UBA2 SUMOylates NQO1 and promotes the proliferation of hepatocellular carcinoma by modulating the MAPK pathway.

In our previous study, we found that small ubiquitin-related modifier (SUMO)-activating enzyme ubiquitin-associated-2 domain (UBA2) was upregulated in hepatocellular carcinoma (HCC) patients who were insensitive to chemoembolization. In this study, we aimed to investigate the role of UBA2 in HCC progression. Three cohorts were used to evaluate the efficacy of UBA2 as a prognostic factor for HCC. Our results indicated that UBA2 was associated with aggressive clinical behaviors and was a strong indicator of poor prognosis in HCC. In vitro experiments demonstrated that UBA2 accelerated cell growth, invasion, and migration. These results were further supported by in vivo experiments. RNA-sequencing analysis indicated NQO1 as a target of UBA2, with its levels altering following UBA2 manipulation. The results were verified by western blotting (WB) and quantitative PCR. The SUMOplot Analysis Program predicted lysine residue K240 as a modification target of UBA2, which was confirmed by immunoprecipitation (IP) assays. Subsequent mutation of NQO1 at K240 in HCC cell lines and functional assays revealed the significance of this modification. In addition, the oncogenic effect of UBA2 could be reversed by the SUMO inhibitor ML792 in vivo and in vitro. In conclusion, our study elucidated the regulatory mechanism of UBA2 in HCC and suggested that the SUMO inhibitor ML792 may be an effective combinatory treatment for patients with aberrant UBA2 expression.

Low-Pressure Pancake Bouncing on Superhydrophobic Surfaces.

A new form of pancake bouncing is discovered in this work when a droplet impacts onto micro-structured superhydrophobic surfaces in an environment pressure less than 2 kPa, and an unprecedented reduction of contact time by ≈85% is obtained. The mechanisms of forming this unique phenomenon are examined by combining experimental observation, numeical modelling and an improved theoretical model for the overpressure effect arising from the vaporisation inside micro-scaled structures. The competition among the vapor overpressure effect, the droplet impact force, and the surface adhesion determines if the pancake bouncing behavior could occur. After the lift-off the lamella, the pancake bouncing is initiated and its subsequent dynamics is controlled by the internal momentum transfer. Complementary to the prior studies, this work enriches the knowledge of droplet dynamics in low pressure, which allows new strategies of surface morphology engineering for droplet control, an area of high importance for many engineering applications.

Effect of Hyperthermal Hybrid Gas Composition on the Interfacial Oxidation and Nitridation Mechanisms of Graphene Sheet.

Graphene is one of the most promising thermal protection materials for high-speed aircraft due to its lightweight and excellent thermophysical properties. At high Mach numbers, the extremely high postshock temperature would dissociate the surrounding air into a mixture of atomic and molecular components in a highly thermochemical nonequilibrium state, which greatly affects the subsequent thermal chemical reactions of the graphene interface. Through establishing a reactive gas-solid interface model, the reactive molecular dynamics method is employed in this study to reveal the influences of the thermochemical nonequilibrium gas mixture on the thermal oxidation and nitridation mechanisms of graphene sheet. The results show that three distinctive stages can be recognized during bombardment of various nonequilibrium gas components toward the graphene sheet: (i) collision and surface adsorption stage, (ii) gas-solid heterogeneous reaction stage, and (iii) gas phase homogeneous reaction stage. The surface catalysis effect is found to be dominant during the first two stages, which can influence the following ablation behavior of graphene significantly at high-temperature conditions. Moreover, surface catalysis, oxidation, nitridation, and ablation mechanisms between nonequilibrium gas and graphene interface are revealed, which is of high relevance for future interfacial design and application of graphene as a thermal protection material.

Control of Polarity in Kagome-NiAs Bismuthides.

A 2×2×1 superstructure of the P63/mmc NiAs structure is reported in which kagome nets are stabilized in the octahedral transition metal layers of the compounds Ni0.7Pd0.2Bi, Ni0.6Pt0.4Bi, and Mn0.99Pd0.01Bi. The ordered vacancies that yield the true hexagonal kagome motif lead to filling of trigonal bipyramidal interstitial sites with the transition metal in this family of "kagome-NiAs" type materials. Further ordering of vacancies within these interstitial layers can be compositionally driven to simultaneously yield kagome-connected layers and a net polarization along the c axes in Ni0.9Bi and Ni0.79Pd0.08Bi, which adopt Fmm2 symmetry. The polar and non-polar materials exhibit different electronic transport behaviour, reflecting the tuneability of both structure and properties within the NiAs-type bismuthide materials family.

Epigenetics as a versatile regulator of fibrosis.

Fibrosis, a process caused by excessive deposition of extracellular matrix (ECM), is a common cause and outcome of organ failure and even death. Researchers have made many efforts to understand the mechanism of fibrogenesis and to develop therapeutic strategies; yet, the outcome remains unsatisfactory. In recent years, advances in epigenetics, including chromatin remodeling, histone modification, DNA methylation, and noncoding RNA (ncRNA), have provided more insights into the fibrotic process and have suggested the possibility of novel therapy for organ fibrosis. In this review, we summarize the current research on the epigenetic mechanisms involved in organ fibrosis and their possible clinical applications.

Fe-Ni/MWCNTs Nano-Composites for Hexavalent Chromium Reduction in Aqueous Environment.

A novel Cr (VI) removal material was designed and produced comprising multi-walled carbon nanotubes (MWCNTs) as a support with a high specific surface area and the loaded Fe-Ni bimetallic particles as catalytic reducing agents. Such a design permits the composite particle to perform the adsorption, reduction, and immobilisation of Cr (VI) quickly and efficiently. Due to MWCNTs' physical adsorption, Cr (VI) in solution aggregates in the vicinity of the composite, and Fe rapidly reduces Cr (VI) to Cr (III) catalysed by Ni. The results demonstrated that the Fe-Ni/MWCNTs exhibits an adsorption capacity of 207 mg/g at pH = 6.4 for Cr (VI) and 256 mg/g at pH 4.8, which is about twice those reported for other materials under similar conditions. The formed Cr (III) is solidified to the surface by MWCNTs and remains stable for several months without secondary contamination. The reusability of the composites was proven by retaining at least 90% of the adsorption capacity for five instances of reutilization. Considering the facile synthesis process, low cost of raw material, and reusability of the formed Fe-Ni/MWCNTs, this work shows great potential for industrialisation.

LRG-1 promotes fat graft survival through the RAB31-mediated inhibition of hypoxia-induced apoptosis.

Autologous adipose tissue is an ideal soft tissue filling material, and its biocompatibility is better than that of artificial tissue substitutes, foreign bodies and heterogeneous materials. Although autologous fat transplantation has many advantages, the low retention rate of adipose tissue limits its clinical application. Here, we identified a secretory glycoprotein, leucine-rich-alpha-2-glycoprotein 1 (LRG-1), that could promote fat graft survival through RAB31-mediated inhibition of hypoxia-induced apoptosis. We showed that LRG-1 injection significantly increased the maintenance of fat volume and weight compared with the control. In addition, higher fat integrity, more viable adipocytes and fewer apoptotic cells were observed in the LRG-1-treated groups. Furthermore, we discovered that LRG-1 could reduce the ADSC apoptosis induced by hypoxic conditions. The mechanism underlying the LRG-1-mediated suppression of the ADSC apoptosis induced by hypoxia was mediated by the upregulation of RAB31 expression. Using LRG-1 for fat grafts may prove to be clinically successful for increasing the retention rate of transplanted fat.

One day versus two days of hepatic arterial infusion with oxaliplatin and fluorouracil for patients with unresectable hepatocellular carcinoma.

BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin and 5-fluorouracil was effective in unresectable hepatocellular carcinoma (HCC). The program of FOLFOX-HAIC in HCC was performed for 1 day (HAIC 1d) or 2 days (HAIC 2d). We hereby retrospectively compared the efficacy and safety between these two treatment regimens and explored the predictive power of thymidylate synthase (TYMS), an enzyme involved in the DNA synthesis process and metabolism of fluorouracil. METHODS: This study included patients with a primary diagnosis of unresectable HCC. These patients received HAIC for 1 day or 2 days. The overall survival (OS), progression-free survival (PFS), tumor response, and adverse events were compared. The propensity score matching (PSM) was used to reduce bias. Peripheral blood samples before the treatments were collected and used to measure the concentration of TYMS through enzyme-linked immunosorbent assay (ELISA). ELISA was performed according to the manufacturers' guidelines. RESULTS: We included 368 patients for this study: 248 in the HAIC 1d group and 120 in the HAIC 2d group. There was no significant difference of OS between the two groups (14.5 for HAIC 1d vs 15.3 months for HAIC 2d, p=0.46). Compared with the HAIC 1d group, the HAIC 2d group did not prolong the PFS (7.3 vs 7.5 months, p=0.91) or elevate the tumor response (42.5% vs 39.1%, p=0.53) per RECIST 1.1. In the PSM cohort, the efficacy between the two groups was similar. The total frequencies of grade 3-4 events were higher with the HAIC 2d group than with the HAIC 1d group, especially in the PSM cohort (p=0.043). Additionally, patients with TYMS low level might benefit longer OS from the HAIC 2d group (18.7 vs 13.6 months, p=0.014). CONCLUSIONS: There was not much of a difference in efficacy between the two groups, but the HAIC for 1 day might be safer, which needed further research. The level of TYMS might be the predictive biomarkers.

A novel qualitative signature based on lncRNA pairs for prognosis prediction in hepatocellular carcinoma.

BACKGROUND: Prognostic assessment is imperative for clinical management of patients with hepatocellular carcinoma (HCC). Most reported prognostic signatures are based on risk scores summarized from quantitative expression level of candidate genes, which are vulnerable against experimental batch effects and impractical for clinical application. We aimed to develop a robust qualitative signature to assess individual survival risk for HCC patients. METHODS: Long non-coding RNA (lncRNA) pairs correlated with overall survival (OS) were identified and an optimal combination of lncRNA pairs based on the majority voting rule was selected as a classification signature to predict the overall survival risk in the cancer genome atlas (TCGA). Then, the signature was further validated in two external datasets. Besides, biomolecular characteristics, immune infiltration status, and chemotherapeutics efficacy of different risk groups were further compared. Finally, we performed key lncRNA screening and validated it in vitro. RESULTS: A signature consisting of 50 lncRNA pairs (50-LPS) was identified in TCGA and successfully validated in external datasets. Patients in the high-risk group, when at least 25 of the 50-LPS voted for high risk, had significantly worse OS than the low-risk group. Multivariate Cox, receiver operating characteristic (ROC) curve and decision curve analyses (DCA) demonstrated that the 50-LPS was an independent prognostic factor and more powerful than other available clinical factors in OS prediction. Comparison analyses indicated that different risk groups had distinct biomolecular characteristics, immune infiltration status, and chemotherapeutics efficacy. TDRKH-AS1 was confirmed as a key lncRNA and associated with cell growth of HCC. CONCLUSIONS: The 50-LPS could not only predict the prognosis of HCC patients robustly and individually, but also provide theoretical basis for therapy. Besides, TDRKH-AS1 was identified as a key lncRNA in the proliferation of HCC. The 50-LPS might guide personalized therapy for HCC patients in clinical practice.

Large-Scale Dewetting via Surfactant-Laden Droplet Impact.

The dewetting phenomenon of a liquid film in the presence of a surfactant exists in various natural, industrial, and biomedical processes but still remains mysterious in some specific scenarios. Here, we investigate the dewetting behavior of water films initiated by surfactant-laden droplet impact and show that the maximum dewetting diameter can even reach more than 50 times that of the droplet size. We identify the S-type variation of the dewetting area and demonstrate its correlation to the dynamic surface tension reduction. From a viewpoint of energy conversion, we attribute the dewetting to the released surface energy caused by the surfactant addition and establish a linear relation between the maximum dewetting and the surfactant concentration in the film, i.e., dmax2 ∝ cfilm, which agrees well with the experiments. These results may advance the physics of liquid film dewetting triggered by surfactant injection, which shall further guide practical applications.

Departure Velocity of Rolling Droplet Jumping.

Droplet jumping phenomenon widely exists in the fields of self-cleaning, antifrosting, and heat transfer enhancement. Numerous studies have been reported on the static droplet jumping while the rolling droplet jumping still remains unnoticed even though it is very common in practice. Here, we used the volume of fluid (VOF) method to simulate the droplet jumping induced by coalescence of a rolling droplet and a stationary one with corresponding experiments conducted to validate the correctness of the simulation model. The departure velocity of the jumping droplet was the main concerned here. The results show that when the center velocity of the rolling droplet (V0 = ωR, where ω is the angular velocity of the rolling droplet and R is the droplet radius) is fixed, the vertical departure velocity satisfies a power law which can be expressed as Vz,depar = aRb. When the droplet radius is fixed, the vertical departure velocity first decreases and then increases if the center velocity exceeds a critical value. Interestingly, the critical center velocity is demonstrated to be approximately 0.76 times the capillary-inertial velocity, corresponding to a constant Weber number of 0.58. Different from the vertical departure velocity, the horizontal departure velocity is basically proportional to the center velocity of the rolling droplet. These results deepen the understanding of the droplet jumping physics, which shall further promote related applications in engineering fields.

Directional Transportation of Impacting Droplets on Wettability-Controlled Surfaces.

Although a superhydrophobic surface could realize rapid rebounding (i.e., short contact time) of an orthogonal impacting droplet, the rebounding along the original impacting route may limit its engineering application; in contrast, the directional transportation seems to be more promising. Here, we achieve directional transportation of a droplet impacting a wettability-controlled surface. When the droplet eccentrically impacts on the boundary between the superhydrophobic part and the hydrophilic part, it undergoes spreading, retracting, departure, throwing, and breaking up stages, and finally bounces off directionally. The directional transportation distance could even reach more than ten times the droplet size, considered the adhesion length (i.e., covering length on the hydrophilic part by the droplet at the maximum spreading) is optimized. However, there is a critical adhesion length, above which the directional transportation does not occur. To be more generalized, the adhesion length is de-dimensionalized by the maximum spreading radius, and the results show that as the dimensionless adhesion length increases, the transportation distance first increases and then decreases to zero. Under the present impacting conditions, the optimal dimensionless adhesion length corresponding to the maximum transportation distance is near 0.4, and the critical dimensionless adhesion length is about 0.7. These results provide a fundamental understanding of droplet directional transportation and could be useful for related engineering applications.

Kinetic Study of Controlled Asphaltene Inhibitor Release from Nanoemulsions.

Asphaltene aggregation and subsequent precipitation in the nonpolar medium may have a profound effect on plugging wellbores and production equipment. Continuing our work on controlled release of asphaltene inhibitor (AI) by using nanoemulsions (NEs), this work provides new evidence about long-term asphaltene stability by using optical measurement and reveals the kinetic processes of inhibitor transport/release mechanisms. Multiple light scattering (Turbiscan) and dynamic light scattering have been used to study "in situ" the effectiveness and performance of the proposed controlled release in three cases of asphaltene aggregation/precipitation in the presence of: (i) strong organic acids (dodecyl benzene sulfonic acid, DBSA), (ii) NEs (blank NEs), and (iii) NEs loaded with DBSA (DBSA NEs). The results suggested that the new approach reduced the amount of AI by ∼20 times and achieved high asphaltene inhibition efficiency of ∼84% with a prolonged release time. A mechanistic understanding of the controlled release effect was proposed based on the effect of DBSA NEs on the asphaltene particle morphology variation, which was related to the hydrophilicity of DBSA and the strong intermolecular interactions among all DBSA NE components. The release mechanism of the AI from the NE was evaluated using eight release models and was found to follow the Korsmeyer-Peppas kinetic model.

Nanoparticle Assisted EOR during Sand-Pack Flooding: Electrical Tomography to Assess Flow Dynamics and Oil Recovery.

Silica nanoparticles have been shown to exhibit many characteristics that allow for additional oil to be recovered during sand-pack flooding experiments. Additionally various imaging techniques have been employed in the past to visually compare flooding procedures including x-ray computed tomography and magnetic resonance imaging; however, these techniques require the sample to be destroyed or sliced after the flooding experiment finishes. Electrical resistance tomography (ERT) overcomes these limitations by offering a non-destructive visualization method allowing for online images to be taken during the flooding process by the determination of spatial distribution of electrical resistivity, thus making it suitable for sand-packs. During the scope of this research a new sand-pack system and methodology was created which utilized ERT as a monitoring tool. Two concentrations, 0.5 wt% and 1.0 wt%, of SiO2 nanoparticles were compared with runs using only brine to compare the recovery efficiency and explore the ability of ERT to monitor the flooding process. Electrical resistance tomography was found to be an effective tool in monitoring local recovery efficiency revealing 1.0 wt% SiO2 to be more effective than 0.5 wt% and brine only runs during the scope of this research. A new method involving the slope function in excel was used to compare the effects of nanofluids on resistivity trends also revealing information about the rate of recovery against time. SiO2 nanofluid recovery mechanisms such interfacial tension reduction and viscosity enhancement were then considered to explain why the nanofluids resulted in greater oil recovery.

Frost Self-Removal Mechanism during Defrosting on Vertical Superhydrophobic Surfaces: Peeling Off or Jumping Off.

Although a superhydrophobic surface has great potential to delay frosting, it tends to become frosted under humid conditions and needs to defrost periodically. So far, the exact mechanism of defrosting still remains unclear. Here, we investigate the frost self-removal mechanism during defrosting on vertical superhydrophobic surfaces. Two self-removal modes are observed: peeling off and jumping off. When the frost thickness is larger than a threshold value, peeling off mode occurs; otherwise, jumping off mode takes place. Compared with the peeling off mode, the jumping off mode is less effective in self-removing frost as jumping is limited by energy transformation. A theoretical model based on frost melting-water permeation mechanism is proposed to determine the threshold value of frost thickness. According to this model, the threshold value of the frost thickness is dependent on the frost porosity and the surface temperature (or heat flux). For our particular experiments, the threshold value of the frost thickness predicted by the proposed model agrees well with our experimental results. Our work may advance the defrosting applications of superhydrophobic surfaces in related engineering fields.

Stability and Aggregation Kinetics of Titania Nanomaterials under Environmentally Realistic Conditions.

Nanoparticle morphology is expected to play a significant role in the stability, aggregation behavior, and ultimate fate of engineered nanomaterials in natural aquatic environments. The aggregation kinetics of ellipsoidal and spherical titanium dioxide (TiO2) nanoparticles (NPs) under different surfactant loadings, pH values, and ionic strengths were investigated in this study. The stability results revealed that alteration of surface charge was the stability determining factor. Among five different surfactants investigated, sodium citrate and Suwannee river fulvic acid (SRFA) were the most effective stabilizers. It was observed that both types of NPs were more stable in monovalent salts (NaCl and NaNO3) as compared with divalent salts (Ca(NO3)2 and CaCl2). The aggregation of spherical TiO2 NPs demonstrated a strong dependency on the ionic strength regardless of the presence of mono or divalent salts; while the ellipsoids exhibited a lower dependency on the ionic strength but was more stable. This work acts as a benchmark study toward understanding the ultimate fate of stabilized NPs in natural environments that are rich in Ca(CO3)2, NaNO3, NaCl, and CaCl2 along with natural organic matters.

Clinical and biomarker analyses of hepatic arterial infusion chemotherapy plus lenvatinib and PD-1 inhibitor for patients with advanced intrahepatic cholangiocarcinoma.

Background: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with a dismal prognosis and few effective therapeutic approaches. This study aimed to investigate the efficacy, safety, and predictive biomarkers of hepatic arterial infusion chemotherapy (FOLFOX-HAIC) in combination with lenvatinib and PD-1 inhibitor for patients with advanced iCCA. Methods: Locally advanced or metastatic iCCA patients receiving the triple combination therapy of lenvatinib, PD-1 inhibitor, and FOLFOX-HAIC were included in this retrospective study. Primary endpoint was the progression-free survival, evaluated using the RECIST criterion. The secondary endpoints included overall survival, objective response rate, and safety. Whole exome and RNA sequencing of tumor biopsy tissues were performed for biomarker exploration. Results: Between May, 2019 and December 2022, a total of 46 patients were included in this study. The primary endpoint showed a median progression-free survival of 9.40 months (95% CI: 5.28-13.52), with a 6-month progression-free survival rate of 76.1%. The median overall survival was 16.77 months (95% CI, 14.20-19.33), with an objective response rate of 47.8% and disease control rate of 91.3% per RECIST. In addition, 4.3% and 8.7% of patients achieved complete response of all lesions and intrahepatic target lesions per mRECIST, respectively. The most common treatment-related adverse events were neutropenia, thrombocytopenia, elevated aspartate aminotransferase and alanine aminotransferase level. Furthermore, integrated analysis of genetic, transcriptomic, and immunohistochemistry data revealed that pre-existing immunity (high expression level of immune-related signatures and intra-tumoral CD8+ T cell density) in baseline tumor tissues was associated with superior clinical benefits. However, the evaluation of tumor mutation burden did not show potential predictive value in this triple combination. Conclusion: FOLFOX-HAIC in combination with lenvatinib and PD-1 inhibitor demonstrated a promising antitumor activity with manageable safety profiles in patients with advanced iCCA. Moreover, our study also revealed new perspectives on potential biomarkers for clinical efficacy.

Mechanisms and translational applications of regeneration in limbs: From renewable animals to humans.

BACKGROUND: The regenerative capacity of organisms declines throughout evolution, and mammals lack the ability to regenerate limbs after injury. Past approaches to achieving successful restoration through pharmacological intervention, tissue engineering, and cell therapies have faced significant challenges. OBJECTIVES: This review aims to provide an overview of the current understanding of the mechanisms behind animal limb regeneration and the successful translation of these mechanisms for human tissue regeneration. RESULTS: Particular attention was paid to the Mexican axolotl (Ambystoma mexicanum), the only adult tetrapod capable of limb regeneration. We will explore fundamental questions surrounding limb regeneration, such as how amputation initiates regeneration, how the limb knows when to stop and which parts to regenerate, and how these findings can apply to mammalian systems. CONCLUSIONS: Given the urgent need for regenerative therapies to treat conditions like diabetic foot ulcers and trauma survivors, this review provides valuable insights and ideas for researchers, clinicians, and biomedical engineers seeking to facilitate the regeneration process or elicit full regeneration from partial regeneration events.

Betaine delays age-related muscle loss by mitigating Mss51-induced impairment in mitochondrial respiration via Yin Yang1.

BACKGROUND: Mitochondrial dysfunction is one of the hallmarks of aging and a leading contributor to sarcopenia. Nutrients are essential for improving mitochondrial function and skeletal muscle health during the aging process. Betaine is a nutrient with potential muscle-preserving properties. However, whether and how betaine could regulate the mitochondria function in aging muscle are poorly understood. We aimed to explore the molecular target and underlying mechanism of betaine in attenuating the age-related mitochondrial dysfunction in skeletal muscle. METHODS: Young mice (YOU, 2 months), old mice (OLD, 15 months), and old mice with betaine treatment (BET, 15 months) were fed for 12 weeks. The effects of betaine on muscle mass, strength, function, and subcellular structure of muscle fibres were assessed. RNA sequencing (RNA-seq) was conducted to identify the molecular target of betaine. The impacts of betaine on mitochondrial-related molecules, superoxide accumulation, and oxidative respiration were examined using western blotting (WB), immunofluorescence (IF) and seahorse assay. The underlying mechanism of betaine regulation on the molecular target to maintain mitochondrial function was investigated by luciferase reporter assay, chromatin immunoprecipitation and electrophoretic mobility shift assay. Adenoassociated virus transfection, succinate dehydrogenase staining (SDH), and energy expenditure assessment were performed on 20-month-old mice for validating the mechanism in vivo. RESULTS: Betaine intervention demonstrated anti-aging effects on the muscle mass (P = 0.017), strength (P = 0.010), and running distance (P = 0.013). Mitochondrial-related markers (ATP5a, Sdha, and Uqcrc2) were 1.1- to 1.5-fold higher in BET than OLD (all P ≤ 0.036) with less wasted mitochondrial vacuoles accumulating in sarcomere. Bioinformatic analysis from RNA-seq displayed pathways related to mitochondrial respiration activity was higher enriched in BET group (NES = -0.87, FDR = 0.10). The quantitative real time PCR (qRT-PCR) revealed betaine significantly reduced the expression of a novel mitochondrial regulator, Mss51 (-24.9%, P = 0.002). In C2C12 cells, betaine restored the Mss51-mediated suppression in mitochondrial respiration proteins (all P ≤ 0.041), attenuated oxygen consumption impairment, and superoxide accumulation (by 20.7%, P = 0.001). Mechanically, betaine attenuated aging-induced repression in Yy1 mRNA expression (BET vs. OLD: 2.06 vs. 1.02, P = 0.009). Yy1 transcriptionally suppressed Mss51 mRNA expression both in vitro and in vivo. This contributed to the preservation of mitochondrial respiration, improvement for energy expenditure (P = 0.008), and delay of muscle loss during aging process. CONCLUSIONS: Altogether, betaine transcriptionally represses Mss51 via Yy1, improving age-related mitochondrial respiration in skeletal muscle. These findings suggest betaine holds promise as a dietary supplement to delay skeletal muscle degeneration and improve age-related mitochondrial diseases.

Topical Application of TT-10 Ameliorates Impaired Wound Healing.

BACKGROUND: In recent decades, chronic wounds have become an increasingly significant clinical concern due to their increasing morbidity and socioeconomic toll. However, there is currently no product available on the market that specifically targets this intricate process. One clear indicator of delayed wound repair is the inhibition of re-epithelialization. Yes-associated protein (YAP), which is a potential focal point for tissue repair and regeneration, has been shown to be prominent in several studies. In this context, we have identified the pharmacological product TT-10, which is a YAP activator, as a potential candidate for the treatment of various forms of chronic wounds. METHODS: The role of TT-10 in regulating YAP activity and subcellular localization was determined by western blotting and immunofluorescence staining. The effect of TT-10 on the biological functions of keratinocytes was assessed by proliferation, wound healing, and apoptosis assays. The impairment of YAP activity in chronic wounds was measured in human and mouse tissues. The in vivo efficacy of TT-10 was examined by gross examination, H&E staining, and measuring wound areas and gaps in normal, diabetic, and ischemic wounds. RESULTS: Our findings suggest that TT-10 facilitates the nuclear transport of YAP, consequently increasing YAP activity, which in turn increases the proliferation and migration of keratinocytes. Moreover, we showed that intracutaneous injection of TT-10 along the wound periphery promoted re-epithelization via YAP activation in the epidermis, culminating in accelerated wound closure in several chronic wound healing models. CONCLUSIONS: Our research highlights the potential of TT-10 to treat chronic wounds, which is a persistent challenge in tissue repair.