Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage.

Tissue homeostasis requires maintenance of functional integrity under stress. A central source of stress is mechanical force that acts on cells, their nuclei, and chromatin, but how the genome is protected against mechanical stress is unclear. We show that mechanical stretch deforms the nucleus, which cells initially counteract via a calcium-dependent nuclear softening driven by loss of H3K9me3-marked heterochromatin. The resulting changes in chromatin rheology and architecture are required to insulate genetic material from mechanical force. Failure to mount this nuclear mechanoresponse results in DNA damage. Persistent, high-amplitude stretch induces supracellular alignment of tissue to redistribute mechanical energy before it reaches the nucleus. This tissue-scale mechanoadaptation functions through a separate pathway mediated by cell-cell contacts and allows cells/tissues to switch off nuclear mechanotransduction to restore initial chromatin state. Our work identifies an unconventional role of chromatin in altering its own mechanical state to maintain genome integrity in response to deformation.

Flexible circuit mechanisms for context-dependent song sequencing.

Sequenced behaviours, including locomotion, reaching and vocalization, are patterned differently in different contexts, enabling animals to adjust to their environments. How contextual information shapes neural activity to flexibly alter the patterning of actions is not fully understood. Previous work has indicated that this could be achieved via parallel motor circuits, with differing sensitivities to context1,2. Here we demonstrate that a single pathway operates in two regimes dependent on recent sensory history. We leverage the Drosophila song production system3 to investigate the role of several neuron types4-7 in song patterning near versus far from the female fly. Male flies sing 'simple' trains of only one mode far from the female fly but complex song sequences comprising alternations between modes when near her. We find that ventral nerve cord (VNC) circuits are shaped by mutual inhibition and rebound excitability8 between nodes driving the two song modes. Brief sensory input to a direct brain-to-VNC excitatory pathway drives simple song far from the female, whereas prolonged input enables complex song production via simultaneous recruitment of functional disinhibition of VNC circuitry. Thus, female proximity unlocks motor circuit dynamics in the correct context. We construct a compact circuit model to demonstrate that the identified mechanisms suffice to replicate natural song dynamics. These results highlight how canonical circuit motifs8,9 can be combined to enable circuit flexibility required for dynamic communication.

Small-molecule inhibitors of human mitochondrial DNA transcription.

Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system1-6. The IMTs efficiently impair mtDNA transcription in a reconstituted recombinant system and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines. To verify the cellular target, we performed exome sequencing of mutagenized cells and identified a cluster of amino acid substitutions in POLRMT that cause resistance to IMTs. We obtained a cryo-electron microscopy (cryo-EM) structure of POLRMT bound to an IMT, which further defined the allosteric binding site near the active centre cleft of POLRMT. The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS7-17, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease.

Factors Influencing Plasma Concentrations of Valproic Acid in Pediatric Patients With Epilepsy and the Clinical Significance of CYP2C9 Genotypes in Personalized Valproic Acid Therapy.

BACKGROUND: The aim of this study was to investigate the factors affecting plasma valproic acid (VPA) concentration in pediatric patients with epilepsy and the clinical significance of CYP2C9 gene polymorphisms in personalized dosing using therapeutic drug monitoring and pharmacogenetic testing. METHODS: The medical records of children with epilepsy who underwent therapeutic drug monitoring at our institution between July 2022 and July 2023 and met the inclusion criteria were reviewed. Statistical analysis was performed to determine whether age, sex, blood ammonia, liver function, kidney function, and other characteristics affected the concentration-to-dose ratio of VPA (CDRV) in these patients. To investigate the effect of CYP2C9 polymorphisms on CDRV, DNA samples were collected from patients and the CYP2C9 genotypes were identified using real-time quantitative PCR. RESULTS: The mean age of 208 pediatric patients with epilepsy was 5.50 ± 3.50 years. Among these patients, 182 had the CYP2C9 *1/*1 genotype, with a mean CDRV (mcg.kg/mL.mg) of 2.64 ± 1.46, 24 had the CYP2C9 *1/*3 genotype, with a mean CDRV of 3.28 ± 1.74, and 2 had the CYP2C9 *3/*3 genotype, with a mean CDRV of 6.46 ± 3.33. There were statistical differences among these 3 genotypes ( P < 0.05). The CDRV in these patients were significantly influenced by age, aspartate aminotransferase, total bilirubin, direct bilirubin, globulin, albumin/globulin ratio, prealbumin, creatinine, and CYP2C9 polymorphisms. In addition, multivariate linear regression analysis identified total bilirubin, direct bilirubin, and CYP2C9 polymorphisms as independent risk factors for high CDRV. CONCLUSIONS: Liver problems and mutations in the CYP2C9 gene increase VPA levels. This underscores the importance of considering these factors when prescribing VPA to children with epilepsy, thereby enhancing the safety and efficacy of the therapy.

Research on the anti-aging efficacy of fermented lysate VHProbi® MixA as the functional skincare ingredient.

AIMS: This study aimed to investigate the efficacy of a cream containing VHProbi® MixA for improving skin aging. METHODS AND RESULTS: In vitro studies demonstrated that the lysate produced from Lacticaseibacillus paracasei E12 (E12) exhibited immunoregulatory effects in a 3D skin model, with significant reductions in levels of interleukin (IL)-1α, IL-1ß, and IL-8 (P < 0.05) compared with the control group. In addition, the lysate of E12 mitigated the hydrogen peroxide-induced mortality of 3D skin cells and enhanced the transepithelial electrical resistance to show significant differences in comparison with control (P < 0.05), suggesting favorable antioxidant effects. The antioxidant capacity of the lysate of E12 was also confirmed using the Caenorhabditis elegans N2 model. C. elegans N2 fed the E12 strain showed a significantly higher % survival than those fed Escherichia coli OP50 (P < 0.05). Subsequently, VHProbi® MixA was formulated using the fermented lysates of E12, Lactiplantibacillus plantarum E15, and Limosilactobacillus reuteri E18. In a clinical study to ascertain if a cream containing VHProbi® MixA could improve the skin aging trends, participants were asked to use the investigational products for 60 days, and six indicators, transepidermal water loss (TEWL), hydration, elasticity, wrinkles, skin texture (roughness), and pores were measured at baseline and the endpoint of the study. A self-evaluation questionnaire analysis was also provided. TEWL, wrinkles, skin texture, and thickness of pores decreased significantly after treatment with the cream for 60 days (P < 0.01), whereas hydration and elasticity increased significantly (P < 0.01), in comparison to the baseline measurements. CONCLUSIONS: We hypothesize that the use of the cream containing VHProbi® MixA could be favorable for skin anti-aging management.

Socioeconomic inequalities in cancer incidence and access to health services among children and adolescents in China: a cross-sectional study.

BACKGROUND: Despite the substantial burden caused by childhood cancer globally, childhood cancer incidence obtained in a nationwide childhood cancer registry and the accessibility of relevant health services are still unknown in China. We comprehensively assessed the most up-to-date cancer incidence in Chinese children and adolescents, nationally, regionally, and in specific population subgroups, and also examined the association between cancer incidence and socioeconomic inequality in access to health services. METHODS: In this national cross-sectional study, we used data from the National Center for Pediatric Cancer Surveillance, the nationwide Hospital Quality Monitoring System, and public databases to cover 31 provinces, autonomous regions, and municipalities in mainland China. We estimated the incidence of cancer among children (aged 0-14 years) and adolescents (aged 15-19 years) in China through stratified proportional estimation. We classified regions by socioeconomic status using the human development index (HDI). Incidence rates of 12 main groups, 47 subgroups, and 81 subtypes of cancer were reported and compared by sex, age, and socioeconomic status, according to the third edition of the International Classification of Childhood Cancer. We also quantified the geographical and population density of paediatric oncologists, pathology workforce, diagnoses and treatment institutions of paediatric cancer, and paediatric beds. We used the Gini coefficient to assess equality in access to these four health service indicators. We also calculated the proportions of cross-regional patients among new cases in our surveillance system. FINDINGS: We estimated the incidence of cancer among children (aged 0-14 years) and adolescents (aged 15-19 years) in China from Jan 1, 2018, to Dec 31, 2020. An estimated 121 145 cancer cases were diagnosed among children and adolescents in China between 2018 and 2020, with world standard age-standardised incidence rates of 122·86 (95% CI 121·70-124·02) per million for children and 137·64 (136·08-139·20) per million for adolescents. Boys had a higher incidence rate of childhood cancer (133·18 for boys vs 111·21 for girls per million) but a lower incidence of adolescent cancer (133·92 for boys vs 141·79 for girls per million) than girls. Leukaemias (42·33 per million) were the most common cancer group in children, whereas malignant epithelial tumours and melanomas (30·39 per million) surpassed leukaemias (30·08 per million) in adolescents as the cancer with the highest incidence. The overall incidence rates ranged from 101·60 (100·67-102·51) per million in very low HDI regions to 138·21 (137·14-139·29) per million in high HDI regions, indicating a significant positive association between the incidence of childhood and adolescent cancer and regional socioeconomic status (p<0·0001). The incidence in girls showed larger variation (48·45% from the lowest to the highest) than boys (36·71% from lowest to highest) in different socioeconomic regions. The population and geographical densities of most health services also showed a significant positive correlation with HDI levels. In particular, the geographical density distribution (Gini coefficients of 0·32-0·47) had higher inequalities than population density distribution (Gini coefficients of 0·05-0·19). The overall proportion of cross-regional patients of childhood and adolescent cancer was 22·16%, and the highest proportion occurred in retinoblastoma (56·54%) and in low HDI regions (35·14%). INTERPRETATION: Our study showed that the burden of cancer in children and adolescents in China is much higher than previously nationally reported from 2000 to 2015. The distribution of the accessibility of health services, as a social determinant of health, might have a notable role in the socioeconomic inequalities in cancer incidence among Chinese children and adolescents. With regards to achieving the Sustainable Development Goals, policy approaches should prioritise increasing the accessibility of health services for early diagnosis to improve outcomes and subsequently reduce disease burdens, as well as narrowing the socioeconomic inequalities of childhood and adolescent cancer. FUNDING: National Major Science and Technology Projects of China, National Natural Science Foundation of China, Chinese Academy of Engineering Consulting Research Project, Wu Jieping Medical Foundation, Beijing Municipal Administration of Hospitals Incubating Program.

The potential benefits and mechanisms of protein nutritional intervention on bone health improvement.

Osteoporosis commonly occurs in the older people and severe patients, with the main reason of the imbalance of bone metabolism (the rate of bone resorption exceeding the rate of bone formation), resulting in a decrease in bone mineral density and destruction of bone microstructure and further leading to the increased risk of fragility fracture. Recent studies indicate that protein nutritional support is beneficial for attenuating osteoporosis and improving bone health. This review summarized the classical mechanisms of protein intervention for alleviating osteoporosis on both suppressing bone resorption and regulating bone formation related pathways (promoting osteoblasts generation and proliferation, enhancing calcium absorption, and increasing collagen and mineral deposition), as well as the potential novel mechanisms via activating autophagy of osteoblasts, altering bone related miRNA profiles, regulating muscle-bone axis, and modulating gut microbiota abundance. Protein nutritional intervention is expected to provide novel approaches for the prevention and adjuvant therapy of osteoporosis.

Discovery of two ent-atisane diterpenoid lactones with AChE inhibitory activity from the roots of Euphorbia fischeriana.

Euphorlactone A (1), a rare rearranged ent-atisane norditerpenoid with an undescribed 3-nor-2,4-olide-ent-atisane scaffold, and euphorlactone B (2), a new ent-atisane diterpenoid with an unprecedented seven-membered lactone ring C, were isolated from the roots of Euphorbia fischeriana. Their planar structures with absolute configurations were extensively elucidated by analysis of 1D and 2D NMR data, electronic circular dichroism (ECD) calculations, Rh2(OCOCF3)4-induced ECD curves, and single-crystal X-ray diffraction. Euphorlactone A (ELA) showed a remarkable AChE (acetylcholinesterase) inhibitory activity (IC50 = 2.13 ± 0.06 µM and Ki = 0.058 µM), which was five times stronger than that of the positive control (rivastigmine, IC50 = 12.46 ± 0.82 µM), and further in vitro enzyme inhibition kinetic analysis and molecular docking studies were performed to investigate the AChE inhibitory mechanism.

Human GTPBP5 is involved in the late stage of mitoribosome large subunit assembly.

Human mitoribosomes are macromolecular complexes essential for translation of 11 mitochondrial mRNAs. The large and the small mitoribosomal subunits undergo a multistep maturation process that requires the involvement of several factors. Among these factors, GTP-binding proteins (GTPBPs) play an important role as GTP hydrolysis can provide energy throughout the assembly stages. In bacteria, many GTPBPs are needed for the maturation of ribosome subunits and, of particular interest for this study, ObgE has been shown to assist in the 50S subunit assembly. Here, we characterize the role of a related human Obg-family member, GTPBP5. We show that GTPBP5 interacts specifically with the large mitoribosomal subunit (mt-LSU) proteins and several late-stage mitoribosome assembly factors, including MTERF4:NSUN4 complex, MRM2 methyltransferase, MALSU1 and MTG1. Interestingly, we find that interaction of GTPBP5 with the mt-LSU is compromised in the presence of a non-hydrolysable analogue of GTP, implying a different mechanism of action of this protein in contrast to that of other Obg-family GTPBPs. GTPBP5 ablation leads to severe impairment in the oxidative phosphorylation system, concurrent with a decrease in mitochondrial translation and reduced monosome formation. Overall, our data indicate an important role of GTPBP5 in mitochondrial function and suggest its involvement in the late-stage of mt-LSU maturation.

Effects of Harvesting Grabbing Type on Grabbing Force and Leaf Injury of Lettuce.

Hydroponic lettuce is the main cultivated leafy vegetable in plant factories, and its scattered leaves are delicate and easily injured. Harvesting is an important process in the production of hydroponic lettuce. To reduce the injury level of hydroponic lettuce during harvesting, the impacts of the flexible finger-grabbing position applied on the grabbing force and the area of the injured leaves were investigated in this study by utilizing thin-film sensors and a high-speed video camera. According to the overlapping structural characteristics of adjacent leaves on lettuce, flexible finger-grabbing positions were divided into areas of the surface of the leaves and the intersections of the leaves. Three grabbing types-which are referred to in this paper as Grabbing Types A, B, and C-were identified according to the number of flexible fingers grabbing the leaf surface and the intersection area of the leaves. The force curves of all the flexible fingers were measured by thin film sensors, and the injury area of the leaves was detected using an image processing method. The results showed the consistency of the grabbing force curves and the motion characteristic parameters of the four flexible fingers. The maximum grabbing force of each flexible finger appeared at the stage of pulling the lettuce. The grabbing force of the flexible fingers acting on the intersection areas of the leaves was less than that acting on the leaf surface. As the number of flexible fingers acting on the intersection areas of the leaves increased, both the injury area of the leaves and the grabbing force decreased gradually. Grabbing Type C had the smallest injury area of the leaves: 120.3 ± 13.6 mm2 with an 11.4% coefficient of variation.

Controlling methane emissions from Integrated Vertical-Flow Constructed Wetlands by using potassium peroxymonosulfate as oxidant.

It is very important to control methane emissions to reduce global warming. In this study, a new attempt of one oxidant (potassium peroxymonosulfate (PMS)) was made to adjust the oxidation-reduction potential (Eh) by adding different mass of (0 g, 31.25 g, 62.5 g, 125 g, 250 g and 500 g) for the reduction of methane emissions from integrated vertical-flow constructed wetland (IVCW), where the IVCW system has been divided into the root-water system and the stem-leaf system of methane emissions. Results show that the reduced CH4 emission from IVCW was the highest with decreased by 43.5% compared to blank group (PMS = 0), when adding 125 g PMS. Importantly, the reduced CH4 from the root-water system of IVCW was higher than that of the stem-leaf system of IVCW, when adding PMS. It's found that Eh not only has a significant correlation with CH4 flux, but also has a significant relationship between PMS quality, DO, water temperature and sampling time (yEh = -0.44XPMS + 6.82XDO + 0.38t - 264.1, R2 = 0.99). It concludes that PMS, as an oxidant, is a very feasible method for controlling methane emissions from IVCW. It's concluded from this study that it is a feasible engineering method by using PMS as an oxidant for reducing methane emissions from IVCWs when treating artificial domestic sewage. Further research may combine other methods together such as microbiology, physical control and hydrology control for mitigating the CH4 emissions from constructed wetlands for more types of wastewater.

Oat ß-glucan alleviates muscle atrophy via promoting myotube formation and suppressing protein degradation.

BACKGROUND: The dangerous inducers of muscle atrophy are inflammatory reaction, oxidative stress, and cachexia, etc. ß-Glucan, an important food derived active ingredient, has been reported to exert anti-inflammatory effects, however, its effects on regulating myoblast differentiation and protein degradation are unclear. This study is aimed to investigate the mechanism of oat ß-glucan on alleviating muscle atrophy. RESULTS: The results showed that oat ß-glucan treatment reversed tumor necrosis factor-α (TNF-α) induced abnormal myoblast differentiation and reduced muscle atrophy related MuRF-1 and Atrogin-1 protein expression. The similar phenomenon was observed after using MCC950 (NLRP3 specific inhibitor) or AS1842856 (FoxO1 specific inhibitor) to suppress NLRP3 and FoxO1 expression, respectively. Exposure to ß-glucan or AS1842856 also inhibited TNF-α induced the activation of TLR4/NF-κB pathway by inactivating FoxO1, and subsequently suppressed the expression of NLRP3. CONCLUSION: Our results indicate that oat ß-glucan exerts essential roles in promoting myoblast differentiation and alleviating muscle atrophy via inactivating FoxO1 and NLRP3 inflammasome signal pathway. © 2023 Society of Chemical Industry.

All-cause mortality risk in older patients with femoral neck fracture.

INTRODUCTION: The mortality rate after hip fracture is high. However, the 1-year mortality rate after femoral intertrochanteric fracture and femoral neck fracture differs (Gibson-Smith D, Klop C, Elders PJ, Welsing PM, van Schoor N, Leufkens HG, et al., Osteoporos Int 25:2555-2563, 2014), although both are types of hip fracture. A previous real-world single-center prospective cohort study showed that older age and high Charlson comorbidity index score were risk factors for femoral intertrochanteric fracture. Additionally, therapy with zoledronic acid 5 mg (Aclasta) was a protective factor (Li XP, Zhang P, Zhu SW, Yang MH, Wu XB, Jiang XY, J Orthop Surg Res. 16:727, 2021). We wished to determine the risk factors for all-cause mortality in femoral neck fracture patients. AIM: To identify the risk factors for postoperative all-cause mortality in aged patients with femoral neck fracture. MATERIALS AND METHODS: We enrolled 307 aged patients with femoral neck fracture; 38 were lost to follow-up after 2-3 years. The patients' general characteristics, bone mineral density, and anti-osteoporosis treatment after operation were recorded as potential risk factors. Kaplan-Meier curves and multivariate Cox proportional hazards models were constructed to analyze the influence of each factor on all-cause mortality. RESULTS: This was a real-world single-center prospective cohort study showing that (1) most of the patients who died were male, older (mean age of the patients who died: 84.8 years vs. 77.9 years for survivors), and had more comorbidities compared with surviving patients. Previous fracture history, body mass index, femoral neck T score, hemoglobin and 25-hydroxy vitamin D levels did not differ significantly between patients who died vs. survived. (2) Differing from patients with intertrochanteric fractures, older patients with femoral neck fracture experienced no reduction in all-cause mortality with treatment with zoledronic acid. CONCLUSION: In Chinese patients with femoral neck fracture, physicians should pay careful attention to male patients, older patients, and those with high numbers of comorbidities.

Two Novel Flavonoids with Lipid-Lowering Activity from Yi Medicine Shekaqi.

Yi medicine Shekaqi is the most attractive traditional ethnic medicine due to its significant and diverse pharmacological activities. Two novel flavonoids, including 5,2'-dihydroxy-6-methoxy-7-decyloxyflavone and tenaxin II-7-O-ß-D-glucuronopyranosyl acid butyl ester, along with six known flavonoids, were isolated from Yi medicine Shekaqi. Their structures were elucidated based on the analysis of their comprehensive spectral data. The in vitro lipid-lowering activities of the eight compounds showed that all the compounds significantly inhibited the lipopolysaccharide (LPS)-induced increase in the total cholesterol (TC) level, while compounds 1, 4, 6, 7, and 8 significantly inhibited the LPS-induced increase in the triglyceride (TG) level.

Transcriptome analysis reveals MYB and WRKY transcription factors involved in banana (Musa paradisiaca AA) magnesium deficiency.

MAIN CONCLUSION: The banana development was inhibited under the long-term magnesium deficiency (MD) stress, resulting in the leaf chlorosis. MYB108 and WRKY75 are involved in regulating the growth and development of banana leaves and roots under long-term MD. Magnesium deficiency (MD) causes plant growth inhibition, ageing acceleration, yield reduction and quality decline of banana (Musa paradisiaca AA), but the molecular regulatory mechanisms underlying the changes in response to long-term MD conditions remain unknown. In this study, a long-term MD experiment was performed with banana seedlings at the four-leaf stage. Compared to those in the control group, the growth of leaves and roots of seedlings in the long-term MD treatment experimental groups was inhibited, and the Mg content and chlorophyll contents were decreased. Leaves and roots of seedlings from the control and experimental groups were subsequently collected for RNA sequencing to identify the genes that respond to long-term MD. More than 50 million reads were identified from each sample, resulting in the detection of 3500 and 948 differentially expressed genes (DEGs) in the leaves and roots, respectively. MYB and WRKY transcription factors (TFs) involved in plant stress responses were selected for further analysis, and 102 MYB and 149 WRKY TFs were differentially expressed. Furthermore, two highly differentially expressed candidate genes, MYB108 and WRKY75, were functionally analyzed using Arabidopsis mutants grown under long-term MD conditions. The results showed that the density of root hairs on the wild type (WT) was than that on the myb108 and wrky75 mutants under MD, implying that the mutants were more sensitive to MD than the WT. This research broadens our understanding the underlying molecular mechanism of banana seedlings adapted to the long-term MD condition.

Changes of bone turnover markers after elderly hip fracture surgery.

INTRODUCTION: Bone turnover markers (BTMs) can be used to monitor bone metabolism, while the actual clinical changing in hip fracture had not been certified to evaluate the changes of BTMs during the healing process after surgery of elderly hip fractures; and to get the effects of operation type, gender, serum 25(OH)D level, and age on bone turnover markers. MATERIALS AND METHODS: A total of 100 elderly cases with hip fracture were selected, including 74 females and 26 males, and the patients were followed to 180-230 days after surgery. Serum levels of N-propeptide of type 1 collagen (P1NP), C-terminal crosslinking telopeptides of type 1 collagen (CTX), Osteocalcin (OC), and 25 hydroxy vitamin D (25OHD) were investigated. Bone mineral density (BMD) was measured with dual-energy X-ray absorptiometry (DXA). RESULTS: (1) P1NP and CTX showed peak time at 30-60 days after operation, while OC keep going even at 180-230 days; P1NP showed less than 4 times elevation during healing, CTX and OC only had less than 2 times rise. (2) Female had higher serum CTX and OC than male, intramedullary nailing for intertrochanteric fracture patients had higher P1NP than hip replacement for femoral neck fracture patients, and both the degrees of increase were less than 50%. (3) Serum average 25(OH)D level had no effect on BTMs during the fracture healing; different from the young old (65-84 years), serum OC level of eldest older patients(≥ 85 years) decreased early in the process of fracture healing. CONCLUSIONS: BTMs reached the peak level in 30-60 days after surgery, P1NP showed less than 4 times elevation, and CTX and OC had less than 2 times rise. It was not necessary to take gender into account when observing P1NP, and it was not necessary to take fracture and operation type into account when observing CTX and OC.

Design, synthesis and evaluation of 1-benzyl-1H-imidazole-5-carboxamide derivatives as potent TGR5 agonists.

TGR5 is emerging as an important and promising target for the treatment of diabetes, obesity and other metabolic syndromes. A series of novel 1-benzyl-1H-imidazole-5-carboxamide derivatives was designed, synthesized and evaluated in vitro and in vivo. The most potent compounds 19d and 19e exhibited excellent agonistic activities against hTGR5, which was superior to those of the reference drugs INT-777 and LCA. In addition, compounds 19d and 19e exhibited good selectivity against FXR and presented significant glucose-lowering effects in vivo. Compound 19d could stimulate GLP-1 secretion by activating of TGR5.

Flexible, Transparent, and Hazy Cellulose Nanopaper with Efficient Near-Infrared Luminescence Fabricated by 2D Lanthanide (Ln = Nd, Yb, or Er) Metal-Organic-Framework-Grafted Oxidized Cellulose Nanofibrils.

Three-dimensional (3D) bulk materials, such as metal-organic frameworks (MOFs) and inorganic phosphors, show the properties of large backscattering and stress concentration, which result in low mechanical and inferior transmittance when these materials are hydridized with a polymer matrix. Inspired by the "reinforcement" effects of two-dimensional (2D) materials, such as grapheme, C3N4, MoS2, and Mxene, it was interesting to examine a 2D lanthanide (Ln)-based MOF-grafted natural polymer (nanocellulose) with the goal of achieving light emission, transparency, and good mechanical properties. A series of near-infrared (NIR) luminescent cellulose nanopapers were prepared via 2D Ln-MOF-grafted (2,2,6,6-tetramethylpiperidin-1-yl)oxyl-oxidized cellulose nanofibrils (tCNFs; Ln = Nd, Yb, or Er). In addition to efficient NIR luminescence, these Ln nanopapers exhibited good flexibility, transparency (>90%), and mechanical properties (>28 MPa). Notably, the haze of these nanopapers was increased by 93-95% from 26% due to compositing with 2D Ln-MOFs, which prevented dense packing among the cellulose and formed air cavities in the nanopaper, inducing internal light scattering and improving optical haze. Moreover, these flexible Ln nanopapers exhibited efficient NIR luminescence, which, together with optical haze and transparency, offered an opportunity for utilization in paper-based anticounterfeiting, NIR-light-emitting diodes, or light softening devices.

Aluminum Exposure and Gestational Diabetes Mellitus: Associations and Potential Mediation by n-6 Polyunsaturated Fatty Acids.

As the earth's third most abundant element with various industrial applications, aluminum (Al) has received increasing concerns over its potential adverse health effects. Although Al exposure has been suggested to increase the risks of type 2 diabetes, little has been done to explore Al exposure in pregnant women and potential impact on the incidence of gestational diabetes mellitus (GDM). Our present study demonstrated positive associations between Al concentrations in maternal plasma collected in the first trimester of pregnancy and GDM risks (Ptrend < 0.001) based on a nested case-control study from Wuhan, China, including 305 GDM cases and 305 healthy controls. The highest tertile of plasma Al concentrations corresponded to an odds ratio of 4.03 (95% confidence interval: [2.14, 7.58]) relative to the lowest tertile, after the adjustment for established GDM risk factors and other plasma metals. We also observed significant correlations between plasma Al and several plasma polyunsaturated fatty acids (PUFA; e.g., linoleic acid 18:2 n-6) levels. In addition, mediation effects on the associations of Al exposure with GDM risks were observed for n-6 PUFAs (estimated mediation percentage: 48.3%) and total PUFAs (48.9%). Our study is not only by far the largest study of its kind to demonstrate maternal Al exposure and the association with GDM risks, but it also offers an insight into the potential mediation roles of n-6 PUFAs in an epidemiological setting. These findings contribute to a better understanding of perinatal Al exposure and GDM risks.

CT2-3, a novel magnolol analogue suppresses NSCLC cells through triggering cell cycle arrest and apoptosis.

Magnolol, a major bioactive component found in Magnolia officinalis with anti-inflammation and anti-oxidation activities as well as minimized cytotoxic effects. Although magnolol has a wide range of clinical applications, the anti-tumor activity of magnolol is not efficient. Herein, we reported the synthesis and anti-cancer activities of three novel magnolol analogues CT2-1, CT2-2, CT2-3, among which CT2-3 revealed more efficient anti-non-small cell lung cancer (NSCLC) activity than magnolol. Our data showed that CT2-3 could significantly inhibit the proliferation of human NSCLC cells in a dose-dependent manner. In addition, we revealed CT2-3 could induce cell cycle arrest through down-regulating mRNA expression of CDK4, CDK6 and cyclin D1. Moreover, we verified that CT2-3 could cause ROS generation, leading to apoptosis of human NSCLC cells. Further more, we also provided strong evidences that CT2-3 down-regulates the expression of c-Myc and topoisomerases, and contributes to the apoptosis of human NSCLC cells. Taken together, the current study is the first to report a promising new chemotherapeutic drug candidate CT2-3 that can efficiently eliminate human NSCLC cells through triggering cell cycle arrest as well as ROS-mediated and c-Myc/topoisomerases-mediated apoptosis.