Differential cytokine expression in gastric tissues highlights helicobacter pylori's role in gastritis.

Helicobacter pylori (H. pylori), known for causing gastric inflammation, gastritis and gastric cancer, prompted our study to investigate the differential expression of cytokines in gastric tissues, which is crucial for understanding H. pylori infection and its potential progression to gastric cancer. Focusing on Il-1ß, IL-6, IL-8, IL-12, IL-18, and TNF-α, we analysed gene and protein levels to differentiate between H. pylori-infected and non-infected gastritis. We utilised real-time quantitative polymerase chain reaction (RT-qPCR) for gene quantification, immunohistochemical staining, and ELISA for protein measurement. Gastric samples from patients with gastritis were divided into three groups: (1) non-gastritis (N-group) group, (2) gastritis without H. pylori infection (G-group), and (3) gastritis with H. pylori infection (GH-group), each consisting of 8 samples. Our findings revealed a statistically significant variation in cytokine expression. Generally, cytokine levels were higher in gastritis, but in H. pylori-infected gastritis, IL-1ß, IL-6, and IL-8 levels were lower compared to H. pylori-independent gastritis, while IL-12, IL-18, and TNF-α levels were higher. This distinct cytokine expression pattern in H. pylori-infected gastritis underscores a unique inflammatory response, providing deeper insights into its pathogenesis.

Diffusion-rate sieving of propylene and propane mixtures in a cooperatively dynamic porous crystal.

Selective molecular recognition is an important alternative to the energy-intensive industrial separation process. Porous coordination polymers (PCPs) offer designing platforms for gas separation because they possess precise controllability over structures at the molecular level. However, PCPs-based gas separations are dominantly achieved using strong adsorptive sites for thermodynamic recognition or pore-aperture control for size sieving, which suffer from insufficient selectivity or sluggish kinetics. Developing PCPs that work at high temperatures and feature both high uptake capacity and selectivity is urgently required but remains challenging. Herein, we report diffusion-rate sieving of propylene/propane (C3H6/C3H8) at 300 K by constructing a PCP material whose global and local dynamics cooperatively govern the adsorption process via the mechanisms of the gate opening for C3H6 and the diffusion regulation for C3H8, respectively, yielding substantial differences in both uptake capacity and adsorption kinetics. Dynamic separation of an equimolar C3H6/C3H8 mixture reveals outstanding sieving performance with a C3H6 purity of 99.7% and a separation factor of 318.

Tenofovir-Diphosphate and Emtricitabine-Triphosphate Adherence Benchmarks in Dried Blood Spots for Persons with HIV Receiving Tenofovir Alafenamide and Emtricitabine-based Antiretroviral Therapy (QUANTI-TAF).

BACKGROUND: QUANTI-TAF aimed to establish tenofovir-diphosphate/emtricitabine-triphosphate (TFV-DP/FTC-TP) adherence benchmarks in dried blood spots (DBS) for persons with HIV (PWH) receiving tenofovir alafenamide/emtricitabine (TAF/FTC)-based antiretroviral therapy (ART). METHODS: During a 16-week pharmacokinetic study, PWH received TAF/FTC-based ART co-encapsulated with an ingestible sensor to directly measure cumulative (enrollment to final visit) and 10-day adherence. At monthly visits, intraerythrocytic concentrations of TAF/FTC anabolites (TFV-DP/FTC-TP) in DBS were quantified by LC-MS/MS and summarized at steady-state (week 12 or 16) as median (IQR). Linear mixed-effects models evaluated factors associated with TFV-DP/FTC-TP. RESULTS: 84 participants (86% male, 11% female, and 4% transgender), predominantly receiving bictegravir/TAF/FTC (73%) enrolled. 92% completed week 12 or 16 (94% receiving unboosted ART). TFV-DP for <85% (7/72), ≥85%-<95% (9/72), and ≥95% (56/72) cumulative adherence was 2696 (2039-4108), 3117 (2332-3339), and 3344 (2605-4293) fmol/punches. All participants with ≥85% cumulative adherence had TFV-DP ≥1800 fmol/punches. Adjusting for cumulative adherence, TFV-DP was higher with boosted ART, lower BMI, and in non-Blacks. FTC-TP for <85% (14/77), ≥85%-<95% (6/77), and ≥95% (57/77) 10-day adherence was 3.52 (2.64-4.48), 4.58 (4.39-5.06), and 4.96 (4.21-6.26) pmol/punches. All participants with ≥85% 10-day adherence had FTC-TP ≥2.5 pmol/punches. Low-level viremia (HIV-1 RNA ≥20-<200 copies/mL) occurred at 60/335 (18%) visits in 33/84 (39%) participants (range: 20-149 copies/mL), with similar TFV-DP (3177 [2494-4149] fmol/punches) compared with HIV-1 RNA <20 copies/mL visits (3279 [2580-4407] fmol/punches). CONCLUSIONS: We propose PK-based TFV-DP (≥1800 fmol/punches)/FTC-TP (≥2.5 pmol/punches) benchmarks in DBS for PWH receiving unboosted TAF/FTC-based ART with ≥85% adherence. In the setting of high adherence, low-level viremia was common.

FEN1-assisted DNA logic amplifier circuit for fast and compact DNA computing.

This work developed DNA amplifier logic gates (AND-OR, OR-AND, FAN-IN, FAN-OUT, and 4-bit square-root circuits) using a flap endonuclease 1 (FEN1)-catalyzed signal amplification reaction, for the fastest and compact DNA computing. Moreover, the logic circuit can use input strands with concentrations of less than 1 nM, which is more than 100 times lower than the input concentration of other DNA logic circuits, providing a promising methodology for constructing fast and compact DNA computations.

Modular Design of Highly Stable Semiconducting Porous Coordination Polymer for Efficient Electrosynthesis of Ammonia.

Developing highly stable porous coordination polymers (PCPs) with integrated electrical conductivity is crucial for advancing our understanding of electrocatalytic mechanisms and the structure-activity relationship of electrocatalysts. However, achieving this goal remains a formidable challenge because of the electrochemical instability observed in most PCPs. Herein, we develop a "modular design" strategy to construct electrochemically stable semiconducting PCP, namely, Fe-pyNDI, which incorporates a chain-type Fe-pyrazole metal cluster and π-stacking column with effective synergistic effects. The three-dimensional electron diffraction (3D ED) technique resolves the precise structure. Both theoretical and experimental investigation confirms that the π-stacking column in Fe-pyNDI can provide an efficient electron transport path and enhance the structural stability of the material. As a result, Fe-pyNDI can serve as an efficient model electrocatalyst for nitrate reduction reaction (NO3RR) to ammonia with a superior ammonia yield of 339.2 µmol h-1 cm-2 (14677 µg h-1 mgcat. -1) and a faradaic efficiency of 87 % at neutral electrolyte, which is comparable to state-of-the-art electrocatalysts. The in-situ X-ray absorption spectroscopy (XAS) reveals that during the reaction, the structure of Fe-pyNDI can be kept, while part of the Fe3+ in Fe-pyNDI was reduced in situ to Fe2+, which serves as the potential active species for NO3RR.

Optimization of Clostridium beijerinckii semi-solid fermentation of rape straw to produce butyric acid by genome analysis.

Butyric acid is a volatile saturated monocarboxylic acid, which is widely used in the chemical, food, pharmaceutical, energy, and animal feed industries. This study focuses on producing butyric acid from pre-treated rape straw using simultaneous enzymatic hydrolysis semi-solid fermentation (SEHSF). Clostridium beijerinckii BRM001 screened from pit mud of Chinese nongxiangxing baijiu was used. The genome of C. beijerinckii BRM001 was sequenced and annotated. Using rape straw as the sole carbon source, fermentation optimization was carried out based on the genomic analysis of BRM001. The optimized butyric acid yield was as high as 13.86 ± 0.77 g/L, which was 2.1 times higher than that of the initial screening. Furthermore, under optimal conditions, non-sterile SEHSF was carried out, and the yield of butyric acid was 13.42 ± 0.83 g/L in a 2.5-L fermentor. This study provides a new approach for butyric acid production which eliminates the need for detoxification of straw hydrolysate and makes full use of the value of fermentation waste residue without secondary pollution, making the whole process greener and more economical, which has a certain industrial potential.

Narazaciclib, a novel multi-kinase inhibitor with potent activity against CSF1R, FLT3 and CDK6, shows strong anti-AML activity in defined preclinical models.

CSF1R is a receptor tyrosine kinase responsible for the growth/survival/polarization of macrophages and overexpressed in some AML patients. We hypothesized that a novel multi-kinase inhibitor (TKi), narazaciclib (HX301/ON123300), with high potency against CSF1R (IC50 ~ 0.285 nM), would have anti-AML effects. We tested this by confirming HX301's high potency against CSF1R (IC50 ~ 0.285 nM), as well as other kinases, e.g. FLT3 (IC50 of ~ 19.77 nM) and CDK6 (0.53 nM). An in vitro proliferation assay showed that narazaciclib has a high growth inhibitory effect in cell cultures where CSF1R or mutant FLT3-ITD variants that may be proliferation drivers, including primary macrophages (IC50 of 72.5 nM) and a subset of AML lines (IC50 < 1.5 µM). In vivo pharmacology modeling of narazaciclib using five AML xenografts resulted in: inhibition of MV4-11 (FLT3-ITD) subcutaneous tumor growth and complete suppression of AM7577-PDX (FLT3-ITD/CSF1Rmed) systemic growth, likely due to the suppression of FLT3-ITD activity; complete suppression of AM8096-PDX (CSF1Rhi/wild-type FLT3) growth, likely due to the inhibition of CSF1R ("a putative driver"); and nonresponse of both AM5512-PDX and AM7407-PDX (wild-type FLT3/CSF1Rlo). Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1Rhi and/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants.

Rapid evolutionary change in trait correlations of single proteins.

Many organismal traits are genetically determined and covary in evolving populations. The resulting trait correlations can either help or hinder evolvability - the ability to bring forth new and adaptive phenotypes. The evolution of evolvability requires that trait correlations themselves must be able to evolve, but we know little about this ability. To learn more about it, we here study two evolvable systems, a yellow fluorescent protein and the antibiotic resistance protein VIM-2 metallo beta-lactamase. We consider two traits in the fluorescent protein, namely the ability to emit yellow and green light, and three traits in our enzyme, namely the resistance against ampicillin, cefotaxime, and meropenem. We show that correlations between these traits can evolve rapidly through both mutation and selection on short evolutionary time scales. In addition, we show that these correlations are driven by a protein's ability to fold, because single mutations that alter foldability can dramatically change trait correlations. Since foldability is important for most proteins and their traits, mutations affecting protein folding may alter trait correlations mediated by many other proteins. Thus, mutations that affect protein foldability may also help shape the correlations of complex traits that are affected by hundreds of proteins.

The death burden of colorectal cancer attributable to modifiable risk factors, trend analysis from 1990 to 2019 and future predictions.

BACKGROUND: The death burden attributable to modifiable risk factors is key to colorectal cancer (CRC) prevention. This study aimed to assess the prevalence and regional distribution of attributable CRC death burden worldwide from 1990 to 2019. METHODS: We extracted data from the Global Burden of Disease Study in 2019 and assessed the mortality, age-standardized death rate (ASDR), population attributable fractions, and time trend in CRC attributable to risk factors by geography, socio-demographic index (SDI) quintile, age, and sex. RESULTS: Over the past 30 years, from high to low SDI region, the number of deaths increased by 46.56%, 103.55%, 249.64%, 231.89%, 163.11%, and the average annual percentage change (AAPC) for ASDR were -1.06%, -0.01%, 1.32%, 1.19%, and 0.65%, respectively. ASDR in males was 1.88 times than in females in 2019; ASDR in males showed an increasing trend (AAPC 0.07%), whereas ASDR in females showed a decreasing trend (AAPC -0.69%) compared to figures in 1990. In 2019, from high to low SDI region, the 15-49 age group accounted for 3%, 6%, 10%, 11%, and 15% of the total population; dietary and metabolic factors contributed 43.4% and 20.8% to CRC-attributable death worldwide. From high to low SDI region, ASDRs caused by dietary and metabolic factors increased by -23.4%, -5.5%, 25.8%, 29.1%, 13.5%, and 1.4%, 33.3%, 100.8%, 128.4%, 77.7% respectively, compared to 1990. CONCLUSIONS: The attributable CRC death burden gradually shifted from higher SDI to lower SDI regions. The limitation in males was more significant, and the gap is expected to be further expanded. In lower SDI regions, the death burden tended to affect younger people. The leading cause of CRC-attributable deaths was the inadequate control of dietary and metabolic risk factors.

VX-509 attenuates the stemness characteristics of colorectal cancer stem-like cells by regulating the epithelial-mesenchymal transition through Nodal/Smad2/3 signaling.

BACKGROUND: Colorectal cancer stem cells (CCSCs) are heterogeneous cells that can self-renew and undergo multidirectional differentiation in colorectal cancer (CRC) patients. CCSCs are generally accepted to be important sources of CRC and are responsible for the progression, metastasis, and therapeutic resistance of CRC. Therefore, targeting this specific subpopulation has been recognized as a promising strategy for overcoming CRC. AIM: To investigate the effect of VX-509 on CCSCs and elucidate the underlying mechanism. METHODS: CCSCs were enriched from CRC cell lines by in conditioned serum-free medium. Western blot, Aldefluor, transwell and tumorigenesis assays were performed to verify the phenotypic characteristics of the CCSCs. The anticancer efficacy of VX-509 was assessed in HCT116 CCSCs and HT29 CCSCs by performing cell viability analysis, colony formation, sphere formation, flow cytometry, and western blotting assessments in vitro and tumor growth, immunohistochemistry and immunofluorescence assessments in vivo. RESULTS: Compared with parental cells, sphere cells derived from HCT116 and HT29 cells presented increased expression of stem cell transcription factors and stem cell markers and were more potent at promoting migration and tumorigenesis, demonstrating that the CRC sphere cells displayed CSC features. VX-509 inhibited the tumor malignant biological behavior of CRC-stem-like cells, as indicated by their proliferation, migration and clonality in vitro, and suppressed the tumor of CCSC-derived xenograft tumors in vivo. Besides, VX-509 suppressed the CSC characteristics of CRC-stem-like cells and inhibited the progression of epithelial-mesenchymal transition (EMT) signaling in vitro. Nodal was identified as the regulatory factor of VX-509 on CRC stem-like cells through analyses of differentially expressed genes and CSC-related database information. VX-509 markedly downregulated the expression of Nodal and its downstream phosphorylated Smad2/3 to inhibit EMT progression. Moreover, VX-509 reversed the dedifferentiation of CCSCs and inhibited the progression of EMT induced by Nodal overexpression. CONCLUSION: VX-509 prevents the EMT process in CCSCs by inhibiting the transcription and protein expression of Nodal, and inhibits the dedifferentiated self-renewal of CCSCs.

Role of CCRL2 in the Pathogenesis of Experimental Autoimmune Myocarditis via P21-Activated Kinase 1/NOD-Like Receptor Protein 3 Pathway.

Myocarditis, a severe inflammatory disease, is becoming a worldwide public health concern. This study aims to elucidate the effect of Chemokine (C C motif) receptor-like 2 (CCRL2) in experimental autoimmune myocarditis (EAM) occurrence and its potential regulatory mechanisms.EAM was simulated in a mouse model injected with α-myosin-heavy chain. The changes on EAM were assessed through histological staining of heart tissues, including measuring cardiac troponin I (cTnI), proinflammatory cytokines, transferase-mediated dUTP nick end labeling (TUNEL) assay, and cardiac function. Then, the heart tissues from the EAM mouse model and control groups were analyzed through transcriptome sequencing to identify the differential expressed genes (DEGs) and hub genes related to pyroptosis. Downregulation of CCRL2 further verified the function of CCRL2 on EAM and p21-activated kinase 1/NOD-like receptor protein 3 (PAK/NLRP3) signaling pathways in vivo.The EAM model was constructed successfully, with the heart weight/body weight ratio, serum level of cTnI, and concentrations of proinflammatory cytokines elevation. Moreover, cell apoptosis was also significantly increased. Transcriptome sequencing revealed 696 and 120 upregulated and downregulated DEGs, respectively. After functional enrichment, CCRL2 was selected as a potential target. Then, we verified that CCRL2 knockdown improved cardiac function, alleviated EAM occurrence, and reduced PAK/NLRP3 protein expression.CCRL2 may act as a novel potential treatment target in EAM by regulating the PAK1/NLRP3 pathway.

High temperature delays and low temperature accelerates evolution of a new protein phenotype.

Since the origin of life, temperatures on earth have fluctuated both on short and long time scales. How such changes affect the rate at which Darwinian evolution can bring forth new phenotypes remains unclear. On the one hand, high temperature may accelerate phenotypic evolution because it accelerates most biological processes. On the other hand, it may slow phenotypic evolution, because proteins are usually less stable at high temperatures and therefore less evolvable. Here, to test these hypotheses experimentally, we evolved a green fluorescent protein in E. coli towards the new phenotype of yellow fluorescence at different temperatures. Yellow fluorescence evolved most slowly at high temperature and most rapidly at low temperature, in contradiction to the first hypothesis. Using high-throughput population sequencing, protein engineering, and biochemical assays, we determined that this is due to the protein-destabilizing effect of neofunctionalizing mutations. Destabilization is highly detrimental at high temperature, where neofunctionalizing mutations cannot be tolerated. Their detrimental effects can be mitigated through excess stability at low temperature, leading to accelerated adaptive evolution. By modifying protein folding stability, temperature alters the accessibility of mutational paths towards high-fitness genotypes. Our observations have broad implications for our understanding of how temperature changes affect evolutionary adaptations and innovations.

Preparation of layer-assembled W/O/W-type microencapsulated beads and application in solid-state fermentation.

In this study, microcapsule beads-0-3-layers (M-0-3 indicates microencapsulated beads with 0, 1, 2, and 3 layers) were prepared, their properties were measured and characterized, and the effects of M-0-3 on solid-state fermentation were investigated. The results showed that in a liquid environment, the releasing glucoamylase activities of M-0-3 were 55.77%, 47.67%, 45.85%, and 42.87% in 360 h, respectively. In the solid environment, the reducing sugar production efficiency of M-0-3 was 29.84%, 27.72%, 19.16%, and 15.93% in 15 days, respectively. Adding M-0-3 improved the alcohol and reduced sugar content while decreasing the residual starch content of the Jiupei, indicating that adding M-0-3 was beneficial to the solid-state fermentation of Baijiu. Solid-state fermentation simulation experiments illustrated that microcapsule beads play a positive role in the production of Baijiu, enhancing raw material utilization and yield of Baijiu production.

Novel Stereo-Induction Pattern in Pudovik Addition/Phospha-Brook Rearrangement Towards Chiral Trisubstituted Allenes.

Despite the significance of chiral allene skeletons in catalysis, organic synthesis and medicinal chemistry et al., there is a scarcity of reports on axially chiral allenyl phosphorus compounds. Here, we disclosed an efficient and straightforward cascade reaction between ethynyl ketones and phosphine oxides, resulting in a broad array of trisubstituted allenes incorporating a phosphorus moiety in high yields with excellent stereoselectivities facilitated by peptide-mimic phosphonium salt (PPS) catalysis, Additionally, comprehensive series of mechanistic experiments have been conducted to elucidate that this cascade reaction proceeds via an asymmetric Pudovik addition reaction followed by a subsequent phospha-Brook rearrangement that occurs concomitantly with kinetic resolution, representing a stereospecific rearrangement and protonation process facilitating central-to-axial chirality transfer in a cascade manner. We anticipate that our research will pave the way for a promising exploration of novel stereo-induction pattern in the Pudovik addition/phospha-Brook rearrangement cascade reaction.

Microplastics in remote coral reef environments of the Xisha Islands in the South China Sea: Source, accumulation and potential risk.

Microplastics (MPs) are of great concern to coral health, particularly enhanced biotoxicity of small microplastics (< 100 µm) (SMPs). However, their fate and harm to remote coral reef ecosystems remain poorly elucidated. This work systematically investigated the distributions and features of MPs and SMPs in sediments from 13 islands/reefs of the Xisha Islands, the South China Sea for comprehensively deciphering their accumulation, sources and risk to coral reef ecosystems. The results show that both MPs (average, 682 items/kg) and SMPs (average, 375 items/kg) exhibit heterogeneous distributions, with accumulation within atolls and dispersion across fringing islands, which controlled by human activities and hydrodynamic conditions. Cluster analysis for the first time reveals a pronounced difference in their compositions between the southern and northern Xisha Islands and resultant distinct sources, i.e., MPs in the north part were leaked mainly from local domestic sewage and fishing waste, while in the south part were probably derived from industrial effluents from adjacent countries. Our ecological risk assessment suggests that the ecosystem within the Yongle Atoll is exposed to a high-risk of MPs pollution. The novel results and proposed framework facilitate to effectively manage and control MPs and accordingly preserve a fragile biosphere in remote coral reefs.

Influence of intraoral scanning coverage on the accuracy of digital implant impressions - An in vitro study.

OBJECTIVES: To evaluate the influence of intraoral scanning coverage (IOSC) on digital implant impression accuracy in various partially edentulous situations and predict the optimal IOSC. METHODS: Five types of resin models were fabricated, each simulating single or multiple tooth loss scenarios with inserted implants and scan bodies. IOSC was subgrouped to cover two, four, six, eight, ten, and twelve teeth, as well as full arch. Each group underwent ten scans. A desktop scanner served as the reference. Accuracy was evaluated by measuring the Root mean square error (RMSE) values of scan bodies. A convolutional neural network (CNN) was trained to predict the optimal IOSC with different edentulous situations. Statistical analysis was performed using one-way ANOVA and Tukey's test. RESULTS: For single-tooth-missing situations, in anterior sites, significantly better accuracy was observed in groups with IOSC ranging from four teeth to full arch (p < 0.05). In premolar sites, IOSC spanning four to six teeth were more accurate (p < 0.05), while in molar sites, groups with IOSC encompassing two to eight teeth exhibited better accuracy (p < 0.05). For multiple-teeth-missing situations, IOSC covering four, six, and eight teeth, as well as full arch showed better accuracy in anterior gaps (p < 0.05). In posterior gaps, IOSC of two, four, six or eight teeth were more accurate (p < 0.05). The CNN predicted distinct optimal IOSC for different edentulous scenarios. CONCLUSIONS: Implant impression accuracy can be significantly impacted by IOSC in different partially edentulous situations. The selection of IOSC should be customized to the specific dentition defect condition. CLINICAL SIGNIFICANCE: The number of teeth scanned can significantly affect digital implant impression accuracy. For missing single or four anterior teeth, scan at least four or six neighboring teeth is acceptable. In lateral cases, two neighboring teeth may suffice, but extending over ten teeth, including contralateral side, might deteriorate the scan.

Pattern-based colorimetric sensor array chip for discrimination of Baijiu aromas.

Gas mixtures are comprised of numerous complex components, making the accurate identification a continuing challenge due to the significant limitations of existing detection methods. Herein, we developed a low-cost and sensitive pattern-based colorimetric sensor array chip for the identification of typical gas mixtures - Baijiu aroma. Specifically, three nanomaterials (AuNPs, MoS2 and ZIF-8) were prepared to adsorb gas molecules and enhance the reaction of trace gases with sensor arrays. The colorimetric sensor array chip took only 5 min to complete the recognition of Baijiu aromas and effectively avoided recognition errors caused by sommelier olfactory fatigue. Notably, the hierarchical cluster analysis (HCA) revealed no confusion or errors in the results of 80 tests across the five trials involving 16 commercial Baijius. Even fake Baijius with similar ingredients could be easily identified, demonstrating the excellent analytical capabilities of the system in Baijiu identification and its significant potential for quality control of Baijius.

Nicotine-derived NNK promotes CRC progression through activating TMUB1/AKT pathway in METTL14/YTHDF2-mediated m6A manner.

Cigarette smoking substantially promotes tumorigenesis and progression of colorectal cancer; however, the underlying molecular mechanism remains unclear. Among 662 colorectal cancer patients, our investigation revealed a significant correlation between cigarette smoking and factors, such as large tumor size, poor differentiation, and high degree of invasion. Among the nicotine-derived nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) emerged as the most critical carcinogen, which significantly promoted the malignant progression of colorectal cancer both in vivo and in vitro. The results of methylated RNA immunoprecipitation and transcriptome sequencing indicated that NNK upregulated transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) via N6-adenosine methylation, which was regulated by methyltransferase-like 14 (METTL14) and YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Elevated TMUB1 levels were associated with a higher risk of cancer invasion and metastasis, leading to a high mortality risk in patients with colorectal cancer. Additionally, TMUB1 promoted lysine63-linked ubiquitination of AKT by interacting with AMFR, which led to the induction of malignant proliferation and metastasis in colorectal cancer cells exposed to NNK. In summary, this study provides a new insight, indicating that targeting TMUB1 expression via METTL14/YTHDF2 mediated N6-adenosine methylation may be a potential therapeutic and prognostic target for patients with colorectal cancer who smoke.

Structurally diverse cucurbitane-type triterpenoids from the tubers of Hemsleya chinensis with cytotoxic activity.

Ten previously undescribed cucurbitane-type triterpenoids, namely hemslyencins A-F (1-6) and hemslyencosides A-D (7-10), together with twenty previously reported compounds (11-30), were isolated from the tubers of Hemsleya chinensis. Their structures were elucidated by unambiguous spectroscopic data (UV, IR, HR-ESI-MS, 1D and 2D NMR data). Hemslyencins A and B (1 and 2) possessing unique 9, 11-seco-ring system with a six-membered lactone moiety, were the first examples among of the cucurbitane-type triterpenoids, and hemslyencins C and D (3 and 4) and hemslyencoside D (10) are the infrequent pentacyclic cucurbitane triterpenes featuring a 6/6/6/5/6 fused system. The cytotoxic activities of all isolated compounds were evaluated against MCF-7, HCT-116, HeLa, and HepG2 cancer cells, and their structure-activity relationships (SARs) was discussed as well. Compounds 17, 25, and 26 showed significant cytotoxic effects with IC50 values ranging from 1.31 to 9.89 µM, among which compound 25 induced both apoptosis and cell cycle arrest at G2/M phase in a dose dependent manner against MCF-7 cells.