Optimal-Transport Analysis of Single-Cell Gene Expression Identifies Developmental Trajectories in Reprogramming.

Understanding the molecular programs that guide differentiation during development is a major challenge. Here, we introduce Waddington-OT, an approach for studying developmental time courses to infer ancestor-descendant fates and model the regulatory programs that underlie them. We apply the method to reconstruct the landscape of reprogramming from 315,000 single-cell RNA sequencing (scRNA-seq) profiles, collected at half-day intervals across 18 days. The results reveal a wider range of developmental programs than previously characterized. Cells gradually adopt either a terminal stromal state or a mesenchymal-to-epithelial transition state. The latter gives rise to populations related to pluripotent, extra-embryonic, and neural cells, with each harboring multiple finer subpopulations. The analysis predicts transcription factors and paracrine signals that affect fates and experiments validate that the TF Obox6 and the cytokine GDF9 enhance reprogramming efficiency. Our approach sheds light on the process and outcome of reprogramming and provides a framework applicable to diverse temporal processes in biology.

Source apportionment of soil PTE in a northern industrial county using PMF model: Partitioning strategies and uncertainty analysis.

Positive matrix factorization (PMF) has commonly been applied for source apportionment of potentially toxic elements (PTE) in agricultural soil, however, spatial heterogeneity of PTE significantly undermines the accuracy and reliability of PMF results. In this study, a representative industrial-agricultural hub in North China (Xuanhua district, Zhangjiakou City) was selected as the research subject, multiple partition processing (PP) strategies and uncertainty analyses were integrated to advance the PMF modeling and associated algorithm mechanisms were comparatively discussed. Specifically, we adopted three methods to split the research area into several subzones according to industrial density (PP-1), population density (PP-2), and the ecological risk index (PP-3) respectively, to rectify the spatial bias phenomenon of PTE concentrations and to achieve a more interpretable result. Our results indicated that the obvious enrichment of Cd, Pb, and Zn was found in the agricultural soil, with Hg and Cd accounted for 83.49% of the overall potential ecological risk. Combining proper PP with PMF can significantly improve the modelling accuracy. Uncertainty analysis showed that interval ratios of tracer species (Cd, Pb, Hg, and Zn) calculated by PP-3 were consistently lower than that of PP-1 and PP-2, indicating that PP-3 coupled PMF can afford the optimal modeling results. It suggested that natural sources, fertilizers and pesticides, atmosphere deposition, mining, and smelting were recognized as the major contributor for the soil PTE contamination. The contribution of anthropogenic activities, specifically fertilizers and pesticides, and atmosphere deposition, increased by 1.64% and 5.91% compared to PMF results. These findings demonstrate that integration of proper partitioning processing into PMF can effectively improve the accuracy of the model even at the case of soil PTE contamination with high heterogeneity, offering support to subsequently implement directional control strategies.

Characteristics analysis of solid waste generation and carbon emission of beer production in China.

As the largest beer producer and consumer in the world, China's endeavors to reduce solid waste generation (SWG) and carbon emissions (CEs) in the course of beer production assume paramount significance. This study aims to assess the SWG and CEs in beer production within China at both national and provincial levels, and further delves into the spatial distribution characteristics and evolving patterns across the country. Key findings of the study include:(1) Peak SWG and CEs were recorded in 2013, reaching 861.62 million tons and 2315.10 tCO2e, respectively, followed by a consistent decline. (2) Among the three types of solid waste, spent grain exhibited the highest generation rate, contributing to 94.38% of the total. (3) The emergence of China's beer industry dates back to the 1980s in the northeastern region, expanding to the southeastern and the Yangtze River Basin during the 1990s, ultimately extending nationwide. (4) The spatial distribution of beer production revealed significant regional disparities and notable industry concentration. Notably, many provinces witnessed reduced CEs from beer production starting in 2015, although the extent of reduction varied in different provinces. These findings serve as a scientific foundation for formulating emission reduction strategies in beer producing and offer insights for other food industries in China.

The Overexpression of Zea mays Strigolactone Receptor Gene D14 Enhances Drought Resistance in Arabidopsis thaliana L.

Strigolactones (SLs) represent a recently identified class of plant hormones that are crucial for plant tillering and mycorrhizal symbiosis. The D14 gene, an essential receptor within the SLs signaling pathway, has been well-examined in crops, like rice (Oryza sativa L.) and Arabidopsis (Arabidopsis thaliana L.), yet the research on its influence in maize (Zea mays L.) remains scarce. This study successfully clones and establishes Arabidopsis D14 gene overexpression lines (OE lines). When compared with the wild type (WT), the OE lines exhibited significantly longer primary roots during germination. By seven weeks of age, these lines showed reductions in plant height and tillering, alongside slight decreases in rosette and leaf sizes, coupled with early aging symptoms. Fluorescence-based quantitative assays indicated notable hormonal fluctuations in OE lines versus the WT, implying that D14 overexpression disrupts plant hormonal homeostasis. The OE lines, exposed to cold, drought, and sodium chloride stressors during germination, displayed an especially pronounced resistance to drought. The drought resistance of OE lines, as evident from dehydration-rehydration assays, outmatched that of the WT lines. Additionally, under drought conditions, the OE lines accumulated less reactive oxygen species (ROS) as revealed by the assessment of the related physiological and biochemical parameters. Upon confronting the pathogens Pseudomonas syringae pv. tomato DC3000 (Pst DC3000), post-infection, fluorescence quantitative investigations showed a significant boost in the salicylic acid (SA)-related gene expression in OE lines compared to their WT counterparts. Overall, our findings designate the SL receptor D14 as a key upregulator of drought tolerance and a regulator in the biotic stress response, thereby advancing our understanding of the maize SL signaling pathway by elucidating the function of the pivotal D14 gene.

Functional analysis of transgenic cry1Ah-1 maize.

Maize is an important food crop in the world, but the yield and quality of maize have been significantly reduced due to the impact of insect pests. In order to address this issue, the cry1Ah gene was subjected to error-prone PCR for mutagenesis, and subsequently, the mutant cry1Ah-1 gene was introduced into maize inbred line GSH9901 callus using the Agrobacterium-mediated method. The T2 generation transformed plants were obtained by subculture, and 9 transgenic positive plants were obtained by molecular detection which was carried out by PCR, qRT-PCR, Bt gold-labeled immunoassay test strips, Western blot and ELISA. It was found that the Cry1Ah-1 gene could be transcribed normally in maize leaves, of which OE1 and OE3 had higher relative expression levels and could successfully express proteins of 71.94 KD size. They were expressed in different tissues at the 6-leaf stage, heading stage and grain-filling stage, and could ensure the protection of maize from corn borer throughout the growth period. The biological activities of OE1 and OE3 were tested indoors and in the field, and the results showed that in indoors, the corn borer that fed on OE1 and OE3 corn leaves had a mortality rate of 100 % after 3 days; in the field, OE1 and OE3 had strong insecticidal activity against corn borer, reaching a high resistance level. In conclusion, the transgenic cry1Ah-1 maize has a strong insecticidal effect on corn borer, and has a good prospect of commercialization.

Design, optimization and application of a highly sensitive microbial electrolytic cell-based BOD biosensor.

Biochemical oxygen demand (BOD) is an important biochemical indicator for determining the degree of water pollution and guiding the design of wastewater treatment processes. BOD sensors based on microbial electrochemical technology can conduct real-time online monitoring of organic matter and have attracted extensive attention. However, research on microbial electrolytic cell (MEC)-type BOD sensors is at the stage of theoretical exploration. Here, we designed and optimized a highly sensitive MEC-type BOD sensor by screening inoculants, comparing electrode materials, and optimizing the reactor configuration. The results showed that effective means to optimize a BOD sensor for fast activation and sensitive testing included the inoculation of the MEC reactor effluent with large amounts of biomass and highly active bacteria, selection of carbon felt electrodes with excellent adsorption and permeability, miniaturization of the reactor, regulation of suitable electrode spacing, and design of the penetrating fluid structure. Then, the optimized sensing system was applied to determine the BOD concentration in model solutions of sodium acetate in a laboratory environment, where it accurately measured BOD concentrations in the range of 10-500 mg/L and maintained good parallelism during long-term operation. Next, the MEC-type BOD sensors were put into practice in the field as an alarm for accidents at an actual sewage plant. The whole BOD sensing system was quickly assembled on site and started up, and it gave an early warning shortly after the concentration of organic matter in the water suddenly increased, thus showing a high potential for engineering applications. This study broadened the domains of application of MEC-type BOD sensors in environmental monitoring, and promoted the development of technological innovation in water ecology and environmental monitoring.

The changes and potential effects of zinc homeostasis in periodontitis microenvironment.

Zinc is a very important and ubiquitous element, which is present in oral environment, daily diet, oral health products, dental restorative materials, and so on. However, there is a lack of attention to the role of both extracellular or intracellular zinc in the progression of periodontitis and periodontal regeneration. This review summarizes the characteristics of immunological microenvironment and host cells function in several key stages of periodontitis progression, and explores the regulatory effect of zinc during this process. We find multiple evidence indicate that zinc may be involved and play a key role in the stages of immune defense, inflammatory response and bone remodeling. Zinc supplementation in an appropriate dose range or regulation of zinc transport proteins can promote periodontal regeneration by either enhancing immune defense or up-regulating local cells proliferation and differentiation functions. Therefore, zinc homeostasis is essential in periodontal remodeling and regeneration. More attention is suggested to be focused on zinc homeostasis regulation and consider it as a potential strategy in the studies on periodontitis treatment, periodontal-guided tissue regeneration, implant material transformation, and so on.

The bidirectional effect of neutrophils on periodontitis model in mice: A systematic review.

OBJECTIVE: To evaluate the regulatory role of neutrophils as the first line of host immune defense in the periodontal microenvironment of mice. METHODS: A systematic search was performed using PubMed, Web of Science, and ScienceDirect databases for articles published between 2012 and 2023. In this review, articles investigating the effect of neutrophils on alveolar bone resorption in a mouse model of periodontitis were selected and evaluated according to eligibility criteria. Important variables that may influence outcomes were analyzed. RESULTS: Eleven articles were included in this systematic review. The results showed that because of their immune defense functions, the functional homeostasis of local neutrophils is critical for periodontal health. Neutrophil deficiency aggravates alveolar bone loss. However, several studies have shown that excessive neutrophil infiltration is positively correlated with alveolar bone resorption caused by periodontitis in mice. Therefore, the homeostasis of neutrophil function needs to be considered in the treatment of periodontitis. CONCLUSIONS: Pooled analysis suggests that neutrophils play a bidirectional role in periodontal tissue remodeling in mouse periodontitis models. Therefore, targeted regulation of local neutrophil function provides a novel strategy for the treatment of periodontitis.

The relationship between adolescent impulsivity, mental health, and internet addiction: a latent profile analysis.

This study aimed to identify group variations in adolescent impulsivity and explore the connections between latent categories of impulsivity and psychological symptoms, social anxiety, and internet addiction. The research involved 2,378 participants from three middle schools in Guangdong Province, China. We assessed the impact of impulsivity levels (measured by BBIS) on depression (measured by KADS-11), anxiety (measured by SCARED), social anxiety (measured by SASC), and internet addiction (measured by YDQ). Latent profile analysis was employed to examine the diversity in adolescent impulsivity, establish latent classifications, and investigate the variances in psychological symptoms, social anxiety, and internet addiction. The middle school students were categorized into five latent groups based on their BBIS scores. Statistical analysis revealed five impulsivity categories, strongly linked to psychological symptoms and social anxiety but less strongly associated with internet addiction. The high impulsivity group (C5) exhibited higher scores in psychological symptoms and social anxiety compared to other groups, whereas the poor self-regulation group (C3) displayed greater psychological symptoms, social anxiety scores, and internet addiction than the impulsive behavior group (C4). Future investigations should investigate the underlying factors contributing to the observed differences among these groups.

One-Step Synthesis of a Non-Precious-Metal Tris (Fe/N/F)-Doped Carbon Catalyst for Oxygen Reduction Reactions.

Advancements in inexpensive, efficient, and durable oxygen reduction catalysts is important for maintaining the sustainable development of fuel cells. Although doping carbon materials with transition metals or heteroatomic doping is inexpensive and enhances the electrocatalytic performance of the catalyst, because the charge distribution on its surface is adjusted, the development of a simple method for the synthesis of doped carbon materials remains challenging. Here, a non-precious-metal tris (Fe/N/F)-doped particulate porous carbon material (21P2-Fe1-850) was synthesized by employing a one-step process, using 2-methylimidazole, polytetrafluoroethylene, and FeCl3 as raw materials. The synthesized catalyst exhibited a good oxygen reduction reaction performance with a half-wave potential of 0.85 V in an alkaline medium (compared with 0.84 V of commercial Pt/C). Moreover, it had better stability and methanol resistance than Pt/C. This was mainly attributed to the effect of the tris (Fe/N/F)-doped carbon material on the morphology and chemical composition of the catalyst, thereby enhancing the catalyst's oxygen reduction reaction properties. This work provides a versatile method for the gentle and rapid synthesis of highly electronegative heteroatoms and transition metal co-doped carbon materials.

Maize plant architecture trait QTL mapping and candidate gene identification based on multiple environments and double populations.

BACKGROUND: The plant architecture traits of maize determine the yield. Plant height, ear position, leaf angle above the primary ear and internode length above the primary ear together determine the canopy structure and photosynthetic efficiency of maize and at the same time affect lodging and disease resistance. A flat and tall plant architecture confers an obvious advantage in the yield of a single plant but is not conducive to dense planting and results in high rates of lodging; thus, it has been gradually eliminated in production. Although using plants that are too compact, short and density tolerant can increase the yield per unit area to a certain extent, the photosynthetic efficiency of such plants is low, ultimately limiting yield increases. Genetic mapping is an effective method for the improvement of plant architecture to identify candidate genes for regulating plant architecture traits. RESULTS: To find the best balance between the yield per plant and the yield per unit area of maize, in this study, the F2:3 pedigree population and a RIL population with the same male parent were used to identify QTL for plant height (PH), ear height (EH), leaf angle and internode length above the primary ear (LAE and ILE) in Changchun and Gongzhuling for 5 consecutive years (2016-2020). A total of 11, 13, 23 and 13 QTL were identified for PH, EH, LAE, and ILE, respectively. A pleiotropic consistent QTL for PH overlapped with that for EH on chromosome 3, with a phenotypic variation explanation rate from 6.809% to 21.96%. In addition, there were major consistent QTL for LAE and ILE, and the maximum phenotypic contribution rates were 24.226% and 30.748%, respectively. Three candidate genes were mined from the three consistent QTL regions and were involved in the gibberellin-activated signal pathway, brassinolide signal transduction pathway and auxin-activated signal pathway, respectively. Analysis of the expression levels of the three genes showed that they were actively expressed during the jointing stage of vigorous maize growth. CONCLUSIONS: In this study, three consistent major QTL related to plant type traits were identified and three candidate genes were screened. These results lay a foundation for the cloning of related functional genes and marker-assisted breeding of related functional genes.

Full-length dystrophin restoration via targeted exon integration by AAV-CRISPR in a humanized mouse model of Duchenne muscular dystrophy.

Targeted gene-editing strategies have emerged as promising therapeutic approaches for the permanent treatment of inherited genetic diseases. However, precise gene correction and insertion approaches using homology-directed repair are still limited by low efficiencies. Consequently, many gene-editing strategies have focused on removal or disruption, rather than repair, of genomic DNA. In contrast, homology-independent targeted integration (HITI) has been reported to effectively insert DNA sequences at targeted genomic loci. This approach could be particularly useful for restoring full-length sequences of genes affected by a spectrum of mutations that are also too large to deliver by conventional adeno-associated virus (AAV) vectors. Here, we utilize an AAV-based, HITI-mediated approach for correction of full-length dystrophin expression in a humanized mouse model of Duchenne muscular dystrophy (DMD). We co-deliver CRISPR-Cas9 and a donor DNA sequence to insert the missing human exon 52 into its corresponding position within the DMD gene and achieve full-length dystrophin correction in skeletal and cardiac muscle. Additionally, as a proof-of-concept strategy to correct genetic mutations characterized by diverse patient mutations, we deliver a superexon donor encoding the last 28 exons of the DMD gene as a therapeutic strategy to restore full-length dystrophin in >20% of the DMD patient population. This work highlights the potential of HITI-mediated gene correction for diverse DMD mutations and advances genome editing toward realizing the promise of full-length gene restoration to treat genetic disease.

The Integration of Metabolomics and Transcriptomics Provides New Insights for the Identification of Genes Key to Auxin Synthesis at Different Growth Stages of Maize.

As a staple food crop, maize is widely cultivated worldwide. Sex differentiation and kernel development are regulated by auxin, but the mechanism regulating its synthesis remains unclear. This study explored the influence of the growth stage of maize on the secondary metabolite accumulation and gene expression associated with auxin synthesis. Transcriptomics and metabonomics were used to investigate the changes in secondary metabolite accumulation and gene expression in maize leaves at the jointing, tasseling, and pollen-release stages of plant growth. In total, 1221 differentially accumulated metabolites (DAMs) and 4843 differentially expressed genes (DEGs) were screened. KEGG pathway enrichment analyses of the DEGs and DAMs revealed that plant hormone signal transduction, tryptophan metabolism, and phenylpropanoid biosynthesis were highly enriched. We summarized the key genes and regulatory effects of the tryptophan-dependent auxin biosynthesis pathways, giving new insights into this type of biosynthesis. Potential MSTRG.11063 and MSTRG.35270 and MSTRG.21978 genes in auxin synthesis pathways were obtained. A weighted gene co-expression network analysis identified five candidate genes, namely TSB (Zm00001d046676 and Zm00001d049610), IGS (Zm00001d020008), AUX2 (Zm00001d006283), TAR (Zm00001d039691), and YUC (Zm00001d025005 and Zm00001d008255), which were important in the biosynthesis of both tryptophan and auxin. This study provides new insights for understanding the regulatory mechanism of auxin synthesis in maize.

Overexpression of ZmDHN15 Enhances Cold Tolerance in Yeast and Arabidopsis.

Maize (Zea mays L.) originates from the subtropical region and is a warm-loving crop affected by low-temperature stress. Dehydrin (DHN) protein, a member of the Group 2 LEA (late embryogenesis abundant proteins) family, plays an important role in plant abiotic stress. In this study, five maize DHN genes were screened based on the previous transcriptome sequencing data in our laboratory, and we performed sequence analysis and promoter analysis on these five DHN genes. The results showed that the promoter region has many cis-acting elements related to cold stress. The significantly upregulated ZmDHN15 gene has been further screened by expression pattern analysis. The subcellular localization results show that ZmDHN15 fusion protein is localized in the cytoplasm. To verify the role of ZmDHN15 in cold stress, we overexpressed ZmDHN15 in yeast and Arabidopsis. We found that the expression of ZmDHN15 can significantly improve the cold resistance of yeast. Under cold stress, ZmDHN15-overexpressing Arabidopsis showed lower MDA content, lower relative electrolyte leakage, and less ROS (reactive oxygen species) when compared to wild-type plants, as well as higher seed germination rate, seedling survival rate, and chlorophyll content. Furthermore, analysis of the expression patterns of ROS-associated marker genes and cold-response-related genes indicated that ZmDHN15 genes play an important role in the expression of these genes. In conclusion, the overexpression of the ZmDHN15 gene can effectively improve the tolerance to cold stress in yeast and Arabidopsis. This study is important for maize germplasm innovation and the genetic improvement of crops.

Overexpression of ZmSRG7 Improves Drought and Salt Tolerance in Maize (Zea mays L.).

Osmotic stress caused by drought and high salinity is the key factor limiting plant growth. However, its underlying molecular regulatory mechanism remains unclear. In this study, we found the stress-related gene Zm00001d019704 (ZmSRG7) based on transcriptome sequencing results previously obtained in the laboratory and determined its biological function in maize. We found that ZmSRG7 was significantly expressed in both roots and leaves under 10% PEG6000 or 150 mM NaCl. Subcellular localization showed that the gene was localized in the nucleus. The germination rate and root length of the ZmSRG7 overexpressing lines were significantly increased under drought or salt stress compared with the control. However, after drought stress, the survival rate and relative water content of maize were increased, while the water loss rate was slowed down. Under salt stress, the Na+ concentration and Na+: K+ ratio of maize was increased. In addition, the contents of antioxidant enzymes and proline in maize under drought or salt stress were higher than those in the control, while the contents of MDA, H2O2 and O2- were lower than those in the control. The results showed that the ZmSRG7 gene played its biological function by regulating the ROS signaling pathway. An interaction between ZmSRG7 and the Zmdhn1 protein was found using a yeast two-hybrid experiment. These results suggest that the ZmSRG7 gene can improve maize tolerance to drought or salt by regulating hydrogen peroxide homeostasis.

A Novel Senescence-Specific Gene (ZmSAG39) Negatively Regulates Darkness and Drought Responses in Maize.

The papain-like cysteine proteases (PLCPs) is a subfamily of cysteine proteases that plays an important role in leaf senescence, and some of its members are involved in the regulation of plant growth and development under stress. In this study, we cloned a new gene, ZmSAG39, from maize. Expression profile analysis showed that ZmSAG39 was induced by darkness and drought treatments. In addition, the ZmSAG39 overexpression in maize accelerated the senescence of maize leaves under darkness and drought treatments. However, the knockout of ZmSAG39 in maize enhanced the resistance of maize to darkness and drought stresses and reduced the degree of senescence of maize leaves. Under drought stress, compared with WT plants, the knockout lines had a higher seed germination rate, seedling survival rate and chlorophyll content, and lower reactive oxygen species (ROS) level and malondialdehyde (MDA) content. In addition, quantitative real-time PCR (qRT-PCR) analysis showed that ZmSAG39 negatively regulated some stress-related genes but positively regulated senescence-related genes under darkness and drought stress conditions. To summarize, these results indicate that ZmSAG39 is a senescence-related gene and plays a negative role in response to darkness and drought stresses. This study laid a theoretical foundation for the innovation of maize germplasm resources with high quality, high yield and strong stress resistance.

Circular RNAs acting as ceRNAs mediated by miRNAs may be involved in the synthesis of soybean fatty acids.

Soybean oil is composed of fatty acids and glycerol. The content and composition of fatty acids partly determine the quality of soybean seeds. Circular RNAs (circRNAs) are endogenous non-coding RNAs that competitively bind to microRNAs (miRNAs) through miRNA recognition elements, thereby acting as sponges to regulate the expression of target genes. Although circRNAs have been identified previously in soybean, only their expression has been investigated without exploration of the competitive endogenous RNAs (ceRNAs) network of circRNAs-miRNAs-mRNAs. In this study, circRNAs in immature pods of a low linolenic acid soybean Mutant 72' (MT72) and the wild-type control 'Jinong 18' (JN18) were systematically identified and analyzed at 30 and 40 days after flowering using high-throughput sequencing technology. We identified 6377 circRNAs, of which 114 were differentially expressed. Gene ontology and KEGG pathway analyses of targeted mRNAs in the ceRNAs network indicated that the differentially expressed circRNAs may be involved in fatty acid transport, suggesting that circRNAs may play a post-transcriptional regulatory role in soybean oil synthesis. This study provides a foundation for future exploration of the function of circRNAs in soybean and presents novel insights to guide further studies of plant circRNAs.

Do intra-articular injections of analgesics improve outcomes after temporomandibular joint arthrocentesis?: A systematic review and meta-analysis.

OBJECTIVES: Intra-articular analgesics are increasingly being used after temporomandibular joint (TMJ) arthrocentesis but without clear evidence on its efficacy. The aim of this study was to review the role of intra-articular analgesic injected after TMJ arthrocentesis in improving post-operative outcomes. METHODS: PubMed, Embase, Scopus, BioMed Central, CENTRAL and Google Scholar databases were searched from inception up to 15th April 2020. Randomised controlled trials (RCTs) on adult patients with temporomandibular joint disorders (TMDs) comparing any intra-articular analgesic with control after arthrocentesis were included. Risk of bias was assessed by Cochrane Collaboration's Risk of Bias-2 tool. RESULTS: Nine RCTs were included. Four studies used non-steroidal anti-inflammatory drugs (NSAIDs) and five used opioids after arthrocentesis. Descriptive analysis of NSAID studies indicated that intra-articular NSAIDs may not improve pain and maximal mouth opening (MMO) after TMJ arthrocentesis. Meta-analysis indicated a statistically significant reduction of pain with the use of opioids at 1 week, 1, 3, and 6 months. Similarly, MMO was significantly improved with intra-articular opioids at 1 week, 1 and 6 months. Data were analysed from a limited number of studies with a small sample size. The quality of the included studies was low. CONCLUSIONS: Low-quality evidence suggests that intra-articular NSAIDs may have no effect on pain and MMO after TMJ arthrocentesis. Intra-articular opioids may improve pain and MMO at short-term follow-up. Results are to be interpreted with caution considering several limitations of the review. Further high-quality trials with large sample size are needed to provide better evidence.

Design and synthesis of tricyclic terpenoid derivatives as novel PTP1B inhibitors with improved pharmacological property and in vivo antihyperglycaemic efficacy.

Overexpression of protein tyrosine phosphatase 1B (PTP1B) induces insulin resistance in various basic and clinical research. In our previous work, a synthetic oleanolic acid (OA) derivative C10a with PTP1B inhibitory activity has been reported. However, C10a has some pharmacological defects and cytotoxicity. Herein, a structure-based drug design approach was used based on the structure of C10a to elaborate the smaller tricyclic core. A series of tricyclic derivatives were synthesised and the compounds 15, 28 and 34 exhibited the most PTP1B enzymatic inhibitory potency. In the insulin-resistant human hepatoma HepG2 cells, compound 25 with the moderate PTP1B inhibition and preferable pharmaceutical properties can significantly increase insulin-stimulated glucose uptake and showed the insulin resistance ameliorating effect. Moreover, 25 showed the improved in vivo antihyperglycaemic potential in the nicotinamide-streptozotocin-induced T2D. Our study demonstrated that these tricyclic derivatives with improved molecular architectures and antihyperglycaemic activity could be developed in the treatment of T2D.