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Non-small cell lung cancer (NSCLC) poses a global health threat, and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib, afatinib, and osimertinib have achieved significant success in clinical treatment. However, the emergence of resistance limits the long-term efficacy of these treatments, necessitating urgent exploration of novel EGFR-TKIs. This review provides an in-depth summary and exploration of the resistance mechanisms associated with EGFR-TKIs, with a specific focus on representative drugs like gefitinib, afatinib, and osimertinib. Additionally, the review introduces a therapeutic strategy involving the combination of Chinese herbal medicines (CHMs) and chemotherapy drugs, highlighting the potential role of CHMs in overcoming NSCLC resistance. Through systematic analysis, we elucidate the primary resistance mechanisms of EGFR-TKIs in NSCLC treatment, emphasizing CHMs as potential treatment medicines and providing a fresh perspective for the development of next-generation EGFR-TKIs. This comprehensive review aims to guide the application of CHMs in combination therapy for NSCLC management, fostering the development of more effective and comprehensive treatment modalities to ultimately enhance patient outcomes.
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Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipoprotein metabolism, known for its potent inhibition on intravascular lipoprotein and endothelial lipase activities. Recent studies have shed light on the cellular functions of ANGPTL3. However, the precise mechanism underlying its regulation of cellular lipid metabolism remains elusive. We recently reported that ANGPTL3 interacts with the chromatin regulator SMARCAL1, which plays a pivotal role in maintaining cellular lipid homeostasis. Here, through a combination of in vitro and in vivo functional analyses, we provide evidence that ANGPTL3 indeed influences cellular lipid metabolism. Increased expression of Angptl3 prompted the formation of lipid droplets (LDs) in response to slow growth conditions. Notably, under the conditions, Angptl3 accumulated within cytoplasmic peroxisomes, where it interacts with SmarcAL1, which translocated from nucleus as observed previously. This translocation induced changes in gene expression favoring triglyceride (TG) accumulation. Indeed, ANGPTL3 gene knockout (KO) in human cells increased the expression of key lipid genes, which could be linked to elevated nuclear localization of SMARCAL1, whereas the expression of these genes decreased in SMARCAL1 KO cells. Consistent with these findings, the injection of Angptl3 protein to mice led to hepatic fat accumulation derived from circulating blood, a phenotype likely indicative of its long-term effect on blood TG, linked to SmarcAL1 activities. Thus, our results suggest that the Angptl3-SmarcAL1 pathway may confer the capacity for TG storage in cells in response to varying growth states, which may have broad implications for this pathway in regulating energy storage and trafficking.
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ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese Medicines (TCMs) have emerged as a promising complementary therapy in the management of prostate cancer (PCa), particularly in addressing resistance to Docetaxel (DTX) chemotherapy. AIM OF THE REVIEW: This review aims to elucidate the mechanisms underlying the development of resistance to DTX in PCa and explore the innovative approach of integrating TCMs in PCa treatment to overcome this resistance. Key areas of investigation include alterations in microtubule proteins, androgen receptor and androgen receptor splice variant 7, ERG rearrangement, drug efflux mechanisms, cancer stem cells, centrosome clustering, upregulation of the PI3K/AKT signaling pathway, enhanced DNA damage repair capability, and the involvement of neurotrophin receptor 1/protein kinase C. MATERIALS AND METHODS: With "Prostate cancer", "Docetaxel", "Docetaxel resistance", "Natural compounds", "Traditional Chinese medicine", "Traditional Chinese medicine compound", "Medicinal plants" as the main keywords, PubMed, Web of Science and other online search engines were used for literature retrieval. RESULTS: Our findings underscore the intricate interplay of molecular alterations that collectively contribute to the resistance of PCa cells to DTX. Moreover, we highlight the potential of TCMs as a promising complementary therapy, showcasing their ability to counteract DTX resistance and enhance therapeutic efficacy. CONCLUSION: The integration of TCMs in PCa treatment emerges as an innovative approach with significant potential to overcome DTX resistance. This review not only provides insights into the mechanisms of resistance but also presents new prospects for improving the clinical outcomes of patients with PCa undergoing DTX therapy. The comprehensive understanding of these mechanisms lays the foundation for future research and the development of more effective therapeutic interventions.
Subject(s)
Docetaxel , Drug Resistance, Neoplasm , Medicine, Chinese Traditional , Prostatic Neoplasms , Humans , Male , Drug Resistance, Neoplasm/drug effects , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Docetaxel/pharmacology , Docetaxel/therapeutic use , Medicine, Chinese Traditional/methods , Animals , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic useABSTRACT
Diabetic retinopathy (DR) is a complication of diabetes with a complex pathophysiology and multiple factors involved. Recently, it has been found that the upregulation of the renin-angiotensin-aldosterone system (RAAS) leads to overexpression of angiotensin II (Ang II), which induces oxidative stress, inflammation, and angiogenesis in the retina. Therefore, RAAS may be a promising therapeutic target in DR. Notably, RAAS inhibitors are often used in the treatment of hypertension. Still, the potential role and mechanism of DR must be further studied. In this review, we discuss and summarize the pathology and potential therapeutic goals of RAAS in DR.
Subject(s)
Diabetic Retinopathy , Renin-Angiotensin System , Humans , Diabetic Retinopathy/drug therapy , Diabetic Retinopathy/physiopathology , Renin-Angiotensin System/physiology , Renin-Angiotensin System/drug effects , Oxidative Stress/drug effects , Oxidative Stress/physiology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Angiotensin II/physiology , AnimalsABSTRACT
BACKGROUND: To assess the relationship between novel insulin resistance (IR) indices and the presence and severity of diabetic retinopathy (DR) in patients with type 2 diabetes. METHODS: This is a cross-sectional study involving 2211 patients. The study outcomes were DR events. The study exposures were IR indices including estimated glucose disposal rate (eGDR), natural logarithm of glucose disposal rate (lnGDR), metabolic insulin resistance score (METS-IR), triglyceride glucose index-body mass index (TyG-BMI), triglyceride glucose index-waist-to-hip ratio (TyG-WHR), and triglyceride/high-density lipoprotein cholesterol(TG/HDL-c ratio). We used binary and multivariate ordered logistic regression models to estimate the association between different IR indices and the presence and severity of DR. Subject work characteristic curves were used to assess the predictive power of different IR indices for DR. RESULTS: DR was present in 25.4% of participants. After adjusting for all covariates, per standard deviation (SD) increases in eGDR (ratio [OR] 0.38 [95% CI 0.32-0.44]), lnGDR (0.34 [0.27-0.42]) were negatively associated with the presence of DR. In contrast, per SD increases in METS-IR (1.97 [1.70-2.28]), TyG-BMI (1.94 [1.68-2.25]), TyG-WHR (2.34 [2.01-2.72]) and TG/HDL-c ratio (1.21 [1.08-1.36]) were positively associated with the presence of DR. eGDR was strongly associated with severity of DR. Of all variables, eGDR had the strongest diagnostic value for DR (AUC = 0.757). CONCLUSIONS: Of the six IR indices, eGDR was significantly associated with the presence and severity of DR in patients with type 2 diabetes. eGDR has a good predictive value for DR. Thus, eGDR maybe a stronger marker of DR.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Retinopathy , Insulin Resistance , Humans , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Cross-Sectional Studies , Glucose , Diabetic Retinopathy/diagnosis , Diabetic Retinopathy/etiology , Triglycerides , Blood Glucose/metabolismABSTRACT
Prostate cancer (PCa) is one of the most common malignancies in males worldwide, and its development and progression involve the regulation of multiple metabolic pathways. Alterations in lipid metabolism affect the proliferation and metastatic capabilities of PCa cells. Cancer cells increase lipid synthesis and regulate fatty acid oxidation to meet their growth and energy demands. Similarly, changes occur in amino acid metabolism in PCa. Cancer cells exhibit an increased demand for specific amino acids, and they regulate amino acid transport and metabolic pathways to fulfill their proliferation and survival requirements. These changes are closely associated with disease progression and treatment response in PCa cells. Therefore, a comprehensive investigation of the metabolic characteristics of PCa is expected to offer novel insights and approaches for the early diagnosis and treatment of this disease.
Subject(s)
Amino Acids , Lipid Metabolism , Prostatic Neoplasms , Humans , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Male , Amino Acids/metabolism , Lipid Metabolism/physiology , Fatty Acids/metabolism , Cell ProliferationABSTRACT
ABSTRACT Diabetic retinopathy (DR) is a complication of diabetes with a complex pathophysiology and multiple factors involved. Recently, it has been found that the upregulation of the renin-angiotensin-aldosterone system (RAAS) leads to overexpression of angiotensin II (Ang II), which induces oxidative stress, inflammation, and angiogenesis in the retina. Therefore, RAAS may be a promising therapeutic target in DR. Notably, RAAS inhibitors are often used in the treatment of hypertension. Still, the potential role and mechanism of DR must be further studied. In this review, we discuss and summarize the pathology and potential therapeutic goals of RAAS in DR.
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Biallelic mutations of the chromatin regulator SMARCAL1 cause Schimke Immunoosseous Dysplasia (SIOD), characterized by severe growth defects and premature mortality. Atherosclerosis and hyperlipidemia are common among SIOD patients, yet their onset and progression are poorly understood. Using an integrative approach involving proteomics, mouse models, and population genetics, we investigated SMARCAL1's role. We found that SmarcAL1 interacts with angiopoietin-like 3 (Angptl3), a key regulator of lipoprotein metabolism. In vitro and in vivo analyses demonstrate SmarcAL1's vital role in maintaining cellular lipid homeostasis. The observed translocation of SmarcAL1 to cytoplasmic peroxisomes suggests a potential regulatory role in lipid metabolism through gene expression. SmarcAL1 gene inactivation reduces the expression of key genes in cellular lipid catabolism. Population genetics investigations highlight significant associations between SMARCAL1 genetic variations and body mass index, along with lipid-related traits. This study underscores SMARCAL1's pivotal role in cellular lipid metabolism, likely contributing to the observed lipid phenotypes in SIOD patients.
Subject(s)
Immunologic Deficiency Syndromes , Animals , Humans , Mice , Chromatin , DNA Helicases/genetics , DNA Helicases/metabolism , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/metabolism , Lipid Metabolism/genetics , LipidsABSTRACT
Vaccariae Semen, derived from the dried ripe seed of Vaccaria segetalis (Neck.) Garcke, has various therapeutic characteristics in traditional Chinese medicine (TCM), containing promoting blood circulation and unblocking meridians. It exhibits significant anti-cancer activity and is therapeutically utilized to treat and reduce chemotherapy adverse effects in cancer patients, notably those with lung cancer. However, the active ingredients responsible for its anti-lung cancer efficacy remain unknown. In this study, we used A549 cell fishing in conjunction with UHPLC-LTQ Orbitrap MS to screen for anti-lung cancer active components in Vaccariae Semen. The cell counting Kit-8 (CCK-8) assay revealed that the n-butanol extract substantially reduced A549 cell growth. Through the cell fishing assay, we found 14 A549 cell-binding compounds in the n-butanol extract, all of which were identified as triterpenoid saponins. The total saponins of Vaccariae Semen were subsequently purified using macroporous adsorption resin (MAR), and they showed a significant inhibitory effect on the proliferation of A549 lung cancer cells, as well as alterations in cell morphology, apoptosis, and fragmentation. In conclusion, saponins were discovered as the key active components responsible for the anti-lung cancer activity of Vaccariae Semen.
Subject(s)
Early Detection of Cancer , Lung Neoplasms , Humans , 1-Butanol , A549 Cells , Chromatography, High Pressure Liquid , Lung Neoplasms/drug therapy , SeedsABSTRACT
AIM: To explore hub genes for glaucoma based on bioinformatics analysis and an experimental model verification. METHODS: In the Gene Expression Omnibus (GEO) database, the GSE25812 and GSE26299 datasets were selected to analyze differentially expressed genes (DEGs) by the GEO2R tool. Through bioinformatics analysis, 9 hub genes were identified. Receiver operating characteristic (ROC) curves and principal component analysis (PCA) were performed to verify whether the hub gene can distinguish glaucoma from normal eyes. The mouse model of glaucoma was constructed, and the real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) assay was performed to detect the expression levels of hub genes in glaucoma. RESULTS: There were 128 overlapping DEGs in the GSE25812 and GSE26299 datasets, mainly involved in intracellular signalling, cell adhesion molecules and the Ras signalling pathway. A total of 9 hub genes were screened out, including GNAL, BGN, ETS2, FCGP4, MAPK10, MMP15, STAT1, TSPAN8, and VCAM1. The area under the curve (AUC) values of 9 hub genes were greater than 0.8. The PC1 axle could provide a 70.5% interpretation rate to distinguish glaucoma from normal eyes. In the ocular tissues of glaucoma in the mice model, the expression of BGN, ETS2, FCGR4, STAT1, TSPAN8, and VCAM1 was increased, while the expression of GNAL, MAPK10, and MMP15 was decreased. CONCLUSION: Nine hub genes in glaucoma are identified, which may provide new biomarkers and therapeutic targets for glaucoma.
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BACKGROUND: A new uric acid (UA) index has recently been proposed, while serum uric acid (SUA), fasting triglyceride, and fasting blood glucose levels in the index are shown to affect cognitive function. This study aims to investigate the clinical value of the UA index for assessing mild cognitive impairment (MCI) in type 2 diabetes (T2D) patients. METHODS: This was an observational cross-sectional study with 616 participants. A generalized additive model was used to determine a linear or curvilinear relationship between cognitive performance and the UA index. Logistic regression and random forest models were both developed. A receiver operating characteristic curve (ROC) was delineated and the area under the curve (AUC) was calculated. RESULTS: MCI was diagnosed in 313 participants (50.81%). Compared with the T2D-normal cognitive function group, MCI subjects had higher UA indexes, lower cognitive scores, and lower education levels (p < 0.001). Generalized additive models showed the UA index and the Montreal Cognitive Assessment (MoCA) score to be decreased linearly (p < 0.001). The UA index AUC was 0.751 (95% CI = 0.713-0.789, p < 0.001). The optimal cut-off point for the identification of MCI based on the UA index was 11.26 (sensitivity: 62.3%, specificity: 75.9%). Results for females in the cohort yielded an AUC change of + 2.5%, the less-educated population (AUC change of + 4.7%), and the hypertensive population (AUC change of + 1.1%). The AUCs were 0.791 (95% CI = 0.720-0.863) for the random forest model and 0.804 (95% CI = 0.770-0.837) for the logistic regression model, and no statistical significance was found (p = 0.758). CONCLUSION: This study showed that the increased UA index was independently associated with MCI in patients with T2D, especially among female, less-educated, and hypertensive patients. It could be a potential indicator of MCI in T2D patients.
Subject(s)
Cognitive Dysfunction , Diabetes Mellitus, Type 2 , Female , Humans , Cognition , Cognitive Dysfunction/diagnosis , Cognitive Dysfunction/etiology , Cross-Sectional Studies , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Uric Acid , MaleABSTRACT
Background: Diabetic retinopathy (DR) is strongly associated with cardiovascular disease, which is a risk factor for sudden cardiac death (SCD). The index of cardiac electrophysiological balance (iCEB) and the frontal QRS-T angle are recommended to predict the risk of ventricular arrhythmias more than other ECG parameters. However, the relationships between these two markers and DR have not yet been explored. The aim of this study was to investigate the variation in the iCEB, corrected iCEB (iCEBc) and frontal QRS-T angle in different stages of DR and determine whether there are associations between these markers and DR. Methods: The sample comprised 665 patients with Type 2 diabetes mellitus (T2DM) who were classified into three groups: no DR (NDR), mild to moderate non-proliferative DR (NPDR), and vision-threatening DR (VTDR). Twelve-lead ECG was performed and the QT, QTc, QRS duration, iCEB, iCEBc and frontal QRS-T angle were recorded and compared across the groups. Results: The VTDR group had a significantly higher iCEBc and frontal QRS-T angle than the NDR and NPDR groups. After controlling for confounding variables, the correlations between the iCEBc (OR=2.217, 95% CI=1.464-3.358, P<0.001), frontal QRS-T angle (OR=1.017, 95% CI=1.008-1.025, P<0.001) and DR risk remained (P<0.05). Subjects in the fourth iCEBc quartile (adjusted OR=2.612, 95% CI=1.411-4.834, p=0.002) had a much higher chance of developing DR compared to those in the first quartile. In comparison to the first frontal QRS-T angle quartile, subjects in the third (adjusted OR=1.998, 95% CI=1.167-3.422, P=0.012) and fourth (adjusted OR=2.430, 95% CI=1.420-4.160, P=0.001) frontal QRS-T angle quartiles had significantly greater risks of DR. Conclusion: With the progression of DR, the iCEBc and frontal QRS-T angle increase. An increased iCEBc and frontal QRS-T angle are associated with an increased risk of DR.
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Background: The triglyceride glucose (TyG) index reflects insulin resistance; the latter being associated with mild cognitive impairment (MCI). Objective: To investigate the clinical value of the TyG index to identify MCI in patients living with type 2 diabetes (T2D) using a cross-sectional study. Methods: This cross-sectional study was performed on 517 patients with T2D. The diagnosis of MCI was based on criteria established by the National Institute on Aging-Alzheimer's Association workgroup, and patients were divided into the MCI group and the normal cognitive function (NCF) group. The logistic regression analysis determines whether the TyG index is related to MCI. Subsequently, we constructed the receiver operating characteristic curve (ROC) and calculated the area under the curve (AUC). The nomogram model of the influence factor was established and verified. Results: Compared to the type 2 diabetes-normal cognitive function (T2D-NCF) group, the MCI subjects were olderand had higher TyG indexes, lower cognitive scores, and lower education levels (p < 0.01). After adjusting for the confounders, the TyG index was associated with MCI (OR = 7.37, 95% CI = 4.72-11.50, p < 0.01), and TyG-BMI was also associated with MCI (OR = 1.02, 95% CI = 1.01-1.02, p<0.01). The TyG index AUC was 0.79 (95% CI = 0.76-0.83). The consistency index of the nomogram was 0. 83[95% CI (0. 79, 0. 86)]. Conclusion: Our results indicate that the TyG index and TyG-BMI are associated with MCI in T2D patients, and the TyG index is an excellent indicator of the risk of MCI in T2D patients. The nomogram incorporating the TyG index is useful to predict MCI risk in patients with T2D.
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BACKGROUND: Globe luxation is rare and is mostly due to direct orbital trauma with fractures of the medial and floor walls, which displace the globe into the maxillary sinus. Only a few cases have been reported; moreover, patients who suffer global luxation rarely achieve eyesight recovery. CASE SUMMARY: This report describes the treatment and prognosis of global luxation occurring in a child. A 6-year-old boy presented with left globe luxation that occurred after a sudden stop on a tricycle, without any injury to the orbital or maxillofacial bony structures. After admission to the hospital, an external canthus incision, globe repositioning, orbital exploration and temporary blepharoplasty were performed. Finally, the child completely recovered and maintained good eyesight in his left eye even though the right eye developed myopia after four years of follow-up. CONCLUSION: The aim of this study was to report the special occurrence of globe luxation in the child and share some experience of the treatment. Immediate surgical management plays an important role in the recovery of visual function, and globe luxation may prevent nearsightedness by reducing the distortion of the eyeball, shortening the axis and improving ciliary function.
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BACKGROUND: Lymph node (LN) metastasis is crucial in determining the prognosis and treatment options for colon cancer patients. Our work was to study whether the lymph nodes beyond D3 station in transverse colon cancer, especially 206 LN, should be dissected. METHODS: A total of 225 patients within our department were reviewed. The primary and secondary endpoints were overall survival (OS) and disease-free survival (DFS). We employed Propensity score weighting (PSW) for weighing participants to balance observed confounders between the 206D+ group and the 206D- group. RESULTS: The rate of metastasis in station 206 was 9.3%. Only T stage (OR, 3.009; 95% CI, 1.018-8.892), N stage (OR, 9.818; 95% CI, 1.158-83.227), and M stage (OR, 26.126; 95% CI, 1.274-535.945) were an independent risk factor for 206 station metastasis in multivariate logistic analysis. The 206D+ group had a similarly survival than the 206D- group (3-year DFS, 89.6% v 85.9%; p = 0.389; 3-year OS, 94.6% v 85.3% p = 0.989). PSW further verified it. Metastasis of 206 station LN is not an independent prognostic factor, but a predictive factor of DFS. CONCLUSION: Station 206 LN positive is a predictive factor for DFS. Only the patient with T1-3, N+ who is at a high risk of 206 station LN metastases should consider dissecting 206 station LN.
Subject(s)
Colon, Transverse , Colonic Neoplasms , Colon, Transverse/pathology , Colonic Neoplasms/pathology , Humans , Lymph Node Excision , Lymph Nodes/pathology , Lymphatic Metastasis/pathology , Neoplasm Staging , Prognosis , Retrospective StudiesABSTRACT
Exosomes are discoid vesicles with a diameter of 40-160 nm. They are mainly derived from the multivesicular body formed by the invagination of lysosomal particles in the cell, which are released into the extracellular matrix after the fusion of the outer membrane. Exosomes are widespread and distributed in various body fluids, they are rich in nucleic acids (microRNA, lncRNA, circRNA, mRNA, tRNA, etc.), proteins, lipids, etc. As an important mediator of cellular communication, exosomes carry and transmit important signaling molecules and are widely involved in intercellular material transport and information transfer, they regulate cellular physiological activities and are closely related to the occurrence and course of various diseases. In recent years, with the deepening of exosome-related research, we discovered that exosomal non-coding RNAs are associated with diabetic complications such as diabetic retinopathy, diabetic nephropathy, diabetic foot ulcer. This article reviews the new findings of exosomal non-coding RNAs (mainly microRNAs, lncRNAs, circRNAs) in diabetic complications, and analyzes the potential of exosomal ncRNA as new biomarkers and new cell-free therapies in the diagnosis and treatment of diabetic complications, hoping to provide new ideas for the prevention, diagnosis, and treatment of diabetic complications.
Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Exosomes , MicroRNAs , RNA, Long Noncoding , Biomarkers/metabolism , Diabetes Mellitus/drug therapy , Diabetes Mellitus/genetics , Diabetes Mellitus/metabolism , Diabetic Nephropathies/metabolism , Exosomes/genetics , Exosomes/metabolism , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , RNA, Circular/genetics , RNA, Long Noncoding/genetics , RNA, Untranslated/metabolismABSTRACT
Febrile seizures are the most common nervous system disease in childhood, and most children have a good prognosis. However, some epilepsy cases are easily induced by fever and are characterized by "fever sensitivity", and it is difficult to differentiate such cases from febrile seizures. Epilepsy related to fever sensitivity includes hereditary epilepsy with febrile seizures plus, Dravet syndrome, and PCDH19 gene-related epilepsy. This article mainly describes the clinical manifestations of these three types of epilepsy and summarizes their clinical features in the early stage of disease onset, so as to achieve early identification, early diagnosis, and early intervention to improve prognosis.
Subject(s)
Epilepsy , Epileptic Syndromes , Seizures, Febrile , Cadherins/genetics , Child , Epilepsy/etiology , Epilepsy/genetics , Humans , Mutation , Protocadherins , Seizures, Febrile/etiology , Seizures, Febrile/geneticsABSTRACT
AIM: To evaluate the efficacy and safety of high-dose ultrasound cyclo-plasty (UCP) for the treatment of refractory glaucoma in Chinese patients. METHODS: In this 6-month retrospective study, 37 eyes of 37 patients suffering from severe glaucoma with uncontrolled intraocular pressure (IOP) of ≥21 mm Hg underwent 8-s ultrasonic cyclocoagulation with ten active piezoelectric elements. A complete ophthalmic examination was performed before and at 1d, 1, 3, 6mo after UCP. Therapeutic success was defined as IOP reduction from baseline ≥20% and IOP ≥5 mm Hg without adding new glaucoma medication compare to baseline at the 6-month follow-up visit. In addition to mean IOP at each follow-up visit, medications used and complications were also detected and compared to baseline. RESULTS: After UCP procedure, the mean IOP was significantly reduced (P<0.01) from the preoperative 44.1±11.9 mm Hg to postoperative 26.7±11.8 mm Hg at 3mo, and 30.4±14.5 mm Hg at 6mo. The overall mean IOP reductions achieved at 3 and 6mo were 39% and 31% compared to baseline IOP. Sixty-one percent of patients responded well to UCP treatment with a mean IOP reduction of 48% at 3mo and 42% at 6mo. Ocular pain in most of patients were alleviated. No serious intraoperative or postoperative complications occurred. CONCLUSION: High-dose UCP treatment is an effective and safe procedure to reduce IOP in Chinese patients with severe glaucoma.
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Population genetic studies highlight a missense variant (G398S) of A1CF that is strongly associated with higher levels of blood triglycerides (TGs) and total cholesterol (TC). Functional analyses suggest that the mutation accelerates the secretion of very low-density lipoprotein (VLDL) from the liver by an unknown mechanism. Here, we used multiomics approaches to interrogate the functional difference between the WT and mutant A1CF. Using metabolomics analyses, we captured the cellular lipid metabolite changes induced by transient expression of the proteins, confirming that the mutant A1CF is able to relieve the TG accumulation induced by WT A1CF. Using a proteomics approach, we obtained the interactomic data of WT and mutant A1CF. Networking analyses show that WT A1CF interacts with three functional protein groups, RNA/mRNA processing, cytosolic translation, and, surprisingly, mitochondrial translation. The mutation diminishes these interactions, especially with the group of mitochondrial translation. Differential analyses show that the WT A1CF-interacting proteins most significantly different from the mutant are those for mitochondrial translation, whereas the most significant interacting proteins with the mutant are those for cytoskeleton and vesicle-mediated transport. RNA-seq analyses validate that the mutant, but not the WT, A1CF increases the expression of the genes responsible for cellular transport processes. On the contrary, WT A1CF affected the expression of mitochondrial matrix proteins and increased cell oxygen consumption. Thus, our studies confirm the previous hypothesis that A1CF plays broader roles in regulating gene expression. The interactions of the mutant A1CF with the vesicle-mediated transport machinery provide mechanistic insight in understanding the increased VLDL secretion in the A1CF mutation carriers.
Subject(s)
Lipid Metabolism , RNA-Binding Proteins , Lipid Metabolism/genetics , Liver/metabolism , RNA Editing , RNA, Messenger/metabolism , RNA-Binding Proteins/metabolismABSTRACT
Human genetics studies have uncovered genetic variants that can be used to guide biological research and prioritize molecular targets for therapeutic intervention for complex diseases. We have identified a missense variant (P746S) in EDEM3 associated with lower blood triglyceride (TG) levels in >300,000 individuals. Functional analyses in cell and mouse models show that EDEM3 deficiency strongly increased the uptake of very-low-density lipoprotein and thereby reduced the plasma TG level, as a result of up-regulated expression of LRP1 receptor. We demonstrate that EDEM3 deletion up-regulated the pathways for RNA and endoplasmic reticulum protein processing and transport, and consequently increased the cell surface mannose-containing glycoproteins, including LRP1. Metabolomics analyses reveal a cellular TG accumulation under EDEM3 deficiency, a profile consistent with individuals carrying EDEM3 P746S. Our study identifies EDEM3 as a regulator of blood TG, and targeted inhibition of EDEM3 may provide a complementary approach for lowering elevated blood TG concentrations.