Folic acids promote in vitro maturation of bovine oocytes by inhibition of ferroptosis via upregulated glutathione and downregulated Fe2+ accumulation.

Bovine embryos by in vitro fertilization have become the primary source of commercial embryo transfers globally. However, the developmental capacity of in vitro maturation (IVM) oocytes is considerably lower than that of in vivo maturation (IVO) oocytes, owing to the production of reactive oxygen species (ROS) via mitochondrial metabolism, which was higher in IVM oocytes than in IVO oocytes. To avoid the negative effects of ROS on embryo quality, folic acid (FA) was supplemented directly into the IVM medium to antagonize ROS production, however, the mechanisms remain unknown. In the present study, five levels of FA (0, 25, 50, 100, and 200 µM) were supplemented into the bovine oocyte culture medium. The maturation, cleavage, and blastocyst formation rates increased by 8.95 %, 6.94 %, and 4.36 %, respectively, in the 50 µM group compared to the 0 µM group. Moreover, 7904 differential genes were identified between 0 µM and 50 µM groups by transcriptome sequencing, and they were mainly enriched in 8 pathways. The glutathione, ROS, and Fe2+ levels in oocytes were found to be associated with ferroptosis. Our results revealed that 50 µM FA promoted the IVM of bovine oocytes and affected the expression of genes involved in the ferroptosis pathway. The downregulation of TFR1 and STEAP3 led to a decrease in intracellular Fe2+ accumulation, and the upregulation of GCL increased oocyte GSH levels, thereby reducing the production of ROS in the ferroptosis pathway. Our study provides a new insight into the molecular mechanisms by which FA promotes bovine oocyte development in vitro.

Prognostic nomogram for patients with advanced unresectable hepatocellular carcinoma treated with TAE combined with HAIC.

Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and often arises in the context of chronic liver disease, such as hepatitis B or C infection, and cirrhosis. Advanced unresectable HCC (uHCC) presents significant treatment challenges due to its advanced stage and inoperability. One efficient treatment method for advanced uHCC is the use of hepatic arterial infusion chemotherapy (HAIC) combined with transcatheter arterial embolization (TAE). Patients and Methods: In this study, we conducted a retrospective collection of clinical data, including basic information, radiological data, and blood test parameters, for patients with advanced uHCC who underwent TAE + HAIC treatment from August 2020 to February 2023. A total of 743 cases involving 262 patients were included. Ultimately, the covariates included in the analysis were the Child-Pugh score, extrahepatic metastasis, tumor number, tumor size, and treatment method. Results: In the study, we performed univariable and multivariable analysis on 23 clinical factors that were screened by LASSO regression, indicating that the five variables aforementionedly were identified as independent factors influencing patient prognosis. Then we developed a nomogram of the sensitive model and calculated concordance indices of prognostic survival models. Conclusion: Based on the uHCC patient cohort, we have developed a prognostic model for OS in patients who received TAE + HAIC treatment. This model can accurately predict OS and has the potential to assist in personalized clinical decision-making.

Sterile water and regional citrate anticoagulation: A simple CRRT strategy for safe correction of severe hyponatraemia.

BACKGROUND: Hyponatraemia is a prevalent electrolyte disturbance observed in critically ill patients. The rapid correction of low plasma sodium levels by continuous renal replacement therapy (CRRT) carries the risk of developing osmotic demyelination syndrome (ODS), which can be prevented by implementing an individualized CRRT method. AIM: This study aims to introduce a CRRT protocol for the safe and gradual correction of severe hyponatraemia. STUDY DESIGN: This retrospective case series study was conducted in an intensive care unit (ICU). All four patients with severe hyponatraemia (<125 mmol/L) and renal failure between October 1, 2022, and September 30, 2023, were treated by CRRT with sterile water and regional citrate anticoagulation (RCA). Data on patient demographics, laboratory biochemical parameters, urine outputs and CRRT-related adverse events were collected. Laboratory parameters and urine outputs were compared by paired t-tests before and after CRRT. RESULTS: After CRRT, sodium levels were significantly increased (112.7 ± 6.7 vs. 141.9 ± 2.8 mmol/L, p = .005). Abnormal urine outputs, potassium, creatinine and bicarbonate were corrected (p for all <.05). Safe and gradual correction of hyponatraemia and internal environmental dysregulation was achieved in all patients without any complications related to CRRT, particularly ODS. CONCLUSION: It is a novel and simple strategy to correct severe hyponatraemia effectively while ensuring the safety of patients that can be easily implemented by experienced nurse staff. RELEVANCE TO CLINICAL PRACTICE: The sterile water-based protocol for postfilter dilution is safe to correct severe hyponatraemia with RCA and can be easily performed by experienced critical care nurses according to the precalculated formula. CRRT-trained, experienced ICU nurses are competent to initiate and adjust sterile water infusion discretely to prevent overcorrection of hyponatraemia.

Association of air pollutants with psychiatric disorders: a two-sample Mendelian randomization.

BACKGROUND: The link between air pollution and increased risk of psychiatric disorders has been growing in evidence. However, the causal relationship between air pollution and psychiatric disorders remains poorly understood. METHODS: Single-nucleotide polymorphisms associated with air pollutants (including NOx, NO2, PM2.5, PM2.5-10, and PM10) from the UK Biobank were used as instrumental variables. Summary-level data for psychiatric disorders (major depressive disorder, anxiety, bipolar disorder, schizophrenia, post-traumatic stress disorder, attention deficit hyperactivity disorder, autism spectrum disorder, anorexia nervosa, and obsessive-compulsive disorder) were procured from the Psychiatric Genomics Consortium and FinnGen consortium. Two-sample Mendelian randomization (MR) analysis was conducted to analyze the causal associations. RESULTS: The MR analysis revealed significant associations between certain air pollutants and specific types of psychiatric disorders. The inverse-variance weighted model of preliminary analysis indicated that genetically predicted NO2 was associated with increased risks of major depressive disorder (odds ratio [OR]: 1.13, 95 % confidence intervals [CI]: 1.00-1.28, P = 0.041), bipolar disorder (OR: 1.26, 95 % CI: 1.00-1.58, P = 0.0497), schizophrenia (OR: 1.57, 95 % CI: 1.23-2.00, P < 0.001), attention deficit hyperactivity disorder (OR: 1.61, 95 % CI: 1.25-2.09, P < 0.001) and autism spectrum disorder (OR: 1.39, 95 % CI: 1.01-1.91, P = 0.044). Genetically predicted PM2.5 showed a positive association with the risk of major depressive disorder (OR: 1.21, 95 % CI: 1.06-1.39, P = 0.006), bipolar disorder (OR: 1.32, 95 % CI: 1.03-1.69, P = 0.030) and attention deficit hyperactivity disorder (OR: 1.57, 95 % CI: 1.16-2.12, P = 0.004). In addition, our results also indicated that NOx (OR: 1.64, 95 % CI: 1.21-2.21, P = 0.0012) and PM10 (OR: 1.70, 95 % CI: 1.23-2.36, P = 0.0014) could increase the risk of attention deficit hyperactivity disorder. CONCLUSIONS: The MR analysis provides evidence for the causality of different air pollutants on specific psychiatric disorders, underscoring the importance of mitigating air pollution to reduce the risk of psychiatric disorders.

Well-Defined Homopolymer Nanoparticles with Uniaxial Molecular Orientation by Synchronized Polymerization and Self-Assembly.

Synthesizing anisotropic polymeric nanoparticles (NPs) with well-defined shapes, dimensions, and molecular orientations is a very challenging task. Herein, we report the synthesis of surprisingly highly uniform shape-anisotropic polymer NPs with uniaxial internal molecular orientation. Keys to our method are synchronized polymerization and self-assembly (SPSA), which can even be realized by regular dispersion polymerization. This is demonstrated using a monomer containing a rigid 4-nitroazobenzene (NAB) side group. The short nucleation period, the completion of microphase separation before molecular motion is frozen, and sufficient low particle/solvent interfacial tension are shown to be the origins of the highly uniform dimensions, single liquid crystal domains, and well-defined anisotropic shape of particles. The liquid crystallization ability of the polymers, control of molecular weight distribution, and the polymerization kinetics are identified as three key factors controlling the NP formation. The uniformity of these NPs facilitates their SA formation into colloidal crystals. The particles exhibit optically anisotropic properties depending on orientations and, in particular, show intriguing photoswitchable LC-glass (order-disorder) transition, which can be used for the detection of ultraviolet (UV) light and allows the fabrication of photoreversible colloidal films.

Topology Effect on Order-Disorder Transition of High-χ Block Copolymers.

This work aims to systematically examine the topology effect on the self-assembly of block copolymers. Compositionally, symmetric polystyrene-block-polydimethylsiloxane block copolymers (BCPs) with different chain topologies (diblock, three-arm star-block, and four-arm star-block) and various molecular weights are synthesized. These purposely designed block copolymers are used as a model system to investigate the topology effect on order-to-disorder transition temperature (T ODT) by temperature-resolved small-angle X-ray scattering experiments. An increase of the T ODT is observed when the arm number of BCPs with equivalent arm length (i.e., molecular weight) is increased from one to four. Based on the random-phase approximation (RPA), Flory-Huggins interaction parameter (χ) is determined from the regression of the measured T ODT. The observation by differential scanning calorimetry also demonstrates the shifting of the endothermic peak from the order-to-disorder transition of star-blocks to the higher temperature region, consistent with the scattering experiments and the RPA prediction.

Enhancement of cadmium uptake in Sedum alfredii through interactions between salicylic acid/jasmonic acid and rhizosphere microbial communities.

The focus on phytoremediation in soil cadmium (Cd) remediation is driven by its cost-effectiveness and eco-friendliness. Selecting suitable hyperaccumulators and optimizing their growth conditions are key to enhance the efficiency of heavy metal absorption and accumulation. Our research has concentrated on the role of salicylic acid (SA) and jasmonic acid (JA) in facilitating Cd phytoextraction by "Sedum alfredii (S. alfredii)" through improved soil-microbe interactions. Results showed that SA or JA significantly boosted the growth, stress resistance, and Cd extraction efficiency in S. alfredii. Moreover, these phytohormones enhanced the chemical and biochemical attributes of the rhizosphere soil, such as pH and enzyme activity, affecting soil-root interactions. High-throughput sequencing analysis has shown that Patescibacteria and Umbelopsis enhanced S. alfredii's growth and Cd extraction by modifying the bioavailability and the chemical conditions of Cd in soil. Structural Equation Model analysis further verified that phytohormones significantly enhanced the interaction between S. alfredii, soil, and microbes, leading to a marked increase in Cd accumulation in the plant. These discoveries emphasized the pivotal role of phytohormones in modulating the hyperaccumulators' response to environmental stress and offered significant scientific support for further enhancing the potential of hyperaccumulators in ecological restoration technologies using phytohormones.

Sequential Self-Assembly of Polystyrene-block-Polydimethylsiloxane for 3D Nanopatterning via Solvent Annealing.

This study aims to develop a strategy for the fabrication of multilayer nanopatterns through sequential self-assembly of lamella-forming polystyrene-block-polydimethylsiloxane (PS-b-PDMS) block copolymer (BCP) from solvent annealing. By simply tuning the solvent selectivity, a variety of self-assembled BCP thin-film morphologies, including hexagonal perforated lamellae (HPL), parallel cylinders, and spheres, can be obtained from single-composition PS-b-PDMS. By taking advantage of reactive ion etching (RIE), topographic SiO2 monoliths with well-ordered arrays of hexagonally packed holes, parallel lines, and hexagonally packed dots can be formed. Subsequently, hole-on-dot and line-on-hole hierarchical textures can be created through a layer-by-layer process with RIE treatment as evidenced experimentally and confirmed theoretically. The results demonstrated the feasibility of creating three-dimensional (3D) nanopatterning from the sequential self-assembly of single-composition PS-b-PDMS via solvent annealing, providing an appealing process for nano-MEMS manufacturing based on BCP lithography.

Study on the expression patterns of inner root sheath-specific genes in Tan sheep hair follicle during different developmental stages.

By analyzing the expression patterns of inner root sheath (IRS) specific genes during different developmental stages of hair follicle (HF) in Tan sheep embryos and at birth, this study aims to reveal the influence of the IRS on crimped wool. Skin tissues from the scapular region of male Tan sheep were collected at 85 days (E85) and 120 days (E120) of fetal development, and at 0 days (D0), 35 days (D35), and 60 days (D60) after birth, with four samples at each stage. Real-time quantitative polymerase chain reaction (RT-qPCR) was employed to determine the relative expression levels of IRS type I keratin genes (KRT25, KRT26, KRT27, KRT28), type II keratin genes (KRT71, KRT72, KRT73, KRT74), and the trichohyalin gene (TCHH) in the skin of Tan sheep at different stages. Results showed that the expression levels of all IRS-specific genes peaked at D0, with the expression of all genes significantly higher than at E85 (P < 0.01), except for KRT73 and TCHH. The expression levels of KRT25, KRT26, and KRT72 were also significantly higher than at E120 (P < 0.01). Furthermore, the expression levels of KRT27, KRT28, KRT71, and KRT74 were significantly higher than both at E120 and D35 (P < 0.01). The expression levels of other genes at different stages showed no significant difference (P > 0.05). Conclusion: The IRS-specific genes exhibit the highest expression levels in Tan sheep at the neonatal stage. The expression levels of KRT71, KRT72, and TCHH, which are consistent with the pattern of wool crimp, may influence the morphology of the IRS and thereby affect the crimp of Tan sheep wool.

Effectiveness of risk-based caries management among Chinese preschool children: a randomized controlled single-blind trial.

BACKGROUND: Early childhood caries (ECC) remain a serious oral health problem on a global scale. Risk-based caries management (RBCM) implemented in some parts of the world has been effective in preventing ECC. However, there is a lack of prospective research on the application of RBCM among Chinese children, and little is known about its effectiveness. The purpose of this study was to evaluate the effectiveness of RBCM in preventing caries among children aged 3-5 years in Wanzhou District, Chongqing Municipality, China. METHODS: Three- to five-year-old children from four kindergartens in Wanzhou were randomly selected for baseline dental examination and caries risk assessment (CRA) and randomly assigned to the experimental group (EG) or the control group (CG) according to the kindergarten. The EG received caries prevention measures of different intensities based on the child's caries risk level. The CG received full-mouth fluoride twice a year according to standard prevention, regardless of their caries risk. One year later, another dental examination and CRA were conducted, to observe changes in the decayed, missing, and filled teeth (dmft) index and caries risk, and to analyze potential factors that may affect the incidence of new caries. RESULTS: Complete data were collected from 291 children (EG, N = 140, 84.8%; CG, N = 181, 83.4%). A total of 25.7% of the EG and 50.3% of the CG children developed new caries, with newly added dmft scores of 0.54 ± 1.12 and 1.32 ± 1.72, respectively (P < 0.05). Multivariate logistic regression indicated that children living in rural areas, assigned to the CG, and rated as high-risk at baseline were more likely to develop new caries (P < 0.05). The proportion of children with an increased caries risk in the EG was significantly lower than that in the CG (P < 0.05). CONCLUSIONS: RBCM effectively prevented new caries in 3- to 5-year-old Wanzhou children and reduced the proportion of children at increased risk of caries. It is an effective approach for preventing ECC. CLINICAL TRIAL REGISTRATION: This trial was registered in the Chinese Clinical Trials Register. The registration number was ChiCTR230067551 (11/01/2023).

Effect of acupuncture intervention time on the therapeutic effect in patients with sudden hearing loss. / é’ˆåˆºä»‹å ¥æ—¶æœºå¯¹çªå‘æ€§è‹æ‚£è€ ç–—æ•ˆçš„å½±å“.

OBJECTIVES: To observe the clinical efficacy of acupuncture intervention at different time for patients with sudden hearing loss. METHODS: According to the timing of acupuncture intervention, 86 patients were divided into early exposure group (n=43) and late exposure group (n=43) . The early exposure group was given acupuncture treatment within 14 days of onset, and the late exposure group was given acupuncture treatment after 14 days of onset. After propensity score matching (PSM, a statistical matching technique for observational data) processing by using SPSS26.0 software, outcomes of 30 cases in the early exposure group and 30 cases in the late exposure group were analyzed. In addition to receiving basic treatment with drugs for vascular dilatation, thrombolysis, nourishing nerve, etc., all patients of the two groups were treated with neck acupuncture ("Neck Seven Meridian Lines" acupuncture), once every other day except Sundays, for a total of 12 time. Before, after the treatment and 3 months after the treatment, the total score of the Tinnitus Handicap Inventory (THI, 0, 2 and 4 points for each of the 25 items, total scores = 100 points) scale was used to evaluate the improvement of tinnitus symptoms caused by hearing loss. The clinical therapeutic effect was evaluated according to the efficacy grading criteria in the Guidelines for Diagnosis and Treatment of Sudden Deafness (2015) and the changes of pure tone audiometry curve. Multivariate Logistic regression was used to analyze the effect of factors that might influence efficacy before propensity score matching. RESULTS: The THI scores of patients in both groups decreased strikingly after the treatment and 3 months' follow-up (P<0.05). Compared with the same time-points of the late exposure group, the total THI scores of post-treatment and 3 months' follow-up were evidently lower in the early exposure group (P<0.05). The effective rate of the early exposure group (22/30, 80.00%) was significantly higher (P<0.05) than that of the late exposure group (16/30, 53.33%). The classification of sudden deafness and the application of traditional Chinese medicine in this study were not independent factors affecting the total effective rate. CONCLUSIONS: The time point of acupuncture intervention is an important factor affecting the effect on hearing and tinnitus disability of patients with sudden deafness. The earlier acupuncture treatment is accepted, the better the therapeutic effect is.

Rejuvenation of peripheral immune cells attenuates Alzheimer's disease-like pathologies and behavioral deficits in a mouse model.

Immunosenescence contributes to systematic aging and plays a role in the pathogenesis of Alzheimer's disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells. The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral Aß plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aß clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

Nanocrystal Assemblies: Current Advances and Open Problems.

We explore the potential of nanocrystals (a term used equivalently to nanoparticles) as building blocks for nanomaterials, and the current advances and open challenges for fundamental science developments and applications. Nanocrystal assemblies are inherently multiscale, and the generation of revolutionary material properties requires a precise understanding of the relationship between structure and function, the former being determined by classical effects and the latter often by quantum effects. With an emphasis on theory and computation, we discuss challenges that hamper current assembly strategies and to what extent nanocrystal assemblies represent thermodynamic equilibrium or kinetically trapped metastable states. We also examine dynamic effects and optimization of assembly protocols. Finally, we discuss promising material functions and examples of their realization with nanocrystal assemblies.

Salicylic Acid's impact on Sedum alfredii growth and cadmium tolerance: Comparative physiological, transcriptomic, and metabolomic study.

With the acceleration of industrialization, Cd pollution has emerged as a major threat to soil ecosystem health and food safety. Hyperaccumulating plants like Sedum alfredii Hance are considered to be used as part of an effective strategy for the ecological remediation of Cd polluted soils. This study delved deeply into the physiological, transcriptomic, and metabolomic responses of S. alfredii under cadmium (Cd) stress when treated with exogenous salicylic acid (SA). We found that SA notably enhanced the growth of S. alfredii and thereby increased absorption and accumulation of Cd, effectively alleviating the oxidative stress caused by Cd through upregulation of the antioxidant system. Transcriptomic and metabolomic data further unveiled the influence of SA on photosynthesis, antioxidant defensive mechanisms, and metal absorption enrichment pathways. Notably, the interactions between SA and other plant hormones, especially IAA and JA, played a central role in these processes. These findings offer us a comprehensive perspective on understanding how to enhance the growth and heavy metal absorption capabilities of hyperaccumulator plants by regulating plant hormones, providing invaluable strategies for future environmental remediation efforts.

CDCA5-EEF1A1 interaction promotes progression of clear cell renal cell carcinoma by regulating mTOR signaling.

BACKGROUND: Cell division cycle associated 5 (CDCA5) plays ontogenetic role in various human cancers. However, its specific function and regulatory mechanism in ccRCC remain uncertain. METHODS: Immunohistochemistry and western blots were performed to investigate the expression of CDCA5 in ccRCC tissues. Genetic knockdown and upregulation of CDCA5 were performed to investigate its functional roles in ccRCC proliferation, migration, apoptosis and sunitinib resistance. Furthermore, Co-IP assay and LC-MS/MS were performed to investigate the underlying mechanisms. RESULTS: We found that CDCA5 expression is frequently upregulated in ccRCC tumors and is associated with poor prognosis of ccRCC patients. Functionally, CDCA5 promotes proliferation, migration, and sunitinib resistance, while inhibiting apoptosis in ccRCC cells. In vivo mouse xenograft model confirms that silencing of CDCA5 drastically inhibits the growth of ccRCC. Mechanistically, we discovered that CDCA5 interacts with Eukaryotic Translation Elongation Factor 1 Alpha 1 (EEF1A1) to regulate mTOR signaling pathway, thereby promoting ccRCC progression. CONCLUSIONS: Taken together, our results demonstrate the significant role of CDCA5 in ccRCC progression. The findings may provide insights for the development of new treatment strategies targeting CDCA5 for ccRCC patients.

Canonical pathways for validating steroid-associated osteonecrosis in mice.

The present study aimed to establish and evaluate a preclinical model of steroid-associated osteonecrosis (SAON) in mice. Sixteen 24-week-old male C57BL/6 mice were used to establish SAON by two intraperitoneal injections of lipopolysaccharide (LPS), followed by three subcutaneous injections of methylprednisolone (MPS). Each injection was conducted on working day, with an interval of 24 h. Six cycles of injections were conducted. Additional twelve mice (age- and gender-matched) were used as normal controls. At 2 and 6 weeks after completing induction, bilateral femora and bilateral tibiae were collected for histological examination, micro-CT scanning, and bulk RNA sequencing. All mice were alive until sacrificed at the indicated time points. The typical SAON lesion was identified by histological evaluation at week 2 and week 6 with increased lacunae and TUNEL+ osteocytes. Micro-CT showed significant bone degeneration at week 6 in SAON model. Histology and histomorphometry showed significantly lower Runx2+ area, mineralizing surface (MS/BS), mineral apposition rate (MAR), bone formation rate (BFR/BS), type H vessels, Ki67+ (proliferating) cells, and higher marrow fat fraction, osteoclast number and TNFα+ areas in SAON group. Bulk RNA-seq revealed changed canonical signaling pathways regulating cell cycle, angiogenesis, osteogenesis, and osteoclastogenesis in the SAON group. The present study successfully established SAON in mice with a combination treatment of LPS and MPS, which could be considered a reliable and reproducible animal model to study the pathophysiology and molecular mechanism of early-stage SAON and to develop potential therapeutic approaches for the prevention and treatment of SAON.

Non-contact wide-field viewing system-assisted scleral buckling surgery for retinal detachment in silicone oil-filled eyes.

AIM: To evaluate scleral buckling (SB) surgery using a non-contact wide-field viewing system and 23-gauge intraocular illumination for the treatment of rhegmatogenous retinal detachment in silicone oil (SO)-filled eyes. METHODS: Totally 9 patients (9 eyes) with retinal detachment in SO-filled eyes were retrospectively analyzed. All patients underwent non-contact wide-field viewing system-assisted buckling surgery with 23-gauge intraocular illumination. SO was removed at an appropriate time based on recovery. The patients were followed up for at least 3mo after SO removal. Retinal reattachment, complications, visual acuity and intraocular pressure (IOP) before and after surgery were observed. RESULTS: Patients were followed up for a mean of 8.22mo (3-22mo) after SO removal. All patients had retinal reattachment. At the final follow-up, visual acuity showed improvement for 8 patients, and no change for 1 patient. The IOP was high in 3 patients before surgery, but it stabilized after treatment; it was not affected in the other patients. None of the patients had infections, hemorrhage, anterior ischemia, or any other complication. CONCLUSION: This new non-contact wide-field viewing system-assisted SB surgery with 23-gauge intraocular illumination is effective and safe for retinal detachment in SO-filled eyes.

Mechanism of Mulberry Leaves and Black Sesame in Alleviating Slow Transit Constipation Revealed by Multi-Omics Analysis.

Traditional Chinese medicine (TCM) possesses the potential of providing good curative effects with no side effects for the effective management of slow transit constipation (STC), an intestinal disease characterized by colonic dyskinesia. Mulberry leaves (Morus alba L.) and black sesame (Sesamum indicum L.), referred to as SH, are processed and conditioned as per standardized protocols. SH has applications as food and medicine. Accordingly, we investigated the therapeutic potential of SH in alleviating STC. The analysis of SH composition identified a total of 504 compounds. The intervention with SH significantly improved intestinal motility, reduced the time for the first black stool, increased antioxidant activity, and enhanced water content, thereby effectively alleviating colon damage caused by STC. Transcriptome analysis revealed the SH in the treatment of STC related to SOD1, MUC2, and AQP1. The analysis of 16S rRNA gene sequences indicated notable differences in the abundance of 10 bacteria between the SH and model. Metabolomic analysis further revealed that SH supplementation increased the levels of nine metabolites associated with STC. Integrative analysis revealed that SH modulated amino acid metabolism, balanced intestinal flora, and targeted key genes (i.e., SOD1, MUC2, AQP1) to exert its effects. SH also inhibited the AQP1 expression and promoted SOD1 and MUC2 expression.

A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis.

Activating Nrf2 by small molecules is a promising strategy to treat postmenopausal osteoporosis. However, there is currently no Nrf2 activator approved for treating chronic diseases, and the downstream mechanism underlying the regulation of Nrf2 on osteoclast differentiation remains unclear. Here, we found that bitopertin, a clinical-stage glycine uptake inhibitor, suppresses osteoclast differentiation and ameliorates ovariectomy-induced bone loss by activating Nrf2. Mechanistically, bitopertin interacts with the Keap1 Kelch domain and decreases Keap1-Nrf2 binding, leading to reduced Nrf2 ubiquitination and degradation. Bitopertin is associated with less adverse events than clinically approved Nrf2 activators in both mice and human subjects. Furthermore, Nrf2 transcriptionally activates ferroportin-coding gene Slc40a1 to reduce intracellular iron levels in osteoclasts. Loss of Nrf2 or iron supplementation upregulates ornithine-metabolizing enzyme Odc1, which decreases ornithine levels and thereby promotes osteoclast differentiation. Collectively, our findings identify a novel clinical-stage Nrf2 activator and propose a novel Nrf2-iron-ornithine metabolic axis in osteoclasts.