Drosophila models used to simulate human ATP1A1 gene mutations that cause Charcot-Marie-Tooth type 2 disease and refractory seizures.

JOURNAL/nrgr/04.03/01300535-202501000-00034/figure1/v/2024-05-14T021156Z/r/image-tiff Certain amino acids changes in the human Na+/K+-ATPase pump, ATPase Na+/K+ transporting subunit alpha 1 (ATP1A1), cause Charcot-Marie-Tooth disease type 2 (CMT2) disease and refractory seizures. To develop in vivo models to study the role of Na+/K+-ATPase in these diseases, we modified the Drosophila gene homolog, Atpα, to mimic the human ATP1A1 gene mutations that cause CMT2. Mutations located within the helical linker region of human ATP1A1 (I592T, A597T, P600T, and D601F) were simultaneously introduced into endogenous DrosophilaAtpα by CRISPR/Cas9-mediated genome editing, generating the AtpαTTTF model. In addition, the same strategy was used to generate the corresponding single point mutations in flies (AtpαI571T, AtpαA576T, AtpαP579T, and AtpαD580F). Moreover, a deletion mutation (Atpαmut) that causes premature termination of translation was generated as a positive control. Of these alleles, we found two that could be maintained as homozygotes (AtpαI571T and AtpαP579T). Three alleles (AtpαA576T, AtpαP579 and AtpαD580F) can form heterozygotes with the Atpαmut allele. We found that the Atpα allele carrying these CMT2-associated mutations showed differential phenotypes in Drosophila. Flies heterozygous for AtpαTTTF mutations have motor performance defects, a reduced lifespan, seizures, and an abnormal neuronal morphology. These Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump.

Ineffective Learning Behaviors and Their Psychological Mechanisms among Adolescents in Online Learning: A Narrative Review.

During the COVID-19 pandemic, many countries and regions experienced a surge in online learning, but the public complained about and questioned its effectiveness. One of the most important reasons for this was the inadequate metacognitive abilities of adolescents. Studies in learning sciences have identified various inefficient learning behaviors among students in online learning, including help abuse, help avoidance, and wheel spinning; all closely related to metacognition. Despite concerns about ecological validity, researchers in psychology have proposed the agenda-based regulation framework, the COPES model, and MAPS model, which may help explain the inefficient learning behaviors among adolescents in online learning. Future studies should aim to verify these theoretical frameworks within the context of online learning and elucidate the causes of inefficient learning behaviors; the design and optimization of online learning systems should be informed by theories in cognitive psychology.

The novel lnc-HZ12 suppresses autophagy degradation of BBC3 by preventing its interactions with HSPA8 to induce trophoblast cell apoptosis.

Abnormal expression of long non-coding RNAs (lncRNAs) is associated with the dysfunctions of human trophoblast cells and the occurrence of miscarriage (abnormal early embryo loss). BBC3/PUMA (BCL2 binding component 3) plays significant roles in regulation of cell apoptosis. However, whether specific lncRNAs might regulate BBC3 in trophoblast cells and further induce apoptosis and miscarriage remains completely unclear. Through screening, we identified a novel lnc-HZ12, which was significantly highly expressed in villous tissues of recurrent miscarriage (RM) patients relative to their healthy control (HC) group. Lnc-HZ12 suppressed chaperone-mediated autophagy (CMA) degradation of BBC3, promoted trophoblast cell apoptosis, and was associated with miscarriage. In mechanism, lnc-HZ12 downregulated the expression levels of chaperone molecules HSPA8 and LAMP2A in trophoblast cells. Meanwhile, lnc-HZ12 (mainly lnc-HZ12-SO2 region in F2 fragment) and HSPA8 competitively bound with the 169RVLYNL174 patch on BBC3, which prevented BBC3 from interactions with HSPA8 and impaired the formation of BBC3-HSPA8-LAMP2A complex for CMA degradation of BBC3. Thus, lnc-HZ12 upregulated the BBC3-CASP9-CASP3 pathway and induced trophoblast cell apoptosis. In villous tissues, lnc-HZ12 was highly expressed, CMA degradation of BBC3 was suppressed, and the apoptosis levels were higher in RM vs HC villous tissues, all of which were associated with miscarriage. Interestingly, knockdown of murine Bbc3 could efficiently suppress placental apoptosis and alleviate miscarriage in a mouse miscarriage model. Taken together, our results indicated that lnc-HZ12 and BBC3 played important roles in trophoblast cell apoptosis and miscarriage and might act as attractive targets for miscarriage treatment.Abbreviation: 7-AAD: 7-aminoactinomycin D; BaP: benzopyrene; BBC3/PUMA: BCL2 binding component 3; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CQ: chloroquine; DMSO: dimethyl sulfoxide; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HC: healthy control; HSPA8: heat shock protein family A (Hsp70) member 8; IP: immunoprecipitation; LAMP2A: lysosomal associated membrane protein 2; LncRNA: long non-coding RNA; mRNA: messenger RNA; MT: mutant-type; NC: negative control; NSO: nonspecific oligonucleotide; PARP1: poly(ADP-ribose) polymerase 1; RIP: RNA immunoprecipitation; RM: recurrent miscarriage; TBP: TATA-box binding protein; WT: wild-type.

Txnrd2 Attenuates Early Brain Injury by Inhibition of Oxidative Stress and Endoplasmic Reticulum Stress via Trx2/Prx3 Pathway after Intracerebral Hemorrhage in Rats.

Thioredoxin-reductase 2 (Txnrd2) belongs to the thioredoxin-reductase family of selenoproteins and is a key antioxidant enzyme in mammalian cells to regulate redox homeostasis. Here, we reported that Txnrd2 exerted a major influence in brain damage caused by Intracerebral hemorrhage (ICH) by suppressing endoplasmic reticulum (ER) stress oxidative stress and via Trx2/Prx3 pathway. Furthermore, we demonstrated that pharmacological selenium (Se) rescued the brain damage after ICH by enhancing Txnrd2 expression. Primarily, expression and localization of Txnrd2, Trx2 and Prx3 were determined in collagenase IV-induced ICH model. Txnrd2 was then knocked down using siRNA interference in rats which were found to develop more severe encephaledema and neurological deficits. Mechanistically, we observed that loss of Txnrd2 leads to increased lipid peroxidation levels and ER stress protein expression in neurons and astrocytes. Additionally, it was revealed that Se effectively restored the expression of Txnrd2 in brain and inhibited both the activity of ER stress protein activity and the generation of reactive oxygen species (ROS) by promoting Trx2/Prx3 kilter when administrating sodium selenite in lateral ventricle. This study shed light on the effect of Txnrd2 in regulating oxidative stress and ER stress via Trx2/Prx3 pathway upon ICH and its promising potential as an ICH therapeutic target.

Association of sleep traits with myopia in children and adolescents: A meta-analysis and Mendelian randomization study.

PURPOSE: The association between sleep and myopia in children and adolescents has been reported, yet it remains controversial and inconclusive. This study aimed to investigate the influence of different sleep traits on the risk of myopia using meta-analytical and Mendelian randomization (MR) techniques. METHODS: The literature search was performed in August 31, 2023 based on PubMed, Embase, Web of Science, and Cochrane library. The meta-analysis of observational studies reporting the relationship between sleep and myopia was conducted. MR analyses were carried out to assess the causal impact of genetic pre-disposition for sleep traits on myopia. RESULTS: The results of the meta-analysis indicated a significant association between the risk of myopia and both short sleep duration [odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.08-1.42, P = 0.003] and long sleep duration (OR = 0.75, 95% CI = 0.66-0.86, P < 0.001). MR analyses revealed no significant causal associations of genetically determined sleep traits with myopia, including chronotype, sleep duration, short sleep duration and long sleep duration (all P > 0.05). CONCLUSIONS: No evidence was found to support a causal relationship between sleep traits and myopia. While sleep may not independently predict the risk of myopia, the potential impact of sleep on the occurrence and development of myopia cannot be disregarded.

A Drosophila Model Reveals the Potential Role for mtt in Retinal Disease.

Congenital stationary night blindness (CSNB) is a genetically heterogeneous inherited retinal disorder, caused by over 300 mutations in 17 different genes. While there are numerous fly models available for simulating ocular diseases, most are focused on mimicking retinitis pigmentosa (RP), with animal models specifically addressing CSNB limited to mammals. Here, we present a CSNB fly model associated with the mtt gene, utilizing RNA interference (RNAi) to silence the mtt gene in fly eyes (homologous to the mammalian GRM6 gene) and construct a CSNB model. Through this approach, we observed significant defects in the eye structure and function upon reducing mtt expression in fly eyes. This manifested as disruptions in the compound eye lens structure and reduced sensitivity to light responses. These results suggest a critical role for mtt in the function of fly adult eyes. Interestingly, we found that the mtt gene is not expressed in the photoreceptor neurons of adult flies but is localized to the inner lamina neurons. In summary, these results underscore the crucial involvement of mtt in fly retinal function, providing a framework for understanding the pathogenic mechanisms of CSNB and facilitating research into potential therapeutic interventions.

Printable Counter Electrode with Metal Nitride as the Conductive Medium for Perovskite Solar Cells.

Perovskite solar cells (PSCs) with a booming high power conversion efficiency (PCE) are on their road toward industrialization. A proper design of the counter electrode (CE) with low cost, high conductivity, chemical stability, and good interface contact with the other functional layer atop the perovskite layer is vital for the overall performance of PSCs. Herein, the application of titanium nitride (TiN) is reported as a conductive medium for the printable CE in hole-conductor-free mesoscopic PSCs. TiN improves the conductivity of the CE and reduces the resistivity from 20 to 10 mΩ∙cm. TiN also improves the wettability of the CE with perovskite and enhances the back interface contact, which promotes charge collection. On the other hand, TiN is chemically stable during processing and undergoes no distinguishable chemical reaction with halide perovskite. Devices with TiN as the conductive media in the CE deliver a champion PCE of 19.01%. This work supplies a considerable choice for the CE design of PSCs toward industrial applications.

The endogenous antioxidant ability of royal jelly in Drosophila is independent of Keap1/Nrf2 by activating oxidoreductase activity.

Royal jelly (RJ) is a biologically active substance secreted by the hypopharyngeal and mandibular glands of worker honeybees. It is widely claimed that RJ reduces oxidative stress. However, the antioxidant activity of RJ has mostly been determined by in vitro chemical detection methods or by external administration drugs that cause oxidative stress. Whether RJ can clear the endogenous production of reactive oxygen species (ROS) in cells remains largely unknown. Here, we systematically investigated the antioxidant properties of RJ using several endogenous oxidative stress models of Drosophila. We found that RJ enhanced sleep quality of aging Drosophila, which is decreased due to an increase of oxidative damage with age. RJ supplementation improved survival and suppressed ROS levels in gut cells of flies upon exposure to hydrogen peroxide or to the neurotoxic agent paraquat. Moreover, RJ supplementation moderated levels of ROS in endogenous gut cells and extended lifespan after exposure of flies to heat stress. Sleep deprivation leads to accumulation of ROS in the gut cells, and RJ attenuated the consequences of oxidative stress caused by sleep loss and prolonged lifespan. Mechanistically, RJ prevented cell oxidative damage caused by heat stress or sleep deprivation, with the antioxidant activity in vivo independent of Keap1/Nrf2 signaling. RJ supplementation activated oxidoreductase activity in the guts of flies, suggesting its ability to inhibit endogenous oxidative stress and maintain health, possibly in humans.

Regulation of NAD+/NADH Redox Involves the Protective Effects of Ginsenoside Rb1 against Oxygen-Glucose Deprivation/Reoxygenation-Induced Astrocyte Lesions.

The aim of this study was to investigate NAD+/NADH redox regulation in astrocytes by Ginsenoside Rb1 subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) and to reveal the neuroprotective mechanism of ginseng. Neonatal mouse brain was used to culture primary astrocytes. The third generation of the primary astrocytes was used for the experiments. OGD/R was introduced by culturing the cells in a glucose-free media under nitrogen for 6 h followed by a regular culture for 24 h. Ginsenoside Rb1 attenuated OGD/R-induced astrocyte injury in a dose-dependent manner. It improved the mitochondrial function of OGD/R astrocytes indicated by improving mitochondrial distribution, increasing mitochondrial membrane potential, and enhancing mitochondrial DNA copies and ATP production. Ginsenoside Rb1 significantly lifted intracellular NAD+/NADH, NADPH/NADP+, and GSH/GSSG in OGD/R astrocytes. It inhibited the protein expression of both PARP1 and CD38, while attenuating the SIRT1 drop in OGD/R cells. In line with its effects on PARP1, Ginsenoside Rb1 significantly reduced the expression of poly-ADP-ribosylation (PARylation) proteins in OGD/R cells. Ginsenoside Rb1 also significantly increased the expression of NAMPT and NMNAT2, both of which are key players in NAD/NADH synthesis. The results suggest that the regulation of NAD+/NADH redox involves the protective effects of ginsenoside Rb1 against OGD/R-induced astrocyte injury.

Phase Behavior of Binary Blends of Diblock Copolymers: Progress and Opportunities.

The phase behavior of binary blends of diblock copolymers has been examined extensively in the past decades. Experimental and theoretical studies have demonstrated that mixing two different block copolymers provides an efficient and versatile route to regulate their self-assembled morphologies. A good understanding of the principles governing the self-assembly of block copolymer blends has been obtained from the study of A1B1/A2B2 diblock copolymer blends. The second (A2B2) diblocks could act synergistically as fillers and cosurfactants to regulate the domain size and interfacial properties, resulting in the formation of ordered phases not found in the parent (A1B1 or A2B2) diblock copolymer melts. The study of A1B1/A2B2 block copolymer blends further provides a solid foundation for future research on more complex block copolymer blends.

Design and Evaluation of CPR Emergency Equipment for Non-Professionals.

Sudden cardiac death is a sudden and highly fatal condition. Implementing high-quality emergency cardiopulmonary resuscitation (CPR) early on is an effective rescue method for this disease. However, the rescue steps of CPR are complicated and difficult to remember, and the quantitative indicators are difficult to control, which leads to a poor quality of CPR emergency actions outside the hospital setting. Therefore, we have developed CPR emergency equipment with a multisensory feedback function, aiming to guide rescuers in performing CPR through visual, auditory, and tactile interaction. This equipment consists of three components: first aid clothing, an audio-visual integrated terminal, and a vital sign detector. These three components are based on a micro-power WiFi-Mesh network, enabling the long-term wireless transmission of the multisensor data. To evaluate the impact of the multisensory feedback CPR emergency equipment on nonprofessionals, we conducted a controlled experiment involving 32 nonmedical subjects. Each subject was assigned to either the experimental group, which used the equipment, or the control group, which did not. The main evaluation criteria were the chest compression (CC) depth, the CC rate, the precise depth of the CC ratio (5-6 cm), and the precise rate of the CC ratio -(100-120 times/min). The results indicated that the average CC depth in the experimental group was 51.5 ± 1.3 mm, which was significantly better than that of the control group (50.2 ± 2.2 mm, p = 0.012). Moreover, the average CC rate in the experimental group (110.1 ± 6.2 times/min) was significantly higher than that of the control group (100.4 ± 6.6 times/min) (p < 0.001). Compared to the control group (66.37%), the experimental group showed a higher proportion of precise CC depth (82.11%), which is closer to the standard CPR rate of 100%. In addition, the CC ratio of the precise rate was 93.75% in the experimental group, which was significantly better than that of 56.52% in the control group (p = 0.024). Following the experiment, the revised System Availability Scale (SUS) was utilized to evaluate the equipment's usability. The average total SUS score was 78.594, indicating that the equipment's acceptability range was evaluated as 'acceptable', and the overall adjective rating was 'good'. In conclusion, the multisensory feedback CPR emergency equipment significantly enhances the CC performance (CC depth, CC rate, the precise depth of CC ratio, the precise rate of CC ratio) of nonprofessionals during CPR, and the majority of participants perceive the equipment as being easy to use.

Toward Earth system modeling with resolved clouds and ocean submesoscales on heterogeneous many-core HPCs.

With the aid of the newly developed 'Sunway' heterogeneous-architecture supercomputer, which has world-leading HPC (high-performance computer) capability, a series of high-resolution coupled Earth system models (SW-HRESMs) with up to 5 km of atmosphere and 3 km of ocean have been developed. These models can meet the needs of multiscale interaction studies with different computational costs. Here we describe the progress of SW-HRESMs development, with an overview of the major advancements made by the international Earth science community in HR-ESMs. We also show the preliminary results of SW-HRESMs with regard to capturing major weather-climate extremes in the atmosphere and ocean, stressing the importance of permitted clouds and ocean submesoscale eddies in modeling tropical cyclones and eddy-mean flow interactions, and paving the way for further model development to resolve finer scales with even higher resolution and more realistic physics. Finally, in addition to increasing model resolution, the development procedure for a non-hydrostatic cloud and ocean submesoscale resolved ESM is discussed, laying out the major scientific directions of such a huge modeling advancement.

Pectin from plantain peels: Green recovery for transformation into reinforced packaging films.

Plantain peels as agro-waste are generated in the millions of tons per year with no profitable management strategies. On the other hand, the excessive use of plastic packaging threatens the environment and human health. This research aimed to address both problems via a green approach. High-quality pectin was recovered from plantain peels via an enzyme-assisted and ethanol-recycling process. The yield and galacturonic acid (GalA) content of the recovered low methoxy pectin was 12.43% and 25.0%, respectively, when cellulase was added at 50 U per 5 g peel powder, with a significantly higher recovery rate and purity than the pectin products extracted with no cellulase (P ≤ 0.05). The recovered pectin was further integrated and reinforced with beeswax solid-lipid nanoparticles (BSLNs) to fabricate films as a potential alternative packaging material to single-use plastics. The reinforced pectin films showed improved light barrier, water resistance, mechanical, conformational, and morphological properties. This study presents a sustainable strategy to transform plantain peels into pectin products and pectin-based packaging films with broad applications.

Nox4-and Tf/TfR-mediated peroxidation and iron overload exacerbate neuronal ferroptosis after intracerebral hemorrhage: Involvement of EAAT3 dysfunction.

Intracerebral hemorrhage (ICH) induces high mortality and disability. Neuronal death is the principal factor to unfavourable prognosis in ICH. However, the mechanisms underlying this association remain unclear. In this study, we investigated the molecular mechanisms by which neuronal ferroptosis occurs after ICH and whether the use of corresponding modulators can inhibit neuronal death and improve early outcomes in a rat ICH model. Our findings indicated that Nox4 and TF/TfR were upregulated in the perihematomal tissues of ICH rats. Oxidative stress and iron overload induced by Nox4 and TF/TfR promoted neuronal ferroptosis post-ICH. In contrast, application of Nox4-siRNA and the deferoxamine (DFO) attenuated peroxidation and iron deposition in the hemorrhagic brain, alleviated neuronal ferroptosis, and improved sensorimotor function in ICH rats. Additionally, our findings indicated that the post-ICH neuronal reduced glutathione (GSH) depletion were not related to dysfunctional glutamine delivery in astrocytes but rather to downregulation of EAAT3 due to lipid peroxidation-induced dysfunction in the neuronal membrane. These findings indicate that ferroptosis is involved in neuronal death in model rats with collagenase-induced ICH. Oxidative stress and iron overload induced by Nox4 and TF/TfR exacerbate ferroptosis after ICH, while Nox4 downregulation and iron chelation exert neuroprotective effects. The present results highlight the cysteine importer EAAT3 as a potential biomarker of ferroptosis and provide insight into the neuronal death process that occurs following ICH, which may aid in the development of translational treatment strategies for ICH.

Knockdown of NADPH oxidase 4 reduces mitochondrial oxidative stress and neuronal pyroptosis following intracerebral hemorrhage.

Intracerebral hemorrhage is often accompanied by oxidative stress induced by reactive oxygen species, which causes abnormal mitochondrial function and secondary reactive oxygen species generation. This creates a vicious cycle leading to reactive oxygen species accumulation, resulting in progression of the pathological process. Therefore, breaking the cycle to inhibit reactive oxygen species accumulation is critical for reducing neuronal death after intracerebral hemorrhage. Our previous study found that increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NADPH oxidase 4, NOX4) led to neuronal apoptosis and damage to the blood-brain barrier after intracerebral hemorrhage. The purpose of this study was to investigate the role of NOX4 in the circle involving the neuronal tolerance to oxidative stress, mitochondrial reactive oxygen species and modes of neuronal death other than apoptosis after intracerebral hemorrhage. We found that NOX4 knockdown by adeno-associated virus (AAV-NOX4) in rats enhanced neuronal tolerance to oxidative stress, enabling them to better resist the oxidative stress caused by intracerebral hemorrhage. Knockdown of NOX4 also reduced the production of reactive oxygen species in the mitochondria, relieved mitochondrial damage, prevented secondary reactive oxygen species accumulation, reduced neuronal pyroptosis and contributed to relieving secondary brain injury after intracerebral hemorrhage in rats. Finally, we used a mitochondria-targeted superoxide dismutase mimetic to explore the relationship between reactive oxygen species and NOX4. The mitochondria-targeted superoxide dismutase mimetic inhibited the expression of NOX4 and neuronal pyroptosis, which is similar to the effect of AAV-NOX4. This indicates that NOX4 is likely to be an important target for inhibiting mitochondrial reactive oxygen species production, and NOX4 inhibitors can be used to alleviate oxidative stress response induced by intracerebral hemorrhage.

Lnc-HZ03 promotes TRBP-mediated splicing of pre-miR-hz03 to generate miR-hz03 in human trophoblast cells.

Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) leads to dysfunctions of human trophoblast cells and further induces miscarriage. In our previous study, we have found that lnc-HZ03 and miR-hz03 are upregulated in BPDE-exposed human trophoblast cells and in recurrent miscarriage tissues; and the upregulated miR-hz03 caused by lnc-HZ03 further promotes the apoptosis of human trophoblast cells and induces miscarriage. However, how lnc-HZ03 upregulates miR-hz03 is completely unknown. In this study, we find that lnc-HZ03 upregulates the expression level of a transcription factor TFIID (a TATA-binding protein) and promotes TFIID-mediated transactivation response element RNA-binding protein (TRBP) transcription. Subsequently, the upregulated TRBP promotes the maturation of miR-hz03 by splicing its precursor pre-miR-hz03 in human trophoblast cells. In BPDE-exposed trophoblast cells or in recurrent miscarriage tissues, lnc-HZ03 was upregulated, which accelerates the TFIID-mediated TRBP transcription and thus promotes TRBP-mediated miR-HZ03 maturation. Subsequently, the upregulated miR-hz03 further promotes the apoptosis of human trophoblast cells and induces miscarriage. This work provides new insights into the regulation of miRNA expression levels by lncRNAs in BPDE-exposed human trophoblast cells.

Dynamic Enhancement for Dual Active Bridge Converter with a Deadbeat Current Controller.

This paper investigates the deadbeat current controllers for isolated bidirectional dual-active-bridge dc-dc converter (IBDC), including the peak current mode (PCM) and middle current mode (MCM). The controller uses an enhanced single phase shift (ESPS) modulation method by exploiting pulse width as an extra control variable in addition to phase shift ratio. The control variables for PCM controllers are derived in detail and the two different current controllers are compared. A double-closed-loop control method is then employed, which could directly control the high-frequency inductor current and eliminate the transient DC current bias of the transformer. Furthermore, load feedforward was introduced to further enhance the dynamic of the converter. With the proposed control method, the settling time could be reduced within several PWM cycles during load disturbance without transient DC current bias. A 5 kW IBDC converter prototype was built and the settling time of 6 PWM cycles during load change with voltage regulation mode was achieved, which verifies the superior dynamic performance of the control method.

Prognostic and clinicopathological value of Twist expression in esophageal cancer: A meta-analysis.

BACKGROUND: Twist is a repressor of E-cadherin transcription that induces epithelial-mesenchymal transition and cancer metastasis. However, the prognostic value of Twist expression in patients with esophageal cancer remains controversial. AIM: To investigate the prognostic and clinicopathological value of Twist expression in esophageal cancer. METHODS: Published literature in databases such as EMBASE, Web of Science, PubMed, China National Knowledge Infrastructure, Wanfang, and VIP databases was searched for eligible articles. Participants with esophageal cancer whose tumor tissues underwent immunohistochemistry to detect the expression of Twist were considered. Our meta-analysis was conducted using Stata version 12.0. The hazard ratio (HR) and relative ratio (RR) with their 95%CI were pooled. Heterogeneity was estimated by I 2 statistics. RESULTS: Eleven articles published between 2009 and 2021 fulfilled the selection criteria. The pooled HR for overall survival was 1.88 (95%CI: 1.32-2.69, I 2 = 68.6%), and the pooled HR for disease-free survival/relapse-free survival/progression-free survival was 1.84 (95%CI: 1.12-3.02, I 2 = 67.1%), suggesting that high Twist expression is associated with poor prognosis in esophageal cancer patients. In addition, overexpression of Twist was correlated with T stage (T3 + T4 vs T1 + T2, RR = 1.38, 95%CI: 1.14-1.67), lymph node metastasis (yes vs no, RR = 1.34, 95%CI: 1.11-1.60), distant metastasis (yes vs no, RR = 1.18, 95%CI: 1.02-1.35), tumor, node and metastasis (TNM) stage (III + IV vs I + II, RR = 1.35, 95%CI: 1.14-1.60), and clinical stage (III + IV vs I + II, RR = 1.58, 95%CI: 1.34-1.87). However, no correlation between Twist expression and age, gender, tumor location, differentiation, or venous invasion was observed. CONCLUSION: High expression of Twist is associated with poor esophageal cancer prognosis. Moreover, Twist overexpression is correlated with T stage, lymph node metastasis, distant metastasis, TNM stage, and clinical stage, which indicates that Twist might accelerate esophageal cancer progression and metastasis.

Nicotinamide N-methyltransferase ameliorates renal fibrosis by its metabolite 1-methylnicotinamide inhibiting the TGF-ß1/Smad3 pathway.

Chronic kidney disease (CKD), a disease involving damage to the kidney structure and function, is a global public health problem. Tubulointerstitial fibrosis (TIF) is both an inevitable pathological change in individuals with CKD and a driving force in the progression of renal fibrosis. Nicotinamide N-methyltransferase (NNMT) and its metabolite 1-methylnicotinamide (MNAM) have been shown to protect against lipotoxicity-induced kidney tubular injury. However, the biological roles of NNMT and MNAM in regulating TIF remain elusive. This study aimed to investigate the protective effect of NNMT and MNAM on TIF and the mechanisms involved. We explored the functions and mechanisms of NNMT and MNAM in TIF, as well as the interaction between NNMT and MNAM, using unilateral ureteral obstruction (UUO) mice and cultured mouse tubular epithelial cells (mTECs) stimulated with transforming growth factor-ß1 (TGF-ß1). Several important findings were obtained as follows: (1) NNMT expression was upregulated in the kidneys of UUO mice and TGF-ß1-induced mTECs, and this upregulation was proposed to be a protective compensatory response to TIF. (2) MNAM was a potentially effective antifibrotic and anti-inflammatory medication in UUO mice. (3) The antifibrotic effect of NNMT overexpression was exerted by increasing the concentration of MNAM. (4) The renoprotective role of MNAM depended on the selective blockade of the interaction of Smad3 with TGFß receptor I. Overall, our study shows that NNMT is involved in the development and progression of CKD and that its metabolite MNAM may be a novel inhibitor of the TGF-ß1/Smad3 pathway with great therapeutic potential for CKD.