanism of IGF2BP2 and STIM1 in LPS-induced A549 cells was further investigated. The results of the present study demonstrated that STIM1 expression was increased in LPS-induced A549 cells and that STIM1 knockdown inhibited LPS-induced A549 cell apoptosis and alleviated LPS-induced A549 cell inflammation and ERS. In addition, IGF2BP2 enhanced the stability of STIM1 mRNA and knockdown of IGF2BP2-regulated STIM1 expression alleviated LPS-induced ERS and inflammatory responses in A549 cells. In conclusion, knockdown of IGF2BP2-regulated STIM1 improved cell damage in the LPS-induced pneumonia cell model by alleviating ERS and the inflammatory response.
{"title":"IGF2BP2‑dependent STIM1 inhibition protects against LPS‑induced pneumonia <i>in vitro</i> by alleviating endoplasmic reticulum stress and the inflammatory response","authors":"Wei Zhou, Qigang Dai, Ning Su, Zhihui Liu, Jinxing Hu","doi":"10.3892/etm.2023.12273","DOIUrl":"https://doi.org/10.3892/etm.2023.12273","url":null,"abstract":"Pneumonia is a disease caused by inflammation and has high morbidity and mortality rates. Stromal interaction molecule 1 (STIM1) is involved in the regulation of inflammatory processes. However, to the best of the authors' knowledge, the role of STIM1 in pneumonia has not yet been reported. In the present study, lipopolysaccharide (LPS) was administered to A549 cells to construct a cell damage model. The expression of STIM1 in the model cells was detected by western blotting and reverse transcription-quantitative PCR. Then, STIM1 expression was inhibited and cell survival was detected by Cell Counting Kit-8 and flow cytometry. The expression of inflammatory factors was detected by enzyme-linked immunosorbent assay and endoplasmic reticulum stress (ERS)-related proteins were detected by immunofluorescence and western blotting. Subsequently, the relationship between insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) and STIM1 was verified by RNA-binding protein immunoprecipitation assay and actinomycin D treatment. Finally, the regulatory mechanism of IGF2BP2 and STIM1 in LPS-induced A549 cells was further investigated. The results of the present study demonstrated that STIM1 expression was increased in LPS-induced A549 cells and that STIM1 knockdown inhibited LPS-induced A549 cell apoptosis and alleviated LPS-induced A549 cell inflammation and ERS. In addition, IGF2BP2 enhanced the stability of STIM1 mRNA and knockdown of IGF2BP2-regulated STIM1 expression alleviated LPS-induced ERS and inflammatory responses in A549 cells. In conclusion, knockdown of IGF2BP2-regulated STIM1 improved cell damage in the LPS-induced pneumonia cell model by alleviating ERS and the inflammatory response.","PeriodicalId":12285,"journal":{"name":"Experimental and therapeutic medicine","volume":"63 5","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134909255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute pancreatitis (AP) is a severe inflammatory condition characterized by the activation of pancreatic enzymes within acinar cells, leading to tissue damage and inflammation. Interleukin (IL)‑22 is a potential therapeutic agent for AP owing to its anti‑inflammatory properties and ability to promote tissue repair. The present study evaluated the differentially expressed proteins in arginine‑induced pancreatic acinar cell injury following treatment with IL‑22, and the possible mechanisms involved in IL‑22‑mediated alleviation of AP. AR42J cells were stimulated using L‑arginine to establish an acinar cell injury model invitro and the damaged cells were subsequently treated with IL‑22. The characteristics of the model and the potential therapeutic effects of IL‑22 were examined by CCK‑8 assay, flow cytometry, TUNEL assay, transmission electron microscopy and ELISA. Differentially expressed proteins in cells induced by arginine and treated with IL‑22 were assessed using liquid chromatography‑mass spectrometry. The identified proteins were further subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis to elucidate their functional roles. The present study demonstrated that arginine‑stimulated cells showed significant pathological changes resembling those in AP, which were alleviated after IL‑22 treatment. Proteomic analysis then demonstrated that in IL‑22‑treated cells, proteins related to the formation and fusion of autophagosomes with lysosomes were significantly downregulated, whereas endocytosis related proteins were enriched in the upregulated proteins. After IL‑22 treatment, western blotting demonstrated reduced expression of autophagy‑associated proteins. In conclusion, by inhibiting the formation and fusion of autophagosomes with lysosomes, IL‑22 may have mitigated premature trypsinogen activation, subsequently minimizing acinar cell injury induced by L‑arginine. This was accompanied by concurrent upregulation of endocytosis, which serves a pivotal role in sustaining regular cellular material transport and signal propagation. This research underscored the potential of IL‑22 in mitigating arginine‑induced AR42J injury, which could be valuable in refining treatment strategies for AP.
{"title":"Interleukin‑22 alleviates arginine‑induced pancreatic acinar cell injury via the regulation of intracellular vesicle transport system: Evidence from proteomic analysis","authors":"Qianqian Xu, Xinjuan Fu, Zhigang Xiu, Hongli Yang, Xiaoxiao Men, Mingyue Liu, Changqin Xu, Bin Li, Shulei Zhao, Hongwei Xu","doi":"10.3892/etm.2023.12277","DOIUrl":"https://doi.org/10.3892/etm.2023.12277","url":null,"abstract":"Acute pancreatitis (AP) is a severe inflammatory condition characterized by the activation of pancreatic enzymes within acinar cells, leading to tissue damage and inflammation. Interleukin (IL)‑22 is a potential therapeutic agent for AP owing to its anti‑inflammatory properties and ability to promote tissue repair. The present study evaluated the differentially expressed proteins in arginine‑induced pancreatic acinar cell injury following treatment with IL‑22, and the possible mechanisms involved in IL‑22‑mediated alleviation of AP. AR42J cells were stimulated using L‑arginine to establish an acinar cell injury model <em>in</em> <em>vitro</em> and the damaged cells were subsequently treated with IL‑22. The characteristics of the model and the potential therapeutic effects of IL‑22 were examined by CCK‑8 assay, flow cytometry, TUNEL assay, transmission electron microscopy and ELISA. Differentially expressed proteins in cells induced by arginine and treated with IL‑22 were assessed using liquid chromatography‑mass spectrometry. The identified proteins were further subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis to elucidate their functional roles. The present study demonstrated that arginine‑stimulated cells showed significant pathological changes resembling those in AP, which were alleviated after IL‑22 treatment. Proteomic analysis then demonstrated that in IL‑22‑treated cells, proteins related to the formation and fusion of autophagosomes with lysosomes were significantly downregulated, whereas endocytosis related proteins were enriched in the upregulated proteins. After IL‑22 treatment, western blotting demonstrated reduced expression of autophagy‑associated proteins. In conclusion, by inhibiting the formation and fusion of autophagosomes with lysosomes, IL‑22 may have mitigated premature trypsinogen activation, subsequently minimizing acinar cell injury induced by L‑arginine. This was accompanied by concurrent upregulation of endocytosis, which serves a pivotal role in sustaining regular cellular material transport and signal propagation. This research underscored the potential of IL‑22 in mitigating arginine‑induced AR42J injury, which could be valuable in refining treatment strategies for AP.","PeriodicalId":12285,"journal":{"name":"Experimental and therapeutic medicine","volume":"183 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136382183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Weiping Cao, Xia Ni, Mengwen Gan, Bing Xie, Yurong Xie, Qin Wang, Lishi Meng, Chao He, Juan Chen, Xinzhi Wang
Hyperlipidemia acute pancreatitis (HLAP) is a specific type of pancreatitis mainly caused by elevated serum triglyceride (TG) levels. Therefore, knowledge of patients' medical history is crucial to the identification of those at high risk of HLAP. Diabetes and obesity are associated with high levels of triglycerides, a risk factor for the development of HLAP, which should be controlled before pregnancy. Moreover, HLAP is associated with additional diagnostic and management challenges related to hyperlipidemia (HL) and pregnancy. HLAP during pregnancy has a rapid onset and rapid progression, and complications are more likely to damage the function of multiple organs. HLAP is more common after 28 weeks of pregnancy, the cause is mostly high TG and the serum TG of the patient is often >1,000 mg/d1. Clinicians should be alert to the occurrence of server acute pancreatitis (AP). Therefore, clinicians need to identify and implement effective treatment in a timely manner to control the progression of HLAP during pregnancy and improve pregnancy outcomes. The present study reported the case of a 26‑year‑old pregnant patient who was hospitalized for epigastric pain at 35 weeks and 2 days of gestation. Medical and family history reported previous diagnoses of diabetes and obesity (weight before pregnancy, 103 kg; BMI, 36.40 kg/m2). Laboratory tests demonstrated high levels of lipase and amylase, a notable systemic inflammatory response, HL, coagulopathy, hypoproteinemia and hyperglycemia. Abdominal ultrasonography demonstrated a hypoechoic pancreatic head. A clinical diagnosis of AP was confirmed using CT scanning. Initial interventions for HLAP included aggressive intravenous hydration, bowel rest, pain control and a combination of heparin and insulin. Lipid‑lowering agents were administered to reduce serum lipid levels. Hemoperfusion and continuous renal replacement therapy were also used to rapidly counteract the elevated lipid levels. Antibiotics were administered in the present case because inflammatory markers such as leukocytes, neutrophils and C‑reactive protein were elevated. The patient and newborn were discharged 11 days after hospitalization, with an improvement in maternal clinical health and the infant was healthy. When evaluating pregnant patients with pre‑obesity and diabetes presenting with abdominal pain, obstetricians should consider HLAP. Timely diagnosis and multi‑team precision treatment are effective for good outcomes for mother and baby.
{"title":"Treatment and diagnosis of hyperlipidemia acute pancreatitis in pregnancy associated with pre‑pregnancy obesity and diabetes: A case report","authors":"Weiping Cao, Xia Ni, Mengwen Gan, Bing Xie, Yurong Xie, Qin Wang, Lishi Meng, Chao He, Juan Chen, Xinzhi Wang","doi":"10.3892/etm.2023.12272","DOIUrl":"https://doi.org/10.3892/etm.2023.12272","url":null,"abstract":"Hyperlipidemia acute pancreatitis (HLAP) is a specific type of pancreatitis mainly caused by elevated serum triglyceride (TG) levels. Therefore, knowledge of patients' medical history is crucial to the identification of those at high risk of HLAP. Diabetes and obesity are associated with high levels of triglycerides, a risk factor for the development of HLAP, which should be controlled before pregnancy. Moreover, HLAP is associated with additional diagnostic and management challenges related to hyperlipidemia (HL) and pregnancy. HLAP during pregnancy has a rapid onset and rapid progression, and complications are more likely to damage the function of multiple organs. HLAP is more common after 28 weeks of pregnancy, the cause is mostly high TG and the serum TG of the patient is often >1,000 mg/d1. Clinicians should be alert to the occurrence of server acute pancreatitis (AP). Therefore, clinicians need to identify and implement effective treatment in a timely manner to control the progression of HLAP during pregnancy and improve pregnancy outcomes. The present study reported the case of a 26‑year‑old pregnant patient who was hospitalized for epigastric pain at 35 weeks and 2 days of gestation. Medical and family history reported previous diagnoses of diabetes and obesity (weight before pregnancy, 103 kg; BMI, 36.40 kg/m<sup>2</sup>). Laboratory tests demonstrated high levels of lipase and amylase, a notable systemic inflammatory response, HL, coagulopathy, hypoproteinemia and hyperglycemia. Abdominal ultrasonography demonstrated a hypoechoic pancreatic head. A clinical diagnosis of AP was confirmed using CT scanning. Initial interventions for HLAP included aggressive intravenous hydration, bowel rest, pain control and a combination of heparin and insulin. Lipid‑lowering agents were administered to reduce serum lipid levels. Hemoperfusion and continuous renal replacement therapy were also used to rapidly counteract the elevated lipid levels. Antibiotics were administered in the present case because inflammatory markers such as leukocytes, neutrophils and C‑reactive protein were elevated. The patient and newborn were discharged 11 days after hospitalization, with an improvement in maternal clinical health and the infant was healthy. When evaluating pregnant patients with pre‑obesity and diabetes presenting with abdominal pain, obstetricians should consider HLAP. Timely diagnosis and multi‑team precision treatment are effective for good outcomes for mother and baby.","PeriodicalId":12285,"journal":{"name":"Experimental and therapeutic medicine","volume":"5 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135266823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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