Steroid receptor coactivators in Treg and Th17 cell biology and function.

Steroid receptor coactivators (SRCs) are master regulators of transcription that play key roles in human physiology and pathology. SRCs are particularly important for the regulation of the immune system with major roles in lymphocyte fate determination and function, macrophage activity, regulation of nuclear factor κB (NF-κB) transcriptional activity and other immune system biology. The three members of the p160 SRC family comprise a network of immune-regulatory proteins that can function independently or act in synergy with each other, and compensate for - or moderate - the activity of other SRCs. Recent evidence indicates that the SRCs are key participants in governing numerous aspects of CD4+ T cell biology. Here we review findings that establish the SRCs as essential regulators of regulatory T cells (Tregs) and T helper 17 (Th17) cells, with a focus on their crucial roles in Treg immunity in cancer and Treg-Th17 cell phenotypic plasticity.

Dysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation.

Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Specifically, we employ adipocyte-specific BECN1 KO (BaKO) mice, which exhibit lipodystrophy due to dysfunctional adipocytes. Our results reveal the activation of YAP/TAZ signaling in both CAAs and BECN1-deficient adipocytes, inducing adipocyte dedifferentiation and formation of a malignant TME. The additional deletion of YAP/TAZ from BaKO mice significantly restores the lipodystrophy and inflammatory phenotypes, leading to tumor regression. Furthermore, mice fed a high-fat diet (HFD) exhibit decreased BECN1 and increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppresses tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Overall, our findings provide insights into the key mediators of CAA and their significance in developing a TME, thereby suggesting a viable approach targeting adipocyte homeostasis to suppress cancer growth.

The synchronized feature of Saururus chinensis and gut microbiota against T2DM, NAFLD, obesity and hypertension via integrated pharmacology.

Type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), obesity (OB) and hypertension (HT) are categorized as metabolic disorders (MDs), which develop independently without distinct borders. Herein, we examined the gut microbiota (GM) and Saururus chinensis (SC) to confirm their therapeutic effects via integrated pharmacology. The overlapping targets from the four diseases were determined to be key protein coding genes. The protein-protein interaction (PPI) networks, and the SC, GM, signalling pathway, target and metabolite (SGSTM) networks were analysed via RPackage. Additionally, molecular docking tests (MDTs) and density functional theory (DFT) analysis were conducted to determine the affinity and stability of the conformer(s). TNF was the main target in the PPI analysis, and equol derived from Lactobacillus paracasei JS1 was the most effective agent for the formation of the TNF complex. The SC agonism (PPAR signalling pathway), and antagonism (neurotrophin signalling pathway) by SC were identified as agonistic bioactives (aromadendrane, stigmasta-5,22-dien-3-ol, 3,6,6-trimethyl-3,4,5,7,8,9-hexahydro-1H-2-benzoxepine, 4α-5α-epoxycholestane and kinic acid), and antagonistic bioactives (STK734327 and piclamilast), respectively, via MDT. Finally, STK734327-MAPK1 was the most favourable conformer according to DFT. Overall, the seven bioactives from SC and equol that can be produced by Lactobacillus paracasei JS1 can exert synergistic effects on these four diseases.

Long-term efficacy and safety of brolucizumab in neovascular age-related macular degeneration: A multicentre retrospective real-world study.

PURPOSE: To investigate the long-term efficacy and safety of intravitreal brolucizumab (BRZ) injections in patients with typical neovascular age-related macular degeneration (typical nAMD) and polypoidal choroidal vasculopathy (PCV). METHODS: This multicentre retrospective study included 401 eyes of 398 patients with nAMD who received BRZ injection(s), with a follow-up duration of ≥12 months. Changes in best-corrected visual acuity (BCVA), retinal fluid evaluation and central subfield thickness (CST) on optical coherence tomography were assessed. The efficacy of BRZ was compared between typical nAMD and PCV groups. RESULTS: Analyses were conducted with 280 eyes of 278 patients with typical nAMD and 121 eyes of 120 patients with PCV (mean age, 71.1 ± 8.6 years). 29 eyes (7.2%) were treatment naïve. The mean follow-up period was 15.3 ± 2.8 months; the mean number of BRZ injections within 1 year was 4.5 ± 1.7. BCVA was maintained during the follow-up period, and CST significantly improved from the first injection month and was maintained for 12 months in both the typical nAMD and PCV groups. The dry macula proportion increased from 2.7% at baseline to 56.1% at 1 month and 42.9% at 12 months. Among the 18 eyes that underwent indocyanine green angiography both before and after treatment, 10 (55.6%) showed polyp regression. Overall, the incidence of intraocular inflammation (IOI), retinal vasculitis and occlusive retinal vasculitis was 9.4% (38 eyes), 1.2% (5 eyes) and 0.5% (2 eyes), respectively. IOI occurred from the first to the sixth injections, with an average IOI onset of 28.5 ± 1.4 days. All eyes achieved IOI resolution, although the two eyes with occlusive retinal vasculitis showed a severe visual decline after IOI resolution. CONCLUSION: Brolucizumab was effective in maintaining BCVA and managing fluid in eyes with nAMD for up to 1 year, exhibiting a high polyp regression rate. However, the not uncommon incidence of IOI and the severe visual decline caused by the rare occlusive retinal vasculitis following BRZ treatment underscore the importance of careful monitoring and timely management.

A Comparative Study of Endoscopic versus Percutaneous Epidural Neuroplasty in Lower Back Pain: Outcomes at Six-Month Follow Up.

Background and Objectives: Endoscopic epidural neuroplasty (EEN) facilitates adhesiolysis through direct epiduroscopic visualization, offering more precise neural decompression than that exhibited by percutaneous epidural neuroplasty (PEN). We aimed to compare the effects of EEN and PEN for 6 months after treatment with lower back and radicular pain in patients. Methods: This retrospective study compared the visual analog scale (VAS) and Oswestry disability index (ODI) scores in patients with low back and radicular pain who underwent EEN or PEN with a steering catheter. The medical records of 107 patients were analyzed, with 73 and 34 undergoing EEN and PEN, respectively. Results: The VAS and ODI scores decreased at all time points after EEN and PEN. VAS and ODI scores decreased more in the EEN group than those in the PEN group at 1 day and 1- and 6-months post-procedure, indicating superior pain relief for both lower back and radicular pain through EEN. Conclusions: EEN is a superior treatment of pain control than PEN in lower back and radicular pain patients.

Multiplex CRISPR-Cas Genome Editing: Next-Generation Microbial Strain Engineering.

Genome editing is a crucial technology for obtaining desired phenotypes in a variety of species, ranging from microbes to plants, animals, and humans. With the advent of CRISPR-Cas technology, it has become possible to edit the intended sequence by modifying the target recognition sequence in guide RNA (gRNA). By expressing multiple gRNAs simultaneously, it is possible to edit multiple targets at the same time, allowing for the simultaneous introduction of various functions into the cell. This can significantly reduce the time and cost of obtaining engineered microbial strains for specific traits. In this review, we investigate the resolution of multiplex genome editing and its application in engineering microorganisms, including bacteria and yeast. Furthermore, we examine how recent advancements in artificial intelligence technology could assist in microbial genome editing and engineering. Based on these insights, we present our perspectives on the future evolution and potential impact of multiplex genome editing technologies in the agriculture and food industry.

Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC.

Cysteine metabolism occurs across cellular compartments to support diverse biological functions and prevent the induction of ferroptosis. Though the disruption of cytosolic cysteine metabolism is implicated in this form of cell death, it is unknown whether the substantial cysteine metabolism resident within the mitochondria is similarly pertinent to ferroptosis. Here, we show that despite the rapid depletion of intracellular cysteine upon loss of extracellular cystine, cysteine-dependent synthesis of Fe-S clusters persists in the mitochondria of lung cancer cells. This promotes a retention of respiratory function and a maintenance of the mitochondrial redox state. Under these limiting conditions, we find that glutathione catabolism by CHAC1 supports the mitochondrial cysteine pool to sustain the function of the Fe-S proteins critical to oxidative metabolism. We find that disrupting Fe-S cluster synthesis under cysteine restriction protects against the induction of ferroptosis, suggesting that the preservation of mitochondrial function is antagonistic to survival under starved conditions. Overall, our findings implicate mitochondrial cysteine metabolism in the induction of ferroptosis and reveal a mechanism of mitochondrial resilience in response to nutrient stress.

N-Myc and STAT Interactor is an endometriosis suppressor.

In patients with endometriosis, refluxed endometrial fragments evade host immunosurveillance, developing into endometriotic lesions. However, the mechanisms underlying this evasion have not been fully elucidated. N-Myc and STAT Interactor (NMI) have been identified as key players in host immunosurveillance, including interferon (IFN)-induced cell death signaling pathways. NMI levels are markedly reduced in the stromal cells of human endometriotic lesions due to modulation by the Estrogen Receptor beta/Histone Deacetylase 8 axis. Knocking down NMI in immortalized human endometrial stromal cells (IHESCs) led to elevated RNA levels of genes involved in cell-to-cell adhesion and extracellular matrix signaling following IFNA treatment. Furthermore, NMI knockdown inhibited IFN-regulated canonical signaling pathways, such as apoptosis mediated by Interferon Stimulated Gene Factor 3, and necroptosis upon IFNA treatment. In contrast, NMI knockdown with IFNA treatment activated non-canonical IFN-regulated signaling pathways that promote proliferation, including ß-Catenin and AKT signaling. Moreover, NMI knockdown in IHESCs stimulated ectopic lesions' growth in mouse endometriosis models. Therefore, NMI is a novel endometriosis suppressor, enhancing apoptosis and inhibiting proliferation and cell adhesion of endometrial cells upon IFN exposure.

A consortium of Hordeum vulgare and gut microbiota against non-alcoholic fatty liver disease via data-driven analysis.

Despite many recent studies on non-alcoholic fatty liver disease (NAFLD) therapeutics, the optimal treatment has yet to be determined. In this unfinished project, we combined secondary metabolites (SMs) from the gut microbiota (GM) and Hordeum vulgare (HV) to investigate their combinatorial effects via network pharmacology (NP). Additionally, we analyzed GM or barley - signalling pathways - targets - metabolites (GBSTMs) in combinatorial perspectives (HV, and GM). A total of 31 key targets were analysed via a protein-protein interaction (PPI) network, and JUN was identified as the uppermost target in NAFLD. On a bubble plot, we revealed that apelin signalling pathway, which had the lowest enrichment factor antagonize NAFLD. Holistically, we scrutinized GBSTM to identify key components (GM, signalling pathways, targets, and metabolites) associated with the Apelin signalling pathway. Consequently, we found that the primary GMs (Eubacterium limosum, Eggerthella sp. SDG-2, Alistipes indistinctus YIT 12060, Odoribacter laneus YIT 12061, Paraprevotella clara YIT 11840, Paraprevotella xylaniphila YIT 11841) to ameliorate NAFLD. The molecular docking test (MDT) suggested that tryptanthrin-JUN is an agonist, conversely, dihydroglycitein-HDAC5, 1,3-diphenylpropan-2-ol-NOS1, and (10[(Acetyloxy)methyl]-9-anthryl)methyl acetate-NOS2, which are antagonistic conformers in the apelin signalling pathway. Overall, these results suggest that combination therapy could be an effective strategy for treating NAFLD.

Effects of dual-task resistance exercise on cognition, mood, depression, functional fitness, and activities of daily living in older adults with cognitive impairment: a single-blinded, randomized controlled trial.

BACKGROUND: Regular exercise is emphasized for the improvement of functional capacity and independence of older adults. This study aimed to compare the effects of a dual-task resistance exercise program and resistance exercise on cognition, mood, depression, physical function, and activities of daily living (ADL) in older adults with cognitive impairment. METHODS: A total of 44 older adults participated in the study. Participants were randomly allocated to an experimental group (n = 22) performing a dual-task resistance exercise program for cognitive function improvement and a control group (n = 22) performing a resistance exercise program. Both groups performed the exercise for 40 min per session, three times a week, for 6 weeks (18 sessions). Cognition, mood, depression, functional fitness, and ADL were quantified before and after the intervention using the Mini-Mental State Examination (MMSE), profile of mood states (POMS), geriatric depression scale (GDS), senior fitness test (SFT), and Korean version of ADL, respectively. RESULTS: There was a significant time and group interaction on the MMSE (p = 0.044). There were no significant time and group interactions in the POMS, GDS, SFT, or ADL. Cognitive function (p < 0.001), mood (p < 0.001), depression (p < 0.001), functional fitness (p < 0.001), and ADL (p < 0.001) significantly improved after dual-task resistance exercise, and cognitive function (p < 0.001), mood (p < 0.001), depression (p < 0.001), functional fitness (p < 0.001), and ADL (p < 0.001) significantly improved after resistance exercise. CONCLUSIONS: Dual-task resistance exercise is more effective than resistance exercise in improving cognitive function in older adults with cognitive impairment. Both dual-task resistance exercise and resistance exercise improves mood, depression, functional fitness, and ADL after the intervention. We propose using dual-task resistance exercises for cognitive and physical health management in the older adults with cognitive impairment. TRIAL REGISTRATION: This study was registered with the Clinical Research Information Service (WHO International Clinical Trials Registry Platform) (Registration ID, KCT0005389; Registration date, 09/09/2020).

A novel vector field analysis for quantitative structure changes after macular epiretinal membrane surgery.

The aim of this study was to introduce novel vector field analysis for the quantitative measurement of retinal displacement after epiretinal membrane (ERM) removal. We developed a novel framework to measure retinal displacement from retinal fundus images as follows: (1) rigid registration of preoperative retinal fundus images in reference to postoperative retinal fundus images, (2) extraction of retinal vessel segmentation masks from these retinal fundus images, (3) non-rigid registration of preoperative vessel masks in reference to postoperative vessel masks, and (4) calculation of the transformation matrix required for non-rigid registration for each pixel. These pixel-wise vector field results were summarized according to predefined 24 sectors after standardization. We applied this framework to 20 patients who underwent ERM removal to obtain their retinal displacement vector fields between retinal fundus images taken preoperatively and at postoperative 1, 4, 10, and 22 months. The mean direction of displacement vectors was in the nasal direction. The mean standardized magnitudes of retinal displacement between preoperative and postoperative 1 month, postoperative 1 and 4, 4 and 10, and 10 and 22 months were 38.6, 14.9, 7.6, and 5.4, respectively. In conclusion, the proposed method provides a computerized, reproducible, and scalable way to analyze structural changes in the retina with a powerful visualization tool. Retinal structural changes were mostly concentrated in the early postoperative period and tended to move nasally.

Jolkinolide B synergistically potentiates the antitumor activity of GPX4 inhibitors via inhibiting TrxR1 in cisplatin-resistant bladder cancer cells.

Glutathione peroxidase 4 (GPX4) is a promising anticancer therapeutic target; however, the application of GPX4 inhibitors (GPX4i) is limited owing to intrinsic or acquired drug resistance. Hence, understanding the mechanisms underlying drug resistance and discovering molecules that can overcome drug resistance are crucial. Herein, we demonstrated that GPX4i killed bladder cancer cells by inducing lipid reactive oxygen species-mediated ferroptosis and apoptosis, and cisplatin-resistant bladder cancer cells were also resistant to GPX4i, representing a higher half-maximal inhibitory concentration value than that of parent bladder cancer cells. In addition, thioredoxin reductase 1 (TrxR1) overexpression was responsible for GPX4i resistance in cisplatin-resistant bladder cancer cells, and inhibiting TrxR1 restored the sensitivity of these cells to GPX4i. In vitro and in vivo studies revealed that Jolkinolide B (JB), a natural diterpenoid and previously identified as a TrxR1 inhibitor, potentiated the antiproliferative efficacy of GPX4i (RSL3 and ML162) against cisplatin-resistant bladder cancer cells. Furthermore, GPX4 knockdown and inhibition could augment JB-induced paraptosis and apoptosis. Our results suggest that inhibiting TrxR1 can effectively improve GPX4 inhibition-based anticancer therapy. A combination of JB and GPX4i, which is well-tolerated and has several anticancer mechanisms, may serve as a promising therapy for treating bladder cancer.

DOT1L is critical for adult vessel maintenance and functions.

Objective: DOT1L is the only known histone H3K79 methyltransferase essential for the development of the embryonic cardiovascular system, including the heart, blood vessels, and lymphatic vessels, through transcriptional regulation. Our previous study demonstrated that Dot1l deletion results in aberrant lymphatic development and function. However, its precise function in the postnatal cardiovascular system remains unknown. Methods: Using conditional and inducible Dot1l knockout (KO) mice, along with a reporter strain carrying the Geo gene at the Dot1l locus, DOT1L expression and its function in the vascular system during postnatal life were investigated. To assess vessel morphology and vascular permeability, we administered Latex or Evans blue dye to KO mice. In addition, in vitro tube formation and cell migration assays were performed using DOT1L-depleted human umbilical vein endothelial cells (HUVECs). Changes in the expression of vascular genes in HUVECs were measured by quantitative polymerase chain reaction. Results: Our findings demonstrate that conditional Dot1l knockout in the Tg (Tie2-cre) strain results in abnormal blood vessel formation and lymphatic anomalies in the intestine. In a mouse model of Rosa26-creER-mediated inducible Dot1l knockout, we observed vascular phenotypes, including increased vascular permeability and brain hemorrhage, when DOT1L was deleted in adulthood. Additionally, DOT1L depletion in cultured HUVECs led to impaired cell migration and tube formation, likely due to altered gene transcription. These findings highlight the essential role of DOT1L in maintaining vascular integrity and function during embryonic development and postnatal life. Conclusion: Our study revealed that DOT1L is required for the maintenance of adult vascular function through the regulation of gene expression.

Nationwide incidence of congenital and infantile cataract requiring surgery in Korea.

Congenital and infantile (CI) cataract is one of the most important and preventable cause of blindness in children, but the incidence has not been studied in Korea. We collected data from the national claims database of the National Health Insurance Service of Korea from 2002 through 2019. We identified children who underwent cataract surgery within the age of 5 years, and cumulative incidence rates were calculated for each of the three age criteria. 989 patients out of 4,221,459 births underwent surgery with CI cataract during the period. The cumulative incidence rates per 10,000 births were 1.60 (0-1 years), 2.38 (0-3 years), and 2.95 (0-5 years), respectively. The incidence peaked in the 2007 birth cohort, which coincides with the start of the national screening program for infants/children. Primary intraocular lens implantation was performed in 439 patients (44%). Strabismus and glaucoma requiring surgery occurred in 291 patients (29.4%) and 32 patients (3.2%), respectively, within 8 years after cataract surgery. The incidence rates of CI cataract in Korea appear to be comparable to previous studies in other regions. The early screening program for infants may reduce delayed diagnosis and increase the proportion of patients undergoing surgery at a critical time for visual development.

Corrigendum: Korean Ginseng Berry Extract Enhances the Male Steroidogenesis Enzymes In Vitro and In Vivo.

This corrects the article on p. 446 in vol. 41, PMID: 36649918.