ZP2 cleavage blocks polyspermy by modulating the architecture of the egg coat.

Following the fertilization of an egg by a single sperm, the egg coat or zona pellucida (ZP) hardens and polyspermy is irreversibly blocked. These events are associated with the cleavage of the N-terminal region (NTR) of glycoprotein ZP2, a major subunit of ZP filaments. ZP2 processing is thought to inactivate sperm binding to the ZP, but its molecular consequences and connection with ZP hardening are unknown. Biochemical and structural studies show that cleavage of ZP2 triggers its oligomerization. Moreover, the structure of a native vertebrate egg coat filament, combined with AlphaFold predictions of human ZP polymers, reveals that two protofilaments consisting of type I (ZP3) and type II (ZP1/ZP2/ZP4) components interlock into a left-handed double helix from which the NTRs of type II subunits protrude. Together, these data suggest that oligomerization of cleaved ZP2 NTRs extensively cross-links ZP filaments, rigidifying the egg coat and making it physically impenetrable to sperm.

Structural Basis of Egg Coat-Sperm Recognition at Fertilization.

Recognition between sperm and the egg surface marks the beginning of life in all sexually reproducing organisms. This fundamental biological event depends on the species-specific interaction between rapidly evolving counterpart molecules on the gametes. We report biochemical, crystallographic, and mutational studies of domain repeats 1-3 of invertebrate egg coat protein VERL and their interaction with cognate sperm protein lysin. VERL repeats fold like the functionally essential N-terminal repeat of mammalian sperm receptor ZP2, whose structure is also described here. Whereas sequence-divergent repeat 1 does not bind lysin, repeat 3 binds it non-species specifically via a high-affinity, largely hydrophobic interface. Due to its intermediate binding affinity, repeat 2 selectively interacts with lysin from the same species. Exposure of a highly positively charged surface of VERL-bound lysin suggests that complex formation both disrupts the organization of egg coat filaments and triggers their electrostatic repulsion, thereby opening a hole for sperm penetration and fusion.

Insights into egg coat assembly and egg-sperm interaction from the X-ray structure of full-length ZP3.

ZP3, a major component of the zona pellucida (ZP) matrix coating mammalian eggs, is essential for fertilization by acting as sperm receptor. By retaining a propeptide that contains a polymerization-blocking external hydrophobic patch (EHP), we determined the crystal structure of an avian homolog of ZP3 at 2.0 Å resolution. The structure unveils the fold of a complete ZP domain module in a homodimeric arrangement required for secretion and reveals how EHP prevents premature incorporation of ZP3 into the ZP. This suggests mechanisms underlying polymerization and how local structural differences, reflected by alternative disulfide patterns, control the specificity of ZP subunit interaction. Close relative positioning of a conserved O-glycan important for sperm binding and the hypervariable, positively selected C-terminal region of ZP3 suggests a concerted role in the regulation of species-restricted gamete recognition. Alternative conformations of the area around the O-glycan indicate how sperm binding could trigger downstream events via intramolecular signaling.

Cryo-EM structure of native human uromodulin, a zona pellucida module polymer.

Assembly of extracellular filaments and matrices mediating fundamental biological processes such as morphogenesis, hearing, fertilization, and antibacterial defense is driven by a ubiquitous polymerization module known as zona pellucida (ZP) "domain". Despite the conservation of this element from hydra to humans, no detailed information is available on the filamentous conformation of any ZP module protein. Here, we report a cryo-electron microscopy study of uromodulin (UMOD)/Tamm-Horsfall protein, the most abundant protein in human urine and an archetypal ZP module-containing molecule, in its mature homopolymeric state. UMOD forms a one-start helix with an unprecedented 180-degree twist between subunits enfolded by interdomain linkers that have completely reorganized as a result of propeptide dissociation. Lateral interaction between filaments in the urine generates sheets exposing a checkerboard of binding sites to capture uropathogenic bacteria, and UMOD-based models of heteromeric vertebrate egg coat filaments identify a common sperm-binding region at the interface between subunits.

Relationship Between Distressing Symptoms and Changes in Disability After Major Surgery Among Community-living Older Persons.

OBJECTIVES: To evaluate the relationship between distressing symptoms and changes in disability after major surgery and to determine whether this relationship differs according to the timing of surgery (nonelective vs elective), sex, multimorbidity, and socioeconomic disadvantage. BACKGROUND: Major surgery is a common and serious health event that has pronounced deleterious effects on both distressing symptoms and functional outcomes in older persons. METHODS: From a cohort of 754 community-living persons, aged 70 or older, 392 admissions for major surgery were identified from 283 participants who were discharged from the hospital. The occurrence of 15 distressing symptoms and disability in 13 activities were assessed monthly for up to 6 months after major surgery. RESULTS: Over the 6-month follow-up period, each unit increase in the number of distressing symptoms was associated with a 6.4% increase in the number of disabilities [adjusted rate ratio (RR): 1.064; 95% CI: 1.053, 1.074]. The corresponding increases were 4.0% (adjusted RR: 1.040; 95% CI: 1.030, 1.050) and 8.3% (adjusted RR: 1.083; 95% CI: 1.066, 1.101) for nonelective and elective surgeries. Based on exposure to multiple (ie, 2 or more) distressing symptoms, the adjusted RRs (95% CI) were 1.43 (1.35, 1.50), 1.24 (1.17, 1.31), and 1.61 (1.48, 1.75) for all, nonelective, and elective surgeries. Statistically significant associations were observed for each of the other subgroups with the exception of individual-level socioeconomic disadvantage for the number of distressing symptoms. CONCLUSIONS: Distressing symptoms are independently associated with worsening disability, providing a potential target for improving functional outcomes after major surgery.

Leveraging Electronic Health Records to Assess Residential Mobility Among Veterans in the Veterans Health Administration.

BACKGROUND: Residential mobility, or a change in residence, can influence health care utilization and outcomes. Health systems can leverage their patients' residential addresses stored in their electronic health records (EHRs) to better understand the relationships among patients' residences, mobility, and health. The Veteran Health Administration (VHA), with a unique nationwide network of health care systems and integrated EHR, holds greater potential for examining these relationships. METHODS: We conducted a cross-sectional analysis to examine the association of sociodemographics, clinical conditions, and residential mobility. We defined residential mobility by the number of VHA EHR residential addresses identified for each patient in a 1-year period (1/1-12/31/2018), with 2 different addresses indicating one move. We used generalized logistic regression to model the relationship between a priori selected correlates and residential mobility as a multinomial outcome (0, 1, ≥2 moves). RESULTS: In our sample, 84.4% (n=3,803,475) veterans had no move, 13.0% (n=587,765) had 1 move, and 2.6% (n=117,680) had ≥2 moves. In the multivariable analyses, women had greater odds of moving [aOR=1.11 (95% CI: 1.10,1.12) 1 move; 1.27 (1.25,1.30) ≥2 moves] than men. Veterans with substance use disorders also had greater odds of moving [aOR=1.26 (1.24,1.28) 1 move; 1.77 (1.72,1.81) ≥2 moves]. DISCUSSION: Our study suggests about 16% of veterans seen at VHA had at least 1 residential move in 2018. VHA data can be a resource to examine relationships between place, residential mobility, and health.

Sialic acid-containing glycolipids mediate binding and viral entry of SARS-CoV-2.

Emerging evidence suggests that host glycans influence severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we reveal that the receptor-binding domain (RBD) of the spike (S) protein on SARS-CoV-2 recognizes oligosaccharides containing sialic acid (Sia), with preference for monosialylated gangliosides. Gangliosides embedded within an artificial membrane also bind to the RBD. The monomeric affinities (Kd = 100-200 µM) of gangliosides for the RBD are similar to another negatively charged glycan ligand of the RBD proposed as a viral co-receptor, heparan sulfate (HS) dp2-dp6 oligosaccharides. RBD binding and infection of SARS-CoV-2 pseudotyped lentivirus to angiotensin-converting enzyme 2 (ACE2)-expressing cells is decreased following depletion of cell surface Sia levels using three approaches: sialyltransferase (ST) inhibition, genetic knockout of Sia biosynthesis, or neuraminidase treatment. These effects on RBD binding and both pseudotyped and authentic SARS-CoV-2 viral entry are recapitulated with pharmacological or genetic disruption of glycolipid biosynthesis. Together, these results suggest that sialylated glycans, specifically glycolipids, facilitate viral entry of SARS-CoV-2.

Is pharmacologic venous Thromboprophylaxis necessary for patients undergoing minimally invasive surgery for endometrial Cancer? A systematic review and Meta-analysis.

OBJECTIVE: Given the low incidence of venous thromboembolism (VTE) in endometrial cancer patients undergoing minimally invasive surgery, coupled with the existing uncertainties within guidelines regarding pharmacologic thromboprophylaxis in this area, there is an urgent need for a comprehensive literature review. This review aims to evaluate the necessity of pharmacologic VTE prophylaxis in these patients. METHODS: PubMed, Embase, Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform, and ClinicalTrials.gov were systematically searched from inception to March 10, 2024. The analysis was performed using R version 4.2.3. RESULTS: Seven studies involving 3931 endometrial cancer patients were included in the analysis. Meta-analysis results revealed that within 30 days postoperatively, the incidence of VTE was 0.51% (5 out of 990) in the pharmacologic prophylaxis group and 0.70% (7 out of 995) in the mechanical prophylaxis group, with a relative risk (RR) of 1.14 (95% CI 0.19-6.95), indicating no significant difference between the groups. Additionally, within the same timeframe, the incidence of VTE was 0.37% (4 out of 1083) in the extended pharmacologic prophylaxis group and 1.14% (4 out of 352) in the non-extended pharmacologic prophylaxis group, yielding an RR of 0.41 (95% CI 0.11-1.54), again showing no significant difference between the groups. CONCLUSIONS: Our study indicates that routine pharmacological VTE prophylaxis may not be imperative for endometrial cancer patients undergoing minimally invasive surgery, as mechanical prophylaxis alone seems to be efficacious. However, it is crucial to acknowledge that a subset of high-risk patients may derive benefit from pharmacological prophylaxis or even extended regimens. Nonetheless, the absence of a validated risk prediction model for identifying such patients underscores the need for further research in this area. PROTOCOL REGISTRATION: CRD 42024516595.

Prognostic value of three-tiered scoring system for lymph-vascular space invasion in endometrial cancer: A systematic review and meta-analysis.

OBJECTIVE: To investigate the impact of lymph-vascular space invasion (LVSI) status on the prognosis of endometrial cancer (EC) according to a three-tiered scoring system for LVSI. METHODS: PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), International Clinical Trials Registry Platform (ICTRP), and Clinical Trials.gov were searched from inception to September 1st, 2023. The analysis was conducted using STATA 16.0. RESULTS: A total of 9 studies with 4456 EC patients were included in the analysis. No LVSI was found in 72% of EC patients (95% CI 0.65-0.79), while focal and substantial LVSI were present in 16% (95% CI 0.11-0.21) and 13% (95% CI 0.08-018) of patients, respectively. Compared to the no LVSI group, the focal and substantial LVSI groups had poorer overall survival (for focal LVSI: HR 1.33, 95% CI 1.02-1.74; for substantial LVSI: HR 2.51, 95% CI 1.61-3.90), poorer disease-free survival (for substantial LVSI: HR 2.86, 95% CI 1.21-6.77), and an increased risk of recurrence, including pelvic recurrence (for focal LVSI: HR 2.05, 95% CI 1.03-4.07; for substantial LVSI: HR 6.06, 95% CI 3.31-11.08), distant recurrence (for focal LVSI: HR 2.04, 95% CI 1.42-2.92; for substantial LVSI: HR 3.36, 95% CI 2.35-4.793), and lymph node involvement (for focal LVSI: OR 3.52, 95% CI 1.339.34; for substantial LVSI: OR 5.42, 95% CI 2.78-10.58). Substantial LVSI was more prone to pelvic recurrence (HR 1.82, 95% CI 1.05-3.15) and distant recurrence (HR 2.21, 95% CI 1.48-3.28) than focal LVSI. CONCLUSIONS: EC patients with focal and substantial LVSI had poorer survival, recurrence, and a higher incidence of lymph node metastasis than patients without LVSI. The substantial LVSI group was associated with even worse prognosis than the focal LVSI group. The three-tiered LVSI scoring system might effectively predict the prognosis of EC and guide clinical decision-making. PROTOCOL REGISTRATION: CRD 42023451793.

Splenectomy as a part of cytoreductive surgery in ovarian cancer: systematic review and meta-analysis.

OBJECTIVE: The role of splenectomy on cytoreductive surgery in patients with ovarian cancer remains controversial. We conducted this meta-analysis to evaluate the safety and impact of survival outcome of splenectomy in patients with ovarian cancer. METHODS: In this meta-analysis we analyzed studies published in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), International Clinical Trials Registry Platform (ICTRP), and Clinical Trials. gov that appeared in our search from inception to November 10, 2023. RESULT: This meta-analysis included 10 studies, totaling 6297 patients, comprising one prospective and nine retrospective analyses. The results indicated no significant disparity in overall survival and mortality (OR 1.14, 95% CI 0.69 to 1.87, p=0.62) between the splenectomy cohort and the no splenectomy (required) cohort. Furthermore, relative to the no splenectomy (required) cohort, the splenectomy group showed a heightened incidence of overall post-operative complications (odds ratio (OR) 1.66, 95% CI 1.65 to 2.61, p=0.03), an extended duration of hospitalization (mean difference (MD) 2.88 days, 95% CI 2.09 to 3.67), an increased interval from surgery to the initiation of adjuvant chemotherapy (MD 4.44 days, 95% CI 2.41 to 6.07, p<0.0001), and a greater probability of undergoing reoperation (OR 4.7, 95% CI 1.91 to 11.55, p=0.0007). However, concerning the occurrence of specific post-operative complications such as anastomotic leakage (OR 0.97, 95% CI 0.33 to 2.84, p=0.95), pancreatic fistula (OR 3.25, 95% CI 0.63 to 16.7, p=0.16), abdominal abscess (OR 1.75, 95% CI 0.25 to 12.33, p=0.57), sepsis (OR 1.46, 95% CI 0.77 to 2.77, p=0.25), and thrombotic events (OR 1.82, 95% CI 0.93 to 3.57, p=0.08), no significant differences were observed between the two cohorts. CONCLUSION: Splenectomy does not impact the overall survival and mortality of patients with ovarian cancer. Thus, it can be considered an acceptably safe procedure to obtain optimal cytoreduction. However, caution should be taken when selecting patients for splenectomy because it is associated with an increased incidence of overall post-operative complications, prolonged hospital stays, delayed initiation of adjuvant chemotherapy, and an increased probability of requiring subsequent surgical interventions.

Genetic Polymorphisms of rs9949644 in MAPK4 Are Associated with Clinical Response to Methotrexate in Patients with Psoriasis.

BACKGROUND: The study aimed to investigate the relationship of MAPK4 genetic variants with the efficacy of methotrexate (MTX) in psoriasis patients. METHODS: Patients treated with MTX were classified as responders or nonresponders if the Psoriasis Area and Severity Index (PASI) at week 12 was reduced to greater than 75% or lower than 75%, respectively. The genotypes of 14 MAPK4 single-nucleotide polymorphisms in 310 patients were analyzed. The expression levels of MAPK4 protein were detected by Western blot. RESULTS: Only rs9949644 polymorphisms were associated with the efficacy after adjusting for the confounding factors. Patients with the rs9949644 AG or GG genotype had a better clinical response compared to patients with the AA genotype. Rs9949644 polymorphisms were significantly associated with the PASI improvement rate. Besides, the protein level of MAPK4, positively associated with the psoriasis severity, was higher in patients. There were no significant differences of MAPK4 protein levels among the three groups. While after treatment, MAPK4 levels in the AG or GG group showed a significantly down-regulated trend. CONCLUSION: By demonstrating the significant association of MAPK4 with the efficacy of MTX, this study indicates that MAPK4 may be involved in the psoriasis progression and act as a predictor of therapeutic response.

Design, synthesis and herbicidal activity of novel cyclohexanedione derivations containing pyrazole and pyridine groups as potential HPPD inhibitors.

4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27; HPPD) is one of the important target enzymes in the development of herbicides. To discover novel HPPD inhibitors with unique molecular, 39 cyclohexanedione derivations containing pyrazole and pyridine groups were designed and synthesized. The preliminary herbicidal activity test results showed that some compounds had obvious inhibitory effects on monocotyledon and dicotyledonous weeds. The herbicidal spectrums of the highly active compounds were further determined, and the compound G31 exhibited the best inhibitory rate over 90% against Plantago depressa Willd and Capsella bursa-pastoris at the dosages of 75.0 and 37.5 g ai/ha, which is comparable to the control herbicide mesotrione. Moreover, compound G31 showed excellent crop safety, with less than or equal to 10% injury rates to corn, sorghum, soybean and cotton at a dosage of 225 g ai/ha. Molecular docking and molecular dynamics simulation analysis revealed that the compound G31 could stably bind to Arabidopsis thaliana HPPD (AtHPPD). This study indicated that the compound G31 could be used as a lead molecular structure for the development of novel HPPD inhibitors, which provided an idea for the design of new herbicides with unique molecular scaffold.

Vitamin D supplementation during pregnancy and the role of maternal prenatal depression.

BACKGROUND: The current study sought to investigate the correlation between vitamin D supplementation in pregnant women with vitamin D deficiency in early pregnancy and the incidence of prenatal depression prior to delivery. METHODS: This is a retrospective, single-center study that was conducted at a tertiary hospital in Chengdu, China. We conducted an analysis on pregnant women who were initially diagnosed with vitamin D deficiency at 12-14 weeks of gestation. After starting vitamin D supplementation at a dose of 800 IU daily from 14 weeks onwards, we measured both their vitamin D concentration and depression scores again during median gestational week 39 prior to delivery. RESULTS: The study cohort comprised 1365 women who had been diagnosed with vitamin D deficiency at 12-14 weeks of gestation between November 1st, 2021 to November 1st, 2022. 537 pairs were matched based on a propensity score to control for other confounding factors. After propensity score matching, the baseline vitamin D levels were made consistent between the groups (P = 0.512). The incidence of depression in patients in vitamin D deficiency group following vitamin D supplementation was significantly higher than insufficiency group and reached statistical significance (P < 0.001). Additionally, we observed that serum 25-(OH) D concentration achieving insufficiency status after supplementation was 59.12%. CONCLUSION: Our study indicates that daily supplementation of 800IU of vitamin D can improve the depressive symptoms of individuals who are vitamin D deficiency during early pregnancy but achieve vitamin D insufficiency after supplementation during prenatal period.

Changes in Restricting Symptoms after Critical Illness among Community-Living Older Adults.

Rationale: Survivors of critical illness have multiple symptoms, but how restricting symptoms change after critical illness and whether these changes differ among vulnerable subgroups is unknown. Objectives: To evaluate changes in restricting symptoms over the six months after critical illness among older adults and to determine whether these changes differ by sex, multimorbidity, and individual- and neighborhood-level socioeconomic disadvantage. Methods: From a prospective longitudinal study of 754 community-living adults ⩾70 years old interviewed monthly (1998-2018), we identified 233 admissions from 193 participants to the ICU. The occurrence of 15 restricting symptoms, defined as those leading to restricted activity, were ascertained during interviews in the month before ICU admission (baseline) and each of the six months after hospital discharge. Measurements and Main Results: The occurrence and number of restricting symptoms increased more than threefold in the six months after a critical illness hospitalization (adjusted rate ratio [95% confidence interval], 3.1 [2.1-4.6] and 3.3 [2.1-5.3], respectively), relative to baseline. These increases were largest in the first month after hospitalization (adjusted rate ratio [95% confidence interval], 5.3 [3.8-7.3] and 5.4 [3.9-7.5], respectively] before declining and becoming nonsignificant in the third month. Increases in restricting symptoms did not differ significantly by sex, multimorbidity, or individual- or neighborhood-level socioeconomic disadvantage. Conclusions: Restricting symptoms increase substantially after a critical illness before returning to baseline three months after hospital discharge. Our findings highlight the need to incorporate symptom management into post-ICU care and for further investigation into whether addressing restricting symptoms can improve quality of life and functional recovery among older ICU survivors.

A highly potent small-molecule antagonist of exportin-1 selectively eliminates CD44+CD24- enriched breast cancer stem-like cells.

Breast cancer stem-like cells (BCSCs) have been suggested as the underlying cause of tumor recurrence, metastasis and drug resistance in triple-negative breast cancer (TNBC). Here, we report the discovery and biological evaluation of a highly potent small-molecule antagonist of exportin-1, LFS-1107. We ascertained that exportin-1 (also named as CRM1) is a main cellular target of LFS-1107 by nuclear export functional assay, bio-layer interferometry binding assay and C528S mutant cell line. We found that LFS-1107 significantly inhibited TNBC tumor cells at low-range nanomolar concentration and LFS-1107 can selectively eliminate CD44+CD24- enriched BCSCs. We demonstrated that LFS-1107 can induce the nuclear retention of Survivin and consequent strong suppression of STAT3 transactivation abilities and the expression of downstream stemness regulators. Administration of LFS-1107 can strongly inhibit tumor growth in mouse xenograft model and eradicate BCSCs in residual tumor tissues. Moreover, LFS-1107 can significantly ablate the patient-derived tumor organoids (PDTOs) of TNBC as compared to a few approved cancer drugs. Lastly, we revealed that LFS-1107 can enhance the killing effects of chemotherapy drugs and downregulate multidrug resistance related protein targets. These new findings provide preclinical evidence of defining LFS-1107 as a promising therapeutic agent to deplete BCSCs for the treatment of TNBC.

Effect of glycolysis on water holding capacity during postmortem aging of Jersey cattle-yak meat.

BACKGROUND: Postmortem muscle moisture loss leads to a decrease in carcass weight and can adversely impact overall meat quality. Therefore, it is critical to investigate water holding capacity (WHC) to enhance meat quality. Current research has primarily focused on examining the correlation between signaling molecules and meat quality in relation to the glycolysis effect on muscle WHC. But there exists a significant knowledge gap regarding the mechanism of WHC in Jersey cattle-yak meat. RESULTS: Jersey cattle-yak meat pH decreased and then increased during postmortem aging. Lactate content, cooking loss, pressing loss, drip loss and centrifuging loss of Jersey cattle-yak meat increased and then decreased during postmortem aging. The glycogen content of Jersey cattle-yak meat was significantly higher than that of yak meat at 6-120 h, being 8.40% higher than that of yak meat at 120 h. The activity of key glycolytic enzymes hexokinase (HK), pyruvate kinase (PK), phosphofructokinase (PFK) and lactate dehydrogenase (LDH) in Jersey cattle-yak meat was lower than that in yak meat. Correlation analysis showed that Jersey cattle-yak meat WHC was positively correlated with the activity of HK, PK, PFK and LDH. CONCLUSIONS: The WHC of Jersey cattle-yak meat was higher than that of Gannan yak meat, and it was significantly positively correlated with the activity of key enzymes of the glycolytic signaling pathway. Therefore, the glycolysis rate can be reduced by inhibiting enzyme activity to improve Jersey cattle-yak meat WHC and meat quality. © 2023 Society of Chemical Industry.

Effect of tremella polysaccharides on the quality of collagen jelly: insight into the improvement of the gel properties and the antioxidant activity of yak skin gelatin.

BACKGROUND: The present study aimed to investigate the effects of tremella polysaccharides on the gel properties and antioxidant activity of yak skin gelatin with a view to improving the quality of collagen jellies. The preparation of composite gels were performed by yak skin gelatin (66.7 mg mL-1) and tremella polysaccharides with different concentrations (0, 2, 4, 6, 8 mg mL-1), and finally the collagen jelly was prepared by composite gel (yak skin gelatin: 66.7 mg mL-1; tremella polysaccharides:6 mg mL-1) with the best performance. RESULTS: Tremella polysaccharides not only improved the hardness, springiness, gel strength, water holding capacity and melting temperature of yak skin gelatin, but also enhanced the composite gel's scavenging activity against ABTS radicals, DPPH radicals, O2 and OH radicals. The filling of tremella polysaccharides into the gelatin network increased the number of crosslinking sites inside the gel, which resulted in the gel network structure becoming dense and orderly. The gel particles became finer and more uniform, and the thermal stability was improved. Furthermore, the sensory score of commercially available gelatin jelly decreased more rapidly during storage compared to the composite gel jelly. CONCLUSION: The gel properties and antioxidant activity of yak skin gelatin were improved by adding tremella polysaccharides, and then the quality and storage properties of the jelly were improved, which also provided technical reference for the development of functional gel food. © 2024 Society of Chemical Industry.

Solamargine enhanced gefitinib antitumor effect via regulating MALAT1/miR-141-3p/Sp1/IGFBP1 signaling pathway in non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) showed great therapeutic efficacy for non-small cell lung cancer (NSCLC) patients. However, acquired resistance severely limits the clinical application and efficacy of EGFR-TKIs. In the current study, we found that solamargine (SM), a natural alkaloid derived from the fruit of Lycium tomato lobelia, has been found to inhibit the progression of NSCLC and enhance the anticancer effect of EGFR-TKIs. In brief, SM significantly inhibited the cell viability of NSCLC cells and enhanced the anticancer effect of gefitinib (GFTN) and erlotinib (ERL). Mechanistically, SM decreased the expression of MALAT1 and induced miR-141-3p, whereas reduced SP1 protein levels. Interestingly, both MALAT1 and Sp1 have classical and conservative binding sites of miR-141-3p in their 3'-UTR regions. Silence of MALAT1 and overexpression of miR-141-3p both decreased the protein expression of Sp1. Subsequently, promoter activity and protein expression of IGFBP1 were upregulated by SM, which was not observed in cells with SP1 overexpression. Moreover, the inhibitory effect of SM on cell growth was significantly blocked by knockdown of IGFBP1 expression. More importantly, the combination of SM and GFTN synergistically inhibited the progression of lung cancer. Similar results were observed in experiments in vivo. Finally, the clinical relevance of MALAT1, Sp1 and IGFBP1 was further validated using bioinformatics analysis. Taken together, we confirmed that SM significantly enhanced the anticancer effect of EGFR-TKIs by regulating the MALAT1/miR-141-3p/Sp1/IGFBP1 signaling pathway. This study unravels a novel mechanism and suggests a new potential NSCLC-associated therapy.

Factors Associated With Days Away From Home in the Year After Major Surgery Among Community-living Older Persons.

OBJECTIVE: To identify the factors associated with days away from home in the year after hospital discharge for major surgery. BACKGROUND: Relatively little is known about which older persons are susceptible to spending a disproportionate amount of time in hospitals and other health care facilities after major surgery. METHODS: From a cohort of 754 community-living persons, aged 70+ years, 394 admissions for major surgery were identified from 289 participants who were discharged from the hospital. Candidate risk factors were assessed every 18 months. Days away from home were calculated as the number of days spent in a health care facility. RESULTS: In the year after major surgery, the mean (SD) and median (interquartile range) number of days away from home were 52.0 (92.2) and 15 (0-51). In multivariable analysis, 5 factors were independently associated with the number of days away from home: age 85 years and older, low score on the Short Physical Performance Battery, low peak expiratory flow, low functional self-efficacy, and musculoskeletal surgery. Based on the presence versus absence of these factors, the absolute mean differences in the number of days away from home ranged from 31.2 for age 85 years and older to 53.5 for low functional self-efficacy. CONCLUSIONS: The 5 independent risk factors can be used to identify older persons who are particularly susceptible to spending a disproportionate amount of time away from home after major surgery, and a subset of these factors can also serve as targets for interventions to improve quality of life by reducing time spent in hospitals and other health care facilities.

MicroRNA-125a-5p regulates the effect of Tregs on Th1 and Th17 through targeting ETS-1/STAT3 in psoriasis.

BACKGROUND: Psoriasis is an inflammatory disease mediated by helper T (Th)17 and Th1 cells. MicroRNA-125a (miR-125a) is reduced in the lesional skin of psoriatic patients. However, the mechanism by which miR-125a participates in psoriasis remains unclear. METHODS: The levels of miR-125a-5p and its downstream targets (ETS-1, IFN-γ, and STAT3) were detected in CD4+ T cells of healthy controls and psoriatic patients by quantitative real-time PCR (qRT-PCR). In vitro, transfection of miR-125a-5p mimics was used to analyze the effect of miR-125a-5p on the differentiation of Th17 cells by flow cytometry. Imiquimod (IMQ)-induced mouse model was used to evaluate the role of upregulating miR-125a-5p by intradermal injection of agomir-125a-5p in vivo. RESULTS: miR-125a-5p was downregulated in peripheral blood CD4+ T cells of psoriatic patients, which was positively associated with the proportion of regulatory T cells (Tregs) and negatively correlated with the Psoriasis Area and Severity Index (PASI) score. Moreover, the miR-125a-5p mimics promoted the differentiation of Tregs and downregulated the messenger RNA (mRNA) levels of ETS-1, IFN-γ, and STAT3 in murine CD4+ T cells. Furthermore, agomir-125a-5p alleviated psoriasis-like inflammation in an IMQ-induced mouse model by downregulating the proportion of Th17 cells. CONCLUSIONS: miR-125a-5p may have therapeutic potential in psoriasis by restoring the suppressive function of Tregs on Th17 cells through targeting STAT3, and on Th1 cells indirectly through targeting ETS-1 and IFN-γ.