The crucial relationship between miRNA-27 and CSE/H2S, and the mechanism of action of GLP-1 in myocardial hypertrophy.

Cardiac hypertrophy is the most prevalent compensatory heart disease that ultimately leads to spontaneous heart failure. Mounting evidence suggests that microRNAs (miRs) and endogenous hydrogen sulfide (H2S) play a crucial role in the regulation of cardiac hypertrophy. In this study, we aimed to investigate whether inhibition of miR-27a could protect against cardiac hypertrophy by modulating H2S signaling. We established a model of cardiac hypertrophy by obtaining hypertrophic tissue from mice subjected to transverse aortic constriction (TAC) and from cells treated with angiotensin-II. Molecular alterations in the myocardium were quantified using quantitative real time PCR (qRT-PCR), Western blotting, and ELISA. Morphological changes were characterized by hematoxylin and eosin (HE) staining and Masson's trichrome staining. Functional myocardial changes were assessed using echocardiography. Our results demonstrated that miR-27a levels were elevated, while H2S levels were reduced in TAC mice and myocardial hypertrophy. Further luciferase and target scan assays confirmed that cystathionine-γ-lyase (CSE) was a direct target of miR-27a and was negatively regulated by it. Notably, enhancement of H2S expression in the heart was observed in mice injected with recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-27a and in cells transfected with a miR-27a inhibitor during cardiac hypertrophy. However, this effect was abolished by co-transfection with CSE siRNA and the miR-27a inhibitor. Conversely, injecting rAAV9-miR-27a yielded opposite results. Interestingly, our findings demonstrated that glucagon-like peptide-1 (GLP-1) agonists could mitigate myocardial damage by down-regulating miR-27a and up-regulating CSE. In summary, our study suggests that inhibition of miR-27a holds therapeutic promise for the treatment of cardiac hypertrophy by increasing H2S levels. Furthermore, our findings unveil a novel mechanism of GLP-1 agonists involving the miR-27a/H2S pathway in the management of cardiac hypertrophy.

Camellia sinensis polysaccharide attenuates inflammatory responses via the ROS-mediated pathway by endocytosis.

Polysaccharide CSTPs extracted from Camellia sinensis tea-leaves possessed unique against oxidative damage by scavenging ROS. Herein, acid tea polysaccharide CSTPs-2 with tightly packed molecular structure was isolated, purified and characterized in this research. Furthermore, the effects of CSTPs-2 on ROS-involved inflammatory responses and its underlying mechanisms were investigated. The results suggest that CSTPs-2 dramatically reduced the inflammatory cytokines overexpression and LPS-stimulated cell damage. CSTPs-2 could trigger the dephosphorylation of downstream AKT/MAPK/NF-κB signaling proteins and inhibit nuclear transfer of p-NF-κB to regulate the synthesis and release of inflammatory mediators in LPS-stimulated cells by ROS scavenging. Importantly, the impact of CSTPs-2 in downregulating pro-inflammatory cytokines and mitigating ROS overproduction is associated with clathrin- or caveolae-mediated endocytosis uptake mechanisms, rather than TLR-4 receptor-mediated endocytosis. This study presents a novel perspective for investigating the cellular uptake mechanism of polysaccharides in the context of anti-inflammatory mechanisms.

Urotensin II receptor deficiency ameliorates ligation-induced carotid intimal hyperplasia partially through the RhoA-YAP1 pathway.

Intimal hyperplasia (IH) is a common pathological feature of vascular proliferative diseases, such as atherosclerosis and restenosis after angioplasty. Urotensin II (UII) and its receptor (UTR) are widely expressed in cardiovascular tissues. However, it remains unclear whether the UII/UTR system is involved in IH. Right unilateral common carotid artery ligation was performed and maintained for 21 days to induce IH in UTR knockout (UTR-/-) and wild-type (WT) mice. Histological analysis revealed that compared with WT mice, UTR-deficient mice exhibited a decreased neointimal area, angiostenosis and intima-media ratio. Immunostaining revealed fewer smooth muscle cells (SMCs), endothelial cells and macrophages in the lesions of UTR-/- mice than in those of WT mice. Protein interaction analysis suggested that the UTR may affect cell proliferation by regulating YAP and its downstream target genes. In vitro experiments revealed that UII can promote the proliferation and migration of SMCs, and western blotting also revealed that UII increased the protein expression of RhoA, CTGF, Cyclin D1 and PCNA and downregulated p-YAP protein expression, while these effects could be partly reversed by urantide. To evaluate the translational value of UTRs in IH management, WT mice were also treated with two doses of urantide, a UTR antagonist, to confirm the benefit of UTR blockade in IH progression. A high dose of urantide (600 µg/kg/day), rather than a low dose (60 µg/kg/day), successfully improved ligation-induced IH compared with that in mice receiving vehicle. The results of the present study suggested that the UII/UTR system may regulate IH partly through the RhoA-YAP signaling pathway.

Repeatability of epithelium thickness measured by an AS-OCT in different grades keratoconus and compared to AS-OCT/Placido topography.

PURPOSE: To compare agreement of corneal epithelium thickness (ET) between AS-OCT system (RTVue, Optovue, Fremont, USA) and AS-OCT/Placido topographer (MS-39, CSO, Florence, Italy) in different stages keratoconus (KC) eyes, and to assess the repeatability of RTVue AS-OCT. DESIGN: Prospective reliability analysis. METHODS: KC eyes were classified into forme fruste KC (FFKC), mild, moderate and severe KC. Agreement was evaluated with Bland-Altman plots and 95% limits of agreement (LoA). The repeatability of RTVue was assessed via within-subject standard deviation (Sw), test-retest variability (TRT), coefficient of variation (CoV), and intraclass correlation coefficient (ICC). RESULTS: Totally, 119 KC eyes were enrolled, with 21 FFKC, 26 mild, 39 moderate, and 34 severe. The 95% LoA ranged between -5.9 and 4.8 µm for center epithelium thickness (CET), between -5.7 and 8.2 µm for thinnest epithelium thickness (TET). At 1mm measuring points, the 95% LoA of superior, inferior, nasal and temporal were -4.2 to 4.7 µm, -5.2 to 6.0 µm, -7.9 to 10.2 µm, -11.2 to 6.0 µm. At 3mm measuring points, the corresponding values were -2.8 to 9.3 µm, -2.0 to 13.0 µm, -4.6 to 9.6 µm, -6.3 to 9.7 µm, indicating the two instruments weren't interchangeable without adjustment. Despite the repeatability of RTVue in KC patients were acceptable, repeatability decreased gradually with the peripheralization of the measurement points. CONCLUSIONS: The two OCT-based devices, RTVue and MS-39, don't provide interchangeable measurements of ET in KC patients. Repeatability decreases in severer KC, emphasizing the importance of grading before clinical examination to avoid diagnostic errors.

Biomimetic and multifunctional nanocomposites for precision fungi theranostics.

Fungi infection is a serious threat to public health, but an effective antifungal strategy remains a challenge. Herein, a biomimetic nanocomposite with multifunctionalities, including fungi diagnosis, antifungal adhesion, precise fungi elimination, and cytokine sequestration, is constructed for battling Candida albicans (C. albicans) infection. By screening a range of cells, we find that the polarized macrophage cells have the strongest binding tendency toward C. albicans. Thus, their membranes were exfoliated to camouflage UCNPs and then decorated with photosensitizers (methylene blue, MB) and DNA sensing elements. The resulting nanocomposite can tightly bind to fungal surfaces, promote DNA recognition, and squeeze pro-inflammatory cytokines to relieve inflammation. Consequently, this nanocomposite can detect C. albicans with enhanced sensitivity and precisely eliminate fungal cells through photodynamic therapy with minimal phototoxicity because of its switchable fluorescence behavior. The developed nanocomposite with good biocompatibility achieves a satisfactory diagnostic and therapeutic effect in a C. albicans-infected mouse model, which offers a unique approach to fight fungi infection.

Synergistic effects of graphene microgrooves and electrical stimulation on M2 macrophage polarization.

Macrophages play a crucial role in host response and wound healing, with M2 polarization contributing to the reduction of foreign-body reactions induced by the implantation of biomaterials and promoting tissue regeneration. Electrical stimulation (ES) and micropatterned substrates have a significant impact on the macrophage polarization. However, there is currently a lack of well-established cell culture platforms for studying the synergistic effects of these two factors. In this study, we prepared a graphene free-standing substrate with 20 µm microgrooves using capillary forces induced by water evaporation. Subsequently, we established an ES cell culture platform for macrophage cultivation by integrating a self-designed multi-well chamber cell culture device. We observed that graphene microgrooves, in combination with ES, significantly reduce cell spreading area and circularity. Results from immunofluorescence, ELISA, and flow cytometry demonstrate that the synergistic effect of graphene microgrooves and ES effectively promotes macrophage M2 phenotypic polarization. Finally, RNA sequencing results reveal that the synergistic effects of ES and graphene microgrooves inhibit the macrophage actin polymerization and the downstream PI3K signaling pathway, thereby influencing the phenotypic transition. Our results demonstrate the potential of graphene-based microgrooves and ES to synergistically modulate macrophage polarization, offering promising applications in regenerative medicine.

Efficient Selective Adsorption of Rubidium and Cesium from Practical Brine Using a Metal-Organic Framework-Based Magnetic Adsorbent.

Rubidium (Rb) and cesium (Cs) have important applications in highly technical fields. Salt lakes contain huge reserves of Rb and Cs with industrial significance, which can be utilized after extraction. In this study, a composite magnetic adsorbent (Fe3O4@ZIF-8@AMP, AMP = ammonium phosphomolybdate) was prepared and its adsorption properties for Rb+ and Cs+ were studied in simulated and practical brine. The structure of the adsorbent was characterized by SEM, XRD, N2 adsorption-desorption, FT-IR, and vibrating sample magnetometer (VSM). The adsorbent had good adsorption affinity for Rb+ and Cs+. The Langmuir model and pseudo-second-order dynamics described the adsorbing isotherm and kinetic dates, respectively. The adsorption capacity and adsorption rate of Fe3O4@ZIF-8@AMP were increased by 1.86- and 2.5-fold compared with those of powdered crystal AMP, owing to the large specific surface area and high dispersibility of the adsorbent in the solution. The adsorbent was rapidly separated from the solution within 17 s using an applied magnetic field owing to the good magnetic properties. The composite adsorbent selectively adsorbed Rb+ and Cs+ from the practical brine even in the presence of a large number of coexisting ions. The promising adsorbent can be used to extract Rb+ and Cs+ from aqueous solutions.

Efficacy and Safety of Topical Traditional Chinese Medicine Monotherapy in Persistent HPV Infection Among Males.

Objective: We studied the efficacy and safety of traditional Chinese medicine paiteling treatment of persistent human papillomavirus (HPV) infection in males. Methods: The study included 159 male patients with persistent HPV infection between January 2018 and July 2022, and categorized into the treatment group (n = 96) and control group (n = 63) based on the treatment. The treatment group was externally treated with paiteling diluent for 4 consecutive days and then stopped for 3 days. The total course of treatment was one month. The treatment group underwent a second test six months after treatment. The control group did not receive any therapy and underwent a second test in the seventh month. Results: 19 of the 159 patients were lost during the 6-month follow-up period, leaving 140 patients. The male HPV infection peaks between the ages of 26-35 years 73(52.14%), and its prevalence decrease with age. 84 (60.0%) were single type infections, and 22 (15.71%) had at least 3 types infections. There were 76 (54.29%) patients with the high-risk types, 34 (24.29%) with the low-risk types, and 30 (21.43%) with the mixed types. After 6 months, complete negative conversion rates and negative conversion rates were 74.7% and 90.8% in the treatment group respectively, compared to the control group (P < .01). A comparison of negative conversion rates among different types reveals that 16 type (89.5%) and 6 type (92.3%) had statistical differences, (P < .01) and (P < .05) respectively. Multivariate analysis revealed that the vaccine status of sexual partners was a protective factor (OR = 0.050-0.848) and multi-type infection was a risk factor (OR = 1.807-22.527) for the curative effect. Conclusion: Paiteling is convenient, safe, and effective for the treatment of persistent HPV infection in males.

Tumor necrosis factor α1 decreases mucosal immune and antioxidant response in the midgut of hybrid fish (white crucian carp ♀ × red crucian carp ♂).

Tumor necrosis factor α1 (TNFα) is a pleiotropic cytokine involved in immune regulation and cellular homeostasis, but the crucial role of TNFα in fish gut remained unclear. The current study aimed to evaluate the immunoregulatory function of TNFα1 on gut barrier in a novel hybrid fish (WR), which was produced by crossing white crucian carp (Carassius cuvieri, ♀) with red crucian carp (Carassius auratus red var, ♂). In this study, WR-tnfα1 sequence was identified, and a high-level expression was detected in the intestine. Elevated levels of WR-tnfα1 expressions were detected in immune-related tissues and cultured fish cells on stimulation. The appearance of vacuolization and submucosal rupture was observed in TNFα1-treated midgut of WR, along with elevated levels of goblet cell atrophy, whereas no significant changes were detected in most expressions of tight-junction genes and mucin genes. In contrast, WR receiving gut perfusion with WR-TNFα1 showed a remarkable decrease in antioxidant status in midgut, whereas the expression levels of apoptotic genes and redox responsive genes increased sharply. These results suggested that TNFα1 could exhibit a detrimental effect on antioxidant defense and immune regulation in the midgut of WR.

Structural and functional changes of binocular corneal innervation and ocular surface function after unilateral SMILE and tPRK.

AIMS: To evaluate the bilateral changes in the sub-basal nerve plexus of the cornea and ocular surface function after unilateral small incision lenticule extraction (SMILE) and transepithelial photorefractive keratectomy (tPRK) procedures. METHODS: 34 patients were enrolled in the study and underwent unilateral SMILE (21 of 34 patients) or unilateral tPRK (13 of 34 patients). Complete ophthalmic examinations, tear film function tests and Cochet-Bonnet esthesiometry were conducted to assess the effects of the surgeries on the corneal nerves and tear function. Morphological changes were assessed using in vivo confocal microscopy to evaluate the corneal sub-basal nerve plexus and dendritic cells. ELISA was used to measure the tear neuromediators. Clinical and morphological data at each follow-up point were compared with preoperative baseline values. RESULTS: All patients who underwent unilateral SMILE or tPRK procedures exhibited bilateral corneal nerve degenerative changes, decreased corneal sensitivity, worsening of dry eye symptoms and changes in bilateral tear neuromediators. In the SMILE group, bilateral corneal sensitivity was positively correlated with corneal nerve fibre length and negatively correlated with dendritic cell area. The dry eye severity was negatively correlated with corneal sensitivity. Tear levels of substance P and nerve growth factor were positively correlated with mean dendritic cell area and dry eye severity, but negatively correlated with corneal sensitivity. In the tPRK group, bilateral corneal sensitivity was positively correlated with corneal nerve fibre density. CONCLUSIONS: Unilateral refractive surgery may bilaterally affect the morphology and function of corneal nerves and ocular surface status postoperatively.

Perfluorooctanoic acid inhibits cell proliferation through mitochondrial damage.

Grown evidence has shown that the liver and reproductive organs were the main target organs of perfluorooctanoic acid (PFOA). Herein, we studied a toxic mechanism of PFOA using HeLa Chang liver epithelial cells. When incubated with PFOA for 24 h or 48 h, cell proliferation was inhibited in a concentration- and time-dependent fashion, but interestingly, the feature of dead cells was not notable. Mitochondrial volume was increased with concentration and time, whereas the mitochondrial membrane potential and produced ATP amounts were significantly reduced. Autophagosome-like vacuoles and contraction of the mitochondrial inner membrane were observed in PFOA-treated cells. The expression of acetyl CoA carboxylase (ACC) and p-ACC proteins rapidly decreased, and that of mitochondrial dynamics-related proteins increased. The expression of solute carrier family 7 genes, ChaC glutathione-specific gamma-glutamylcyclotransferase 1, and 5S ribosomal RNA gene was up-regulated the most in cells exposed to PFOA for 24 h, and the KEGG pathway analysis revealed that PFOA the most affected metabolic pathways and olfactory transduction. More importantly, PPAR alpha, fatty acid binding protein 1, and CYP450 family 1 subfamily A member 1 were identified as the target proteins for binding between PFOA and cells. Taken together, we suggest that disruption of mitochondrial integrity and function may contribute closely to PFOA-induced cell proliferation inhibition.

Identification of miR-20b-5p as an inhibitory regulator in cardiac differentiation via TET2 and DNA hydroxymethylation.

BACKGROUND: Congenital heart disease (CHD) is a prevalent congenital cardiac malformation, which lacks effective early biological diagnosis and intervention. MicroRNAs, as epigenetic regulators of cardiac development, provide potential biomarkers for the diagnosis and treatment of CHD. However, the mechanisms underlying miRNAs-mediated regulation of cardiac development and CHD malformation remain to be further elucidated. This study aimed to explore the function of microRNA-20b-5p (miR-20b-5p) in cardiac development and CHD pathogenesis. METHODS AND RESULTS: miRNA expression profiling identified that miR-20b-5p was significantly downregulated during a 12-day cardiac differentiation of human embryonic stem cells (hESCs), whereas it was markedly upregulated in plasma samples of atrial septal defect (ASD) patients. Our results further revealed that miR-20b-5p suppressed hESCs-derived cardiac differentiation by targeting tet methylcytosine dioxygenase 2 (TET2) and 5-hydroxymethylcytosine, leading to a reduction in key cardiac transcription factors including GATA4, NKX2.5, TBX5, MYH6 and cTnT. Additionally, knockdown of TET2 significantly inhibited cardiac differentiation, which could be partially restored by miR-20b-5p inhibition. CONCLUSIONS: Collectively, this study provides compelling evidence that miR-20b-5p functions as an inhibitory regulator in hESCs-derived cardiac differentiation by targeting TET2, highlighting its potential as a biomarker for ASD.

Evaluation of three decades of the burden of low back pain in China before COVID-19: Estimates from the Global Burden of Disease Database 2019.

Background: Low back pain (LBP) is reported as an urgent public-health concern globally because it occurs in all age groups and is now the leading cause of disability, with health systems unable to cope with this burden. We present China's burden of LBP by estimating its prevalence and years lived with disability (YLDs) from 1990 to 2019. Methods: We obtained the data relating to LBP from the Global Burden of Disease Database (GBD) 2019. Then we calculated years lived with disability caused by LBP by multiplying the prevalence of LBP sequelae by their corresponding disability weights. We performed an analysis of the age-, sex-, and province-specific prevalence and YLDs of 33 provinces/regions in China, as well as their relationship with the sociodemographic index (SDI). Results: China has the largest numbers of people with LBP (91.3 million) and YLDs (8.6 million) globally, and LBP is the leading cause of YLDs. The age-standardised prevalence was 7.25% in 1990, and this decreased to 5.13% in 2019. The age-standardised YLD rate was 579/100 000 in 2019, having decreased by 28.97%. Both measurements increased with age, being higher in women and varying across the 33 provinces/regions. For the 5-to-14-year age group, the prevalence (4.50%) and YLD rate (4.51%) increased in 2019 from 1990 (3.21% and 3.21%, respectively) when compared to the elderly group. Age-standardised YLD rates experienced decreases with increasing SDI, while there was an increasing tendency as SDI increased further; the changes for women were more obvious. Conclusions: Over the three decades considered, China has continued to have the largest number of people with LBP in the world, even though the age-standardised prevalence has decreased. YLDs were found to decrease as SDI increased, but they subsequently increased again. LBP still presents a burden, particularly for children and postmenopausal women.

Anaerostipes hadrus, a butyrate-producing bacterium capable of metabolizing 5-fluorouracil.

Anaerostipes hadrus (A. hadrus) is a dominant species in the human gut microbiota and considered a beneficial bacterium for producing probiotic butyrate. However, recent studies have suggested that A. hadrus may negatively affect the host through synthesizing fatty acid and metabolizing the anticancer drug 5-fluorouracil, indicating that the impact of A. hadrus is complex and unclear. Therefore, comprehensive genomic studies on A. hadrus need to be performed. We integrated 527 high-quality public A. hadrus genomes and five distinct metagenomic cohorts. We analyzed these data using the approaches of comparative genomics, metagenomics, and protein structure prediction. We also performed validations with culture-based in vitro assays. We constructed the first large-scale pan-genome of A. hadrus (n = 527) and identified 5-fluorouracil metabolism genes as ubiquitous in A. hadrus genomes as butyrate-producing genes. Metagenomic analysis revealed the wide and stable distribution of A. hadrus in healthy individuals, patients with inflammatory bowel disease, and patients with colorectal cancer, with healthy individuals carrying more A. hadrus. The predicted high-quality protein structure indicated that A. hadrus might metabolize 5-fluorouracil by producing bacterial dihydropyrimidine dehydrogenase (encoded by the preTA operon). Through in vitro assays, we validated the short-chain fatty acid production and 5-fluorouracil metabolism abilities of A. hadrus. We observed for the first time that A. hadrus can convert 5-fluorouracil to α-fluoro-ß-ureidopropionic acid, which may result from the combined action of the preTA operon and adjacent hydA (encoding bacterial dihydropyrimidinase). Our results offer novel understandings of A. hadrus, exceptionally functional features, and potential applications. IMPORTANCE: This work provides new insights into the evolutionary relationships, functional characteristics, prevalence, and potential applications of Anaerostipes hadrus.

Pharmacokinetics, safety, and tolerability of the novel tetrameric gadolinium-based MRI contrast agent gadoquatrane in healthy Chinese and Japanese men: Two randomized dose-escalation studies including concentration-QTc modeling.

PURPOSE: To investigate the pharmacokinetics, safety, and tolerability of the novel tetrameric high-relaxivity gadolinium-based contrast agent gadoquatrane in Japanese (Study 1) and Chinese men (Study 2). PARTICIPANTS AND METHODS: In two similarly designed single-center, randomized, single-blind, placebo-controlled, consecutive-cohort dose-escalation studies, healthy volunteers were randomly assigned to intravenous administration of gadoquatrane (0.01-0.1 mmol gadolinium/kg body weight) or placebo. Study procedures included blood sampling and collection of urine for pharmacokinetic analyses and safety assessments. RESULTS: Twenty-five healthy Japanese men (mean age ± standard deviation: 26±5.9 years) and 23 healthy Chinese men (31±7.6 years old) were evaluated. In both studies, the pharmacokinetic profile of gadoquatrane was characterized by rapid distribution of the drug into the extracellular space and fast renal elimination. Postdose gadolinium concentrations rapidly declined with a geometric mean effective half-life of 1.3-1.4 h. The exposure increased approximately dose-proportionally with dose. The body weight-normalized volume of distribution was constant across dose levels (0.21-0.24 L/kg). Total recovery of gadolinium in urine amounted to 82-95 % (Study 1) and 96-99 % (Study 2) of the dose administered. Only a few mild, transient adverse events were reported, none of which gave rise to any safety concerns. Exploratory drug concentration-QTc modeling indicated no risk of a clinically relevant QT/QTc prolongation at the anticipated diagnostic dose. CONCLUSION: Gadoquatrane was safe and well tolerated at all doses tested. The pharmacokinetic profile was essentially the same as that of other extracellular macrocyclic gadolinium-based contrast agents and was consequentially also similar for Japanese and Chinese participants.

Evaluation of a new dynamic real-time visualization 25 kHz swept-source optical coherence tomography based biometer.

BACKGROUND: To evaluate the intraobserver repeatability and interobserver reproducibility of a newly developed dynamic real-time visualization 25 kHz swept-source optical coherence tomography (SS-OCT) based biometer (ZW-30, TowardPi Medical Technology Ltd, China) and compare its agreement with another SS-OCT based biometer (IOLMaster 700, Carl Zeiss Meditec AG, Jena, Germany). METHODS: Eighty-two healthy right eyes were enrolled in this prospective observational study. Measurements were repeated for three times using the ZW-30 and IOLMaster 700 in a random order. Obtained parameters included axial length (AL), central corneal thickness (CCT), aqueous depth (AQD), anterior chamber depth (ACD), lens thickness (LT), mean keratometry (Km), astigmatism magnitude (AST), vector J0, vector J45, and corneal diameter (CD). The within-subject standard deviation (Sw), test-retest (TRT) variability, coefficient of variation (CoV), and intraclass correlation coefficient (ICC) were adopted to assess the intraobserver repeatability and interobserver reproducibility. The double-angle plot was also used to display the distribution of AST. To estimate agreement, Bland-Altman plots were used. RESULTS: For the intraobserver repeatability and interobserver reproducibility, the Sw, TRT and CoV for all parameters were low. Meanwhile, the ICC values were all close to 1.000, except for the J45 (ICC = 0.887 for the intraobserver repeatability). The double-angle plot showed that the distribution of AST measured by these two devices was similar. For agreement, the Bland-Altman plots showed narrow 95% limits of agreements (LoAs) for AL, CCT, AQD, ACD, LT, Km AST, J0, J45, and CD (- 0.02 mm to 0.02 mm, - 7.49 µm to 8.08 µm, - 0.07 mm to 0.04 mm, - 0.07 mm to 0.04 mm, - 0.07 mm to 0.08 mm, - 0.16 D to 0.30 D, - 0.30 D to 0.29 D, - 0.16 D to 0.16 D, - 0.23 D to 0.13 D, and - 0.39 mm to 0.10 mm, respectively). CONCLUSIONS: The newly dynamic real-time visualization biometer exhibited excellent intraobserver repeatability and interobserver reproducibility. The two devices both based on the SS-OCT principle had similar ocular parameters measurement values and can be interchanged in clinical practice.

Pharmacokinetics, Pharmacodynamics, and Safety of Evocalcet (KHK7580), a Novel Calcimimetic Agent: An Open-Label, Single- and Multiple-Dose, Phase I Trial in Healthy Chinese Subjects.

Purpose: This study explored the pharmacokinetics (PK), pharmacodynamics (PD), and safety of evocalcet (KHK7580), a new calcimimetic agent, in healthy Chinese subjects following single and multiple doses. Methods: This was a single-center, open-label phase I trial conducted in China. The study started from the single-dose cohorts (1, 3, 6, 12 mg evocalcet, step-by-step administration) and proceeded to the multiple-dose cohort (6 mg evocalcet once daily for eight days). Blood and urine samples were collected at the designated time points for pharmacokinetic and pharmacodynamic analysis. Safety was evaluated by treatment-emergent adverse events (TEAEs), clinical laboratory tests, vital signs, electrocardiograms (ECGs), and ophthalmological examination. Results: Among 42 enrolled subjects, eight in each single-dose cohort and 10 in multiple-dose cohort, 40 subjects completed the study. In single-dose cohorts, tmax was 1.00-2.00 h and declined biphasically. The mean t1/2 was 15.99-20.84 h. Evocalcet exposure in AUC0-inf, AUC0-t, and Cmax showed a dose-proportional increase. In the multiple-dose cohort, tmax was 2.00 h and declined biphasically after multiple administrations. The accumulation was negligible. Ctrough levels were similar across days and steady from 24 hours after the first administration. The mean t1/2 was 15.59 h. PD analysis showed that evocalcet decreased intact parathyroid hormone and corrected calcium levels in a dose-dependent manner. Seventeen (40.5%) subjects reported TEAEs. No serious or severe TEAE occurred. Conclusion: In healthy Chinese subjects, evocalcet demonstrated dose-dependent PK and PD properties and was well-tolerated.

The Role of Oxidative Stress in Tumorigenesis and Progression.

Oxidative stress refers to the imbalance between the production of reactive oxygen species (ROS) and the endogenous antioxidant defense system. Its involvement in cell senescence, apoptosis, and series diseases has been demonstrated. Advances in carcinogenic research have revealed oxidative stress as a pivotal pathophysiological pathway in tumorigenesis and to be involved in lung cancer, glioma, hepatocellular carcinoma, leukemia, and so on. This review combs the effects of oxidative stress on tumorigenesis on each phase and cell fate determination, and three features are discussed. Oxidative stress takes part in the processes ranging from tumorigenesis to tumor death via series pathways and processes like mitochondrial stress, endoplasmic reticulum stress, and ferroptosis. It can affect cell fate by engaging in the complex relationships between senescence, death, and cancer. The influence of oxidative stress on tumorigenesis and progression is a multi-stage interlaced process that includes two aspects of promotion and inhibition, with mitochondria as the core of regulation. A deeper and more comprehensive understanding of the effects of oxidative stress on tumorigenesis is conducive to exploring more tumor therapies.

Enrichment of milk antioxidant activity by dietary supplementation of red clover isoflavone in cows and its improvement on mice intestinal health.

Red clover (Trifolium pratense) isoflavone was supplemented to dairy cows, and antioxidant capacity of milk was assessed. Treated cows increased the activities of antioxidant enzymes, reduced production of oxidation products, and enhanced the concentrations of vitamin E and vitamin C. Moreover, milk fatty acid profile was positive influenced by 8 g/kg red clover isoflavone, with changes in the lower saturated and higher unsaturated fatty acids. We further demonstrated the efficacy of antioxidant capacity of milk in mice, found that milk from cows feeding red clover isoflavone increased the expressions of antioxidant enzymes, and alleviated lipopolysaccharide (LPS)-stimulated tissue damage of duodenum and jejunum, which was related to upregulated metabolism pathways of carbohydrate, lipid, and amino acid, as well as downregulated inflammatory related pathways. Together, dietary supplementation of red clover isoflavone is an effective way to improve milk antioxidant capacity, providing a natural strategy for developing functional foods.

Enhancing anti-tumor potential: low-intensity vibration suppresses osteosarcoma progression and augments MSCs' tumor-suppressive abilities.

Rationale: Osteosarcoma (OS), a common malignant bone tumor, calls for the investigation of novel treatment strategies. Low-intensity vibration (LIV) presents itself as a promising option, given its potential to enhance bone health and decrease cancer susceptibility. This research delves into the effects of LIV on OS cells and mesenchymal stem cells (MSCs), with a primary focus on generating induced tumor-suppressing cells (iTSCs) and tumor-suppressive conditioned medium (CM). Methods: To ascertain the influence of vibration frequency, we employed numerical simulations and conducted experiments to determine the most effective LIV conditions. Subsequently, we generated iTSCs and CM through LIV exposure and assessed the impact of CM on OS cells. We also explored the underlying mechanisms of the tumor-suppressive effects of LIV-treated MSC CM, with a specific focus on vinculin (VCL). We employed cytokine array, RNA sequencing, and Western blot techniques to investigate alterations in cytokine profiles, transcriptomes, and tumor suppressor proteins. Results: Numerical simulations validated LIV frequencies within the 10-100 Hz range. LIV induced notable morphological changes in OS cells and MSCs, confirming its dual role in inhibiting OS cell progression and promoting MSC conversion into iTSCs. Upregulated VCL expression enhanced MSC responsiveness to LIV, significantly bolstering CM's efficacy. Notably, we identified tumor suppressor proteins in LIV-treated CM, including procollagen C endopeptidase enhancer (PCOLCE), histone H4 (H4), peptidylprolyl isomerase B (PPIB), and aldolase A (ALDOA). Consistently, cytokine levels decreased significantly in LIV-treated mouse femurs, and oncogenic transcript levels were downregulated in LIV-treated OS cells. Moreover, our study demonstrated that combining LIV-treated MSC CM with chemotherapy drugs yielded additive anti-tumor effects. Conclusions: LIV effectively impeded the progression of OS cells and facilitated the transformation of MSCs into iTSCs. Notably, iTSC-derived CM demonstrated robust anti-tumor properties and the augmentation of MSC responsiveness to LIV via VCL. Furthermore, the enrichment of tumor suppressor proteins within LIV-treated MSC CM and the reduction of cytokines within LIV-treated isolated bone underscore the pivotal tumor-suppressive role of LIV within the bone tumor microenvironment.