Hepatocellular carcinoma(HCC)is one of the most common tumor types and remains a major clinical challenge.Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC.However,few mitophagy inhibitors have been approved for clinical use in humans.Pyrimethamine(Pyr)is used to treat infections caused by protozoan parasites.Recent studies have reported that Pyr may be beneficial in the treatment of various tumors.However,its mechanism of action is still not clearly defined.Here,we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis.Mechanistically,Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells.In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29(SNAP29)-vesicle-associated membrane protein 8(VAMP8)interaction.Moreover,Pyr acted synergistically with sorafenib(Sora)to induce apoptosis and inhibit HCC proliferation in vitro and in vivo.Pyr enhances the sensitivity of HCC cells to Sora,a common chemotherapeutic,by inhibiting mitophagy.Thus,these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor.Notably,Pyr and Sora combination therapy could be a promising treatment for malignant HCC.

Objective:To explore the feasibility and application value of indocyanine green(ICG)lymph node tracer in clinical early stage cervical cancer staging surgery.Methods:A retrospective analysis was performed on 31 patients with early clinical stage(ⅠA1-ⅡA1)cervical cancer who underwent laparoscopic radical hysterectomy,pelvic lymph node resection and para-aortic lymph node sampling were selected as the study subjects in Sichuan Provincial Maternal and Child Health Care Hospital from April 1,2022 to July 31,2023.They were divided into the ICG fluorescence tracer group(ICG group,17 cases)and the conventional surgery group(control group,14 ca-ses)based on whether ICG was injected or not.The resected lymph nodes were classified and submitted for ex-amination according to location and whether they presented visualization.The method of contingency coefficient was used to analyze the correlations between lymph node visualization patterns and lymph node metastasis and clinicopathological characteristics,and the perioperative data of the two groups were compared.Results:①The postoperative stage of 8 patients(25.8％)(4 in each group)were improved compared with the preoperative clini-cal stage.The number of resected lymph nodes in the ICG group was less than that in the control group(18±9 nodes/person vs.26±11 nodes/person,P＜0.05).There were no statistically significant differences in operation time,intraoperative blood loss,postoperative FIGO(2018)staging,lymph node metastasis rate,and positive rate of resected lymph nodes between the two groups(P＞0.05).②The visualization rate in the ICG group was 64.71％(11/17).There was no statistically significant difference in the positive rate between the visualized and non-visualized lymph nodes(P＞0.05).There was a significant correlation between lymph node visualization and lymph node metastasis(C=0.707,P＜0.05),and a significant correlation was found between lymph node visual-ization and lymph node metastasis in the same patient(C=0.557,P＜0.05).Conclusions:The rate of lymph node metastasis in clinical early stage cervical cancer is low.ICG fluorescence visualization can trace lymph nodes and predict the risk of metastasis.By only resecting the visualized lymph nodes under the guidance of ICG tracer,the lymph node metastasis status of early-stage cervical cancer can be fully evaluated,which is worthy of further research.

Severe asthma stands as a formidable contributor to both mortality and morbidity of pa-tients suffering asthma,casting substantial social and economic shadows on communities.As our un-derstanding of asthma's pathophysiology deepens,a beacon of hope emerges in the form of biological targeted therapies,offering a promising avenue for the management of this challenging condition.These therapies,by precisely inhibiting or modulat-ing pivotal molecules in the inflammatory cascade,offer potential benefits in symptom alleviation,lung function enhancement,and risk reduction of acute exacerbations.They signify a paradigm shift in severe asthma treatment.Within the confines of this article,we embark on a systematic exploration of the immunological underpinnings that define se-vere asthma.By delving into the intricacies of the immune system's role in exacerbating this condi-tion,we aim to offer a comprehensive assessment of both the current landscape and the future pros-pects of biological therapies.Our objective is to provide a scientifically robust and valuable refer-ence that can guide the individualized treatment of patients grappling with severe asthma.

Severe asthma stands as a formidable contributor to both mortality and morbidity of patients suffering asthma, casting substantial social and economic shadows on communities. As our understanding of asthma's pathophysiology deepens, a beacon of hope emerges in the form of biological targeted therapies, offering a promising avenue for the management of this challenging condition. These therapies, by precisely inhibiting or modulating pivotal molecules in the inflammatory cascade, offer potential benefits in symptom alleviation, lung function enhancement, and risk reduction of acute exacerbations. They signify a paradigm shift in severe asthma treatment. Within the confines of this article, we embark on a systematic exploration of the immunological underpinnings that define severe asthma. By delving into the intricacies of the immune system's role in exacerbating this condition, we aim to offer a comprehensive assessment of both the current landscape and the future prospects of biological therapies. Our objective is to provide a scientifically robust and valuable reference that can guide the individualized treatment of patients grappling with severe asthma.

Objective To analyze the effect of circLRP6 on high glucose-induced renal tubular epithelial cell injury via miR-31-5p/high mobility group protein A1(HMGA1)axis regulation.Methods Human renal tubular epithelial HK-2 cells were cultured in vitro and divided into eight groups:control,high glucose,high glucose+si-NC,high glucose+si-circLRP6,high glucose+si-circLRP6+miR-NC,high glucose+si-circLRP6+miR-31-5p inhibitor,high glucose+si-circLRP6+miR-31-5p inhibitor+si-NC,and high glucose+si-circ-LRP6+ miR-31-5p inhibitor+si-HMGA1.The circLRP6,miR-31-5p,and HMGA1 mRNA levels were determined using real-time quantitative PCR.Cell supernatant IL-6 and tumor necrosis factor-α(TNF-α)levels,lactate dehydrogenase(LDH)activity,and malondialdehyde(MDA)content were also determined.Furthermore,flow cytometry was used to observe cell apoptosis.HMGA1,Bax,and Bcl-2 protein expression was detected by Western blotting.Finally,dual luciferase assay was used to report the targeting relationship of miR-31-5p with circLRP6 and HMGA1.Results Compared with the high glucose group,the HK-2 cell proliferation inhibition rate;cell superserum IL-6,TNF-α,LDH,and MDA levels;apoptosis rate;and Bax protein expression in the high glucose+si-circLRP6 group decreased significantly,whereas Bcl-2 protein expression increased significantly(all P＜0.05).Consequently,miR-31-5p downregulation possibly weakened the protective effect of si-circLRP6 on high glucose-induced renal tubular epithelial cell injury.HMGA1 expression inhibition reversed the effect of the si-circLRP6+miR-31-5p inhibitor on high glucose-induced renal tubular epithelial cell injury.Finally,miR-31-5p exhibited a targeting relationship with circLRP6 and HMGA1.Conclusion Si-circLRP6 protects high glucose-induced renal tubular epithelial cell injury via miR-31-5p upregulation and HMGA1 expression inhibition.

Objective:To explore the feasibility and application value of indocyanine green(ICG)lymph node tracer in clinical early stage cervical cancer staging surgery.Methods:A retrospective analysis was performed on 31 patients with early clinical stage(ⅠA1-ⅡA1)cervical cancer who underwent laparoscopic radical hysterectomy,pelvic lymph node resection and para-aortic lymph node sampling were selected as the study subjects in Sichuan Provincial Maternal and Child Health Care Hospital from April 1,2022 to July 31,2023.They were divided into the ICG fluorescence tracer group(ICG group,17 cases)and the conventional surgery group(control group,14 ca-ses)based on whether ICG was injected or not.The resected lymph nodes were classified and submitted for ex-amination according to location and whether they presented visualization.The method of contingency coefficient was used to analyze the correlations between lymph node visualization patterns and lymph node metastasis and clinicopathological characteristics,and the perioperative data of the two groups were compared.Results:①The postoperative stage of 8 patients(25.8％)(4 in each group)were improved compared with the preoperative clini-cal stage.The number of resected lymph nodes in the ICG group was less than that in the control group(18±9 nodes/person vs.26±11 nodes/person,P＜0.05).There were no statistically significant differences in operation time,intraoperative blood loss,postoperative FIGO(2018)staging,lymph node metastasis rate,and positive rate of resected lymph nodes between the two groups(P＞0.05).②The visualization rate in the ICG group was 64.71％(11/17).There was no statistically significant difference in the positive rate between the visualized and non-visualized lymph nodes(P＞0.05).There was a significant correlation between lymph node visualization and lymph node metastasis(C=0.707,P＜0.05),and a significant correlation was found between lymph node visual-ization and lymph node metastasis in the same patient(C=0.557,P＜0.05).Conclusions:The rate of lymph node metastasis in clinical early stage cervical cancer is low.ICG fluorescence visualization can trace lymph nodes and predict the risk of metastasis.By only resecting the visualized lymph nodes under the guidance of ICG tracer,the lymph node metastasis status of early-stage cervical cancer can be fully evaluated,which is worthy of further research.

Severe asthma stands as a formidable contributor to both mortality and morbidity of pa-tients suffering asthma,casting substantial social and economic shadows on communities.As our un-derstanding of asthma's pathophysiology deepens,a beacon of hope emerges in the form of biological targeted therapies,offering a promising avenue for the management of this challenging condition.These therapies,by precisely inhibiting or modulat-ing pivotal molecules in the inflammatory cascade,offer potential benefits in symptom alleviation,lung function enhancement,and risk reduction of acute exacerbations.They signify a paradigm shift in severe asthma treatment.Within the confines of this article,we embark on a systematic exploration of the immunological underpinnings that define se-vere asthma.By delving into the intricacies of the immune system's role in exacerbating this condi-tion,we aim to offer a comprehensive assessment of both the current landscape and the future pros-pects of biological therapies.Our objective is to provide a scientifically robust and valuable refer-ence that can guide the individualized treatment of patients grappling with severe asthma.

Objective:To explore the feasibility and application value of indocyanine green(ICG)lymph node tracer in clinical early stage cervical cancer staging surgery.Methods:A retrospective analysis was performed on 31 patients with early clinical stage(ⅠA1-ⅡA1)cervical cancer who underwent laparoscopic radical hysterectomy,pelvic lymph node resection and para-aortic lymph node sampling were selected as the study subjects in Sichuan Provincial Maternal and Child Health Care Hospital from April 1,2022 to July 31,2023.They were divided into the ICG fluorescence tracer group(ICG group,17 cases)and the conventional surgery group(control group,14 ca-ses)based on whether ICG was injected or not.The resected lymph nodes were classified and submitted for ex-amination according to location and whether they presented visualization.The method of contingency coefficient was used to analyze the correlations between lymph node visualization patterns and lymph node metastasis and clinicopathological characteristics,and the perioperative data of the two groups were compared.Results:①The postoperative stage of 8 patients(25.8％)(4 in each group)were improved compared with the preoperative clini-cal stage.The number of resected lymph nodes in the ICG group was less than that in the control group(18±9 nodes/person vs.26±11 nodes/person,P＜0.05).There were no statistically significant differences in operation time,intraoperative blood loss,postoperative FIGO(2018)staging,lymph node metastasis rate,and positive rate of resected lymph nodes between the two groups(P＞0.05).②The visualization rate in the ICG group was 64.71％(11/17).There was no statistically significant difference in the positive rate between the visualized and non-visualized lymph nodes(P＞0.05).There was a significant correlation between lymph node visualization and lymph node metastasis(C=0.707,P＜0.05),and a significant correlation was found between lymph node visual-ization and lymph node metastasis in the same patient(C=0.557,P＜0.05).Conclusions:The rate of lymph node metastasis in clinical early stage cervical cancer is low.ICG fluorescence visualization can trace lymph nodes and predict the risk of metastasis.By only resecting the visualized lymph nodes under the guidance of ICG tracer,the lymph node metastasis status of early-stage cervical cancer can be fully evaluated,which is worthy of further research.

Severe asthma stands as a formidable contributor to both mortality and morbidity of pa-tients suffering asthma,casting substantial social and economic shadows on communities.As our un-derstanding of asthma's pathophysiology deepens,a beacon of hope emerges in the form of biological targeted therapies,offering a promising avenue for the management of this challenging condition.These therapies,by precisely inhibiting or modulat-ing pivotal molecules in the inflammatory cascade,offer potential benefits in symptom alleviation,lung function enhancement,and risk reduction of acute exacerbations.They signify a paradigm shift in severe asthma treatment.Within the confines of this article,we embark on a systematic exploration of the immunological underpinnings that define se-vere asthma.By delving into the intricacies of the immune system's role in exacerbating this condi-tion,we aim to offer a comprehensive assessment of both the current landscape and the future pros-pects of biological therapies.Our objective is to provide a scientifically robust and valuable refer-ence that can guide the individualized treatment of patients grappling with severe asthma.

Objective:To explore the feasibility and application value of indocyanine green(ICG)lymph node tracer in clinical early stage cervical cancer staging surgery.Methods:A retrospective analysis was performed on 31 patients with early clinical stage(ⅠA1-ⅡA1)cervical cancer who underwent laparoscopic radical hysterectomy,pelvic lymph node resection and para-aortic lymph node sampling were selected as the study subjects in Sichuan Provincial Maternal and Child Health Care Hospital from April 1,2022 to July 31,2023.They were divided into the ICG fluorescence tracer group(ICG group,17 cases)and the conventional surgery group(control group,14 ca-ses)based on whether ICG was injected or not.The resected lymph nodes were classified and submitted for ex-amination according to location and whether they presented visualization.The method of contingency coefficient was used to analyze the correlations between lymph node visualization patterns and lymph node metastasis and clinicopathological characteristics,and the perioperative data of the two groups were compared.Results:①The postoperative stage of 8 patients(25.8％)(4 in each group)were improved compared with the preoperative clini-cal stage.The number of resected lymph nodes in the ICG group was less than that in the control group(18±9 nodes/person vs.26±11 nodes/person,P＜0.05).There were no statistically significant differences in operation time,intraoperative blood loss,postoperative FIGO(2018)staging,lymph node metastasis rate,and positive rate of resected lymph nodes between the two groups(P＞0.05).②The visualization rate in the ICG group was 64.71％(11/17).There was no statistically significant difference in the positive rate between the visualized and non-visualized lymph nodes(P＞0.05).There was a significant correlation between lymph node visualization and lymph node metastasis(C=0.707,P＜0.05),and a significant correlation was found between lymph node visual-ization and lymph node metastasis in the same patient(C=0.557,P＜0.05).Conclusions:The rate of lymph node metastasis in clinical early stage cervical cancer is low.ICG fluorescence visualization can trace lymph nodes and predict the risk of metastasis.By only resecting the visualized lymph nodes under the guidance of ICG tracer,the lymph node metastasis status of early-stage cervical cancer can be fully evaluated,which is worthy of further research.