Comparison of the clinical efficacy of bone grafting and bone grafting combined with guided tissue regeneration in periodontal regenerative therapy: a meta-analysis.

OBJECTIVE: This study aims to compare the clinical efficacy of simple bone grafting and bone grafting combined with guided tissue regeneration (GTR) in periodontal regenerative therapy. METHODS: The authors systematically searched PubMed, the Web of Science, The National Library of Medicine, the China National Knowledge Infrastructure database and the Wanfang database and collected randomized controlled trials relating to bone graft co-guided tissue regeneration. The retrieval was conducted between January 1990 and December 2022. This study included relevant literature about the clinical efficacy of bone grafting combined with GTR according to the population, intervention, control and outcomes principle and excluded studies using other materials in addition to bone graft and membrane materials. After independently screening the literature, extracting the data and evaluating the risk of bias in the included studies, data analysis was performed using RevMan 5.3 software.  Results: Eighteen studies met the inclusion criteria, and, after further evaluation, a total of 327 teeth that were featured in 15 articles were finally included for meta-analysis. The meta-analysis showed that there was no significant statistical difference in clinical attachment level, probing depth and bone gain between the test group (bone grafting with GTR) and the control group (bone grafting only) at 6 months after the operation (p > 0.05). In terms of gingival recession (GR), the use of non-resorbable membranes produced more recession in the test group compared with the control group (p < 0.05), whereas the use of resorbable membranes produced less recession (p < 0.05). CONCLUSION: Both simple bone grafting and bone grafting combined with membrane materials have good clinical efficacy in periodontal regenerative therapy, and no significant difference in clinical efficacy is indicated between the two, with the exception of GR.

Allogeneic tendons in the treatment of malunited lateral malleolar avulsion fractures with chronic lateral ankle instability.

BACKGROUND: The aim of this study is to report our institution's experience regarding the application of allogeneic tendons for the reconstruction of malunited lateral malleolar avulsion fractures with chronic lateral ankle instability. METHODS: This retrospective study included 34 (34 ankles) patients surgically treated for malunited lateral malleolar avulsion fractures with chronic lateral ankle instability from January 2016 to December 2019. All patients underwent allogeneic tendon reconstruction. The pre- and postoperative American Orthopaedic Foot and Ankle Society (AOFAS) scores、Karlsson Ankle Functional Scores (KAFS) and visual analogue scale (VAS) scores were used to evaluate the functional recovery of the ankle joint. The final follow-up, based on radiographic assessment, including talar tilt and anterior talar translation, was performed to evaluate the stability of the postoperative ankle joints. RESULTS: Thirty-two patients (32 ankles) returned for final clinical and radiologic follow-up at an average of 29 (range 24-35) months and 2 patients (2 ankles) were lost to follow-up. The preoperative talus inclination angle (13.6 ± 1.9°) and anterior displacement (9.6 ± 2.8 mm) were re-examined under X-ray and found to be reduced to 3.4 ± 1.2° and 3.8 ± 1.1 mm, respectively (p＜0.01). The AOFAS scores increased from 58.5 ± 4.0 to 90.9 ± 3.8 and the Karlsson scores improved from 52.2 ± 3.6 to 89.8 ± 4.5, which was obviously better and the difference was statistically significant (P < 0.01). The VAS scores were significantly reduced from a preoperative mean of 6.8 ± 1.0 to 2.8 ± 0.9 postoperatively (p＜0.01). CONCLUSION: In this population and with this follow-up, the application of allogeneic tendons to treat malunited lateral malleolar avulsion fractures combined with chronic lateral ankle instability appeared safe and effective.

Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation.

This study aimed to evaluate the efficacy and safety of venetoclax plus azacitidine and donor lymphocyte infusion (DLI) in treating patients with relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-six AML patients who relapsed after allo-HSCT were enrolled and treated with venetoclax plus azacitidine and DLI. Complete remission with incomplete recovery (CRi), partial remission (PR), and objective remission rate (ORR) were assessed, and then event-free survival (EFS) and overall survival (OS) were evaluated. Besides, adverse events were documented. Additionally, whole exome sequencing was performed in bone marrow samples. The CRi, PR, and ORR rates were 26.9%, 34.6%, and 61.5%, respectively. The median time of EFS and OS was 120 (95% CI: 71-610) days and 284.5 (95% CI: 81-610) days, respectively. The most common adverse events were hematologic system adverse events including agranulocytosis, anemia, and thrombocytopenia, while the adverse events of other systems were relatively less and milder. In addition, no serious adverse events existed. Of note, there were 6 (23.1%) patients who developed GVHD. As for gene mutation, 49 mutated genes were found, which were categorized as first-, second-, and third-class mutations, and then further analysis revealed that the first-class mutations were not correlated with EFS or OS. Additionally, the most frequent mutated genes were FLT3, CEBPA, DNMT3A, KIT, KRAS, and NRAS. Venetoclax plus azacitidine and DLI is efficient and tolerant in treating patients with relapsed AML after allo-HSCT, implying this combined therapy as a potential treatment option in the studied patients.

Comparative transcriptomic reveals the molecular mechanism of maize hybrid Zhengdan538 in response to water deficit.

Heterosis, known as one of the most successful strategies for increasing grain yield and abiotic/biotic stress tolerance, has been widely exploited in maize breeding. However, the underlying molecular processes are still to be elucidated. The maize hybrid "Zhengdan538" shows high tolerance to drought stress. The transcriptomes of the seedling leaves of its parents, "ZhengA88" and "ZhengT22" and their reciprocal F1 hybrid under well-watered and water deficit conditions, were analyzed by RNA sequencing (RNA-Seq). Transcriptome profiling of the reciprocal hybrid revealed 2994-4692 differentially expressed genes (DEGs) under well-watered and water-deficit conditions, which were identified by comparing with their parents. The reciprocal hybrid was more closely related to the parental line "ZhengT22" than to the parental line "ZhengA88" in terms of gene expression patterns under water-deficit condition. Furthermore, genes showed expression level dominance (ELD), especially the high-parental ELD (Class 3 and 5), accounted for the largest proportion of DEGs between the reciprocal F1 hybrid and their parental lines under water deficit. These ELD genes mainly participated in photosynthesis, energy biosynthesis, and metabolism processes. The results indicated that ELD genes played important roles in hybrid tolerance to water deficit. Moreover, a set of important drought-responsive transcription factors were found to be encoded by the identified ELD genes and are thought to function in improving drought tolerance in maize hybrid plants. Our results provide a better understanding of the molecular mechanism of drought tolerance in hybrid maize.

Randomized, double-blind, noninferiority study of diclofenac diethylamine 2.32% gel applied twice daily versus diclofenac diethylamine 1.16% gel applied four times daily in patients with acute ankle sprain.

BACKGROUND: Diclofenac diethylamine (DDEA) gel has demonstrated efficacy for treatment of ankle sprains in both the 1.16% four-times-daily (QID) and 2.32% twice-daily (BID) formulations. The objective of this study was to compare, for the first time, the efficacy of DDEA 2.32% gel BID and DDEA 1.16% gel QID. METHODS: This was a phase 3, randomized, double-blind, multicenter, active-controlled, parallel-group study conducted in China from October 2019 to November 2020, designed to determine the noninferiority of DDEA 2.32% gel BID relative to DDEA 1.16% gel QID for treatment of grade I-II ankle sprain. At study entry, patients must have had pain on movement (POM) ≥50 mm on a 100-mm visual analogue scale (VAS), and not received any pain medication. The primary efficacy endpoint was the noninferiority of DDEA 2.32% gel BID vs DDEA 1.16% gel QID for POM as assessed by the patient using the 100-mm VAS, conducted on day 5. Secondary endpoints included measures of ankle tenderness, joint function, swelling, and patient-reported pain intensity and pain relief. RESULTS: A total of 302 patients were randomized and 95.4% completed the study. The mean (SD) change in POM from baseline to day 5 using the 100-mm VAS was - 42.8 mm (19.7 mm) with DDEA 2.32% gel BID and - 43.1 mm (18.1 mm) with DDEA 1.16% gel QID for the per-protocol population. The least squares mean difference (DDEA gel 2.32% - DDEA gel 1.16%) at this timepoint was 1.11 mm (95% CI - 3.00, 5.22; P = 0.595), and the upper limit (5.22 mm) of the 95% CI was less than the noninferiority margin of 13 mm, demonstrating that DDEA 2.32% gel BID was noninferior to DDEA 1.16% gel QID. Similar trends were seen for the secondary efficacy endpoints. There was no significant difference in the incidence of treatment-emergent adverse events or adverse events adjudicated as being treatment related. All treatment-related adverse events were dermatological; one patient discontinued from the DDEA 2.32% gel BID arm due to application-site inflammation. CONCLUSIONS: DDEA 2.32% gel BID offers a convenient alternative to DDEA 1.16% gel QID, with similar pain reduction and relief, anti-inflammatory effects, and tolerability. TRIAL REGISTRATION: NCT04052620.

Comparisons between ankle distraction arthroplasty and supramalleolar osteotomy for treatment of post-traumatic varus ankle osteoarthritis.

BACKGROUND: Ankle distraction arthroplasty and supramalleolar osteotomy were both options for post-traumatic varus ankle arthritis (VAA), but their comparative effectiveness was scarcely reported. This study aimed to compare the outcomes of two operative methods for treatment of Takakura-Tanaka stage 3 post-traumatic VAA. METHODS: This was a retrospective study, comprising 73 consecutive patients who presented with Takakura-Tanaka stage 3 post-traumatic VAA treated by either ankle distraction arthroplasty (n = 32) or supramalleolar osteotomy (n = 41) from January 2016 to December 2019. All patients had a minimum 24-month follow-up assessments. The outcome measures were visual analog scale (VAS), the American Orthopedic Foot & Ankle Society (AOFAS) ankle-hindfoot scores, complications, patient-rated overall satisfaction and ankle function. RESULTS: At an average of 32 months (range, 24-52 months) follow-up, significant improvement was observed for VAS, AOFAS, range of motion (ROM) and most radiographic parameters (except for TAS and TLS for ankle distraction arthroplasty group) compared to preoperative baselines (p < 0.05) for both groups. However, both groups did not differ significantly in terms of VAS or AOFAS, excellent and good rate (78.1% versus 85.4%, p = 0.422), overall rate of postoperative complications (28.1% vs. 17.1%, p = 0.257), or various radiographic parameters (e.g. tibial anterior surface angle, talar tilt angle and tibial lateral surface angle) (all p > 0.05). The ankle distraction arthroplasty group had a better postoperative ankle motion than did the supramalleolar osteotomy group, in terms of plantarflexion (37.8 ± 4.2 vs. 30.4 ± 3.6, p = 0.006), dorsiflexion (36.5 ± 6.4 vs. 28.3 ± 5.5, p = 0.004), varus (32.1 ± 4.5 vs. 27.1 ± 3.1, p = 0.017) and valgus (28.4 ± 3.7 vs. 25.2 ± 2.8, p = 0.046). CONCLUSIONS: Both operative treatments are effective for Takakura-Tanaka stage 3 post-traumatic VAA. In practice, individualized treatment option tailored to the ankle condition and patients' specific need should be considered. LEVEL OF EVIDENCE:  III, retrospective comparative series.

Guidelines on the treatment with integrated traditional Chinese medicine and western medicine for severe coronavirus disease 2019.

Severe Coronavirus Disease 2019 (COVID-19) is characterized by numerous complications, complex disease, and high mortality, making its treatment a top priority in the treatment of COVID-19. Integrated traditional Chinese medicine (TCM) and western medicine played an important role in the prevention, treatment, and rehabilitation of COVID-19 during the epidemic. However, currently there are no evidence-based guidelines for the integrated treatment of severe COVID-19 with TCM and western medicine. Therefore, it is important to develop an evidence-based guideline on the treatment of severe COVID-19 with integrated TCM and western medicine, in order to provide clinical guidance and decision basis for healthcare professionals, public health personnel, and scientific researchers involved in the diagnosis, treatment, and care of COVID-19 patients. We developed and completed the guideline by referring to the standardization process of the "WHO handbook for guideline development", the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, and the Reporting Items for Practice Guidelines in Healthcare (RIGHT).

Bulk analysis by resequencing and RNA-seq identifies candidate genes for maintaining leaf water content under water deficit in maize.

Drought is one of the main abiotic stresses adversely affecting maize growth and grain yield. Identifying drought tolerance-related genes and breeding varieties with enhanced tolerance are effective strategies for minimizing the effects of drought stress. In this study, the leaf relative water content (LRWC) was used for evaluating drought tolerance. QTL-seq analysis of 419 F2 individuals from a cross between ZhengT22 (the drought-tolerant line with high LRWC) and ZhengA88 (the drought-sensitive line with low LRWC) revealed four LRWC-related QTLs (qLRWC2, qLRWC10a, qLRWC10b, and qLRWC10c) in maize seedlings under water deficit. Of these QTLs, qLRWC2 was located in a 2.03-Mb interval on chromosome 2, whereas qLRWC10a, qLRWC10b, and qLRWC10c were located in 2.85-, 3.99-, and 2.05-Mb intervals, respectively, on chromosome 10, and the 93 genes contained the variation loci locating in the four QTLs regions. To identify the candidate genes within the QTLs, an RNA-seq analysis was performed for the parents exposed to water deficit. Seven genes with effective variation loci showed significant difference in expression either in ZhengA88 or ZhengT22 in response to water deficit. Moreover, among the genes, ZmPrx64, ZmCIPK, HSP90, and ABCG34 have all been shown to be related to water stress in the previous studies. Thus, they are primary considered as the potential candidate genes controlling LRWC under water deficit at the seeding stage of maize in this study. These findings will help clarify the molecular basis of drought tolerance in maize seedlings and may be relevant for future functional analysis and for breeding drought-tolerant maize varieties.

Molecular mapping of quantitative trait loci for grain moisture at harvest and field grain drying rate in maize (Zea mays L.).

Maize (Zea mays L.) grain moisture (GM) at harvest is an important trait that affects seed preservation during storage, grain quality and artificial drying costs. To date, most of the work on understanding GM dynamics in maize has focused on the grain filling period, while the period of postmaturity grain drying remains unexplored. The field grain drying rate (FDR) is one of the most important factors in determining GM at harvest. Therefore, understanding the genetic basis of FDR will be useful for obtaining low-GM varieties. In this study, a single-cross population (330 F2:3 -generation plants) derived from a cross of two divergent inbred lines was evaluated in two planting environments with a measurement method - Area under the Dry Down Curve (AUDDC). A high-density genetic linkage map of 2491 single nucleotide polymorphism (SNP) loci covering 2415.56 cM was constructed. Using composite interval mapping, four quantitative trait loci (QTL), q45dGM1-1, qHTGM2-2, qAUDDC2-1 and qAUDDC10-1, which were detected on chromosomes 1, 2 and 10, were stable across environments and could explain more than 10% of phenotypic variance. These may be the major QTLs, with non-significant environmental interactions for GM at 45 days, GM at harvest and FDR, respectively. Additionally, several predicted candidate genes for FDR were identified, including several transcription factors, hormone responsive genes, energy-related and DNA replication-related genes. These results will provide useful information for our understanding of the genetic basis of FDR, as well as providing tools for marker-assisted selection in maize breeding.

Modified Bunnell suture repair versus bundle-to-bundle suture repair for acute Achilles tendon rupture: a prospective comparative study of patients aged <45 years.

BACKGROUND: This study aimed to compare the operative outcome of percutaneous repair (modified Bunnell suture technique) versus open repair (bundle-to-bundle suture technique) of acute Achilles tendon rupture. METHODS: Seventy-two consecutive patients who underwent surgical treatment of Achilles tendon rupture were evaluated in this prospective study. Thirty-six patients were treated using the bundle-to-bundle suture technique (group A), and 36 patients were treated using the modified Bunnell suture technique (group B). All patients underwent functional examination comprising measurement of the calf muscle circumference and performance of the single-leg heel-rise test. The length and diameter of the Achilles tendon were compared between the injured and uninjured sides on magnetic resonance imaging. The number of single-leg heel rises (height > 5 cm) performed within 15 s was compared between the injured and uninjured sides. The ankle range of motion was also recorded. The Achilles tendon total rupture score (ATRS), American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale score, and visual analog scale (VAS) pain score were used to evaluate the clinical outcome at 12 months postoperatively. RESULTS: A total of 61 patients were followed up. The mean follow-up duration did not significantly differ between group A (23.73 ± 2.81 months) and group B (22.61 ± 3.96 months). However, there were significant differences between groups in the heel-rise test (group A, 1.74 ± 0.96; group B, 2.37 ± 1.42) and length of the Achilles tendon (group A, 11.98 ± 1.64 cm; group B, 11.11 ± 1.74 cm). The calf circumference of the injured side was significantly larger in group A than in group B (p = 0.043). The cross-sectional diameter of the Achilles tendon was significantly smaller in group A than group B. At final follow-up, there were no significant differences between the two groups in the ATRS, AOFAS score, or VAS score. One patient in group A had delayed wound healing, which resolved in 40 days. CONCLUSIONS: Patients with acute Achilles tendon rupture treated with open repair (bundle-to-bundle suture technique) achieved a better clinical outcome regarding the heel-rise test and calf circumference compared with those treated with percutaneous repair (modified Bunnell suture technique). TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000035229 , 8/4/2020, Retrospectively registered.

Syntenic quantitative trait loci and genomic divergence for Sclerotinia resistance and flowering time in Brassica napus.

Oilseed rape (Brassica napus) is an allotetraploid with two subgenomes descended from a common ancestor. Accordingly, its genome contains syntenic regions with many duplicate genes, some of which may have retained their original functions, whereas others may have diverged. Here, we mapped quantitative trait loci (QTL) for stem rot resistance (SRR), a disease caused by the fungus Sclerotinia sclerotiorum, and flowering time (FT) in a recombinant inbred line population. The population was genotyped using B. napus 60K single nucleotide polymorphism arrays and phenotyped in six (FT) and nine (SSR) experimental conditions or environments. In total, we detected 30 SRR QTL and 22 FT QTL and show that some of the major QTL associated with these two traits were co-localized, suggesting a genetic linkage between them. Two SRR QTL on chromosome A2 and two on chromosome C2 were shown to be syntenic, suggesting the functional conservation of these regions. We used the syntenic properties of the genomic regions to exclude genes for selection candidates responsible for QTL-associated traits. For example, 152 of the 185 genes could be excluded from a syntenic A2-C2 region. These findings will help to elucidate polyploid genomics in future studies, in addition to providing useful information for B. napus breeding programs.

Reconstruction of the lateral ankle ligaments using the anterior half of peroneus longus tendon graft.

BACKGROUND: This study aimed to report our institution's experience in the treatment of chronic lateral ankle instability using the anterior half of the peroneus longus tendon (AHPLT) to reconstruct the lateral ligament. METHODS: This retrospective study included 32 consecutive patients with chronic lateral ankle instability who underwent surgery from January 2013 to December 2014. All patients had failed to resolve with conservative treatment. A total of 32 ankles underwent AHPLT transfer. Patients returned for a clinical and radiologic follow-up evaluation at an average of 28 (range, 24-35) months postoperatively. Outcomes were assessed by comparison of pre- and postoperative American Orthopaedic Foot and Ankle Society (AOFAS) scores, visual analog scale pain scores, and Karlsson scores, and the radiographic assessment including talar tilt and anterior talar translation. RESULTS: Thirty-two patients (32 ankles) (100%) returned for final evaluation. All patients had an excellent or good outcome on patient subjective self-assessment, pain scores, AOFAS scores, and Karlsson scores at final follow-up. Ankle range of motion was not affected by lateral ankle reconstruction. The talar tilt was significantly reduced from a preoperative mean of 14.1±4.2° to 3.4±1.3° postoperatively (P<.001), and the anterior drawer was significantly reduced from a preoperative mean of 13.8±3.4mm to 3.6±1.5mm after lateral ankle ligamentous reconstruction (P<.001). CONCLUSIONS: AHPLT transfer to reconstruct the lateral ligament resulted in a high percentage of successful results, with excellent ankle stability and not affected of ankle motion. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Point of Anchor: Impacts on Interfacial Charge Transfer of Metal Oxide Nanoparticles.

Photoinduced charge transfer across the metal oxide-organic ligand interface plays a key role in the diverse applications of metal oxide nanomaterials/nanostructures, such as photovoltaics, photocatalysis, and optoelectronics. Thus far, most studies are focused on molecular engineering of the organic chromophores, where the charge-transfer properties have been found to dictate the photo absorption efficiency and eventual device performance. Yet, as the chromophores are mostly bound onto the metal oxide surfaces by hydroxyl or carboxyl anchors, the impacts of the bonding interactions at the metal oxide-ligand interface on interfacial charge transfer have remained largely unexplored. Herein, acetylene derivatives are demonstrated as effective surface capping ligands for metal oxide nanoparticles, as exemplified with TiO2, RuO2, and ZnO. Experimental studies and first-principles calculations suggest the formation of M-O-C≡C- core-ligand linkages that lead to effective interfacial charge delocalization, in contrast to hopping/tunneling by the conventional M-O-CO- interfacial bonds in the carboxyl-capped counterparts. This leads to the generation of an interfacial state within the oxide bandgap and much enhanced sensitization of the nanoparticle photoluminescence emissions as well as photocatalytic activity, as manifested in the comparative studies with TiO2 nanoparticles functionalized with ethynylpyrene and pyrenecarboxylic acid. These results highlight the significance of the unique interfacial bonding chemistry by acetylene anchoring group in facilitating efficient charge transfer through the oxide-ligand interfacial linkage and hence the fundamental implication in their practical applications.

Deep surgical site infection after ankle fractures treated by open reduction and internal fixation in adults: A retrospective case-control study.

Information on ankle fractures is limited. The purpose of this study was to investigate the incidence and risk factors for deep surgical site infection (DSSI) after open reduction and internal fixation (ORIF). Adult patients who underwent ORIF for an ankle fractures at 3 level-I centres between January 2013 and June 2017 were included. Data on demographic, injury-related, and surgery-related variables and biochemical indexes from the laboratory were collected from patients' electronic medical records. Univariate analysis and multivariate logistic regression analysis model were used to perform the data analysis through SPSS 19.0. Within 1-year postoperatively, 2.83% (74/2617) of cases developed DSSI, with the earliest occurring at the 4th and latest at 147th day. Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and methicillin-susceptible Staphylococcus aureus were the top 3 bacteria, causing 73% (37/51) of all the cases. Age (45-64 and ≥65 years), current smoking status, chronic heart disease, lower preoperative albumin level, open injury, and prolonged surgical duration were identified to be independently associated with DSSI occurrence. Preoperative active supplementation of nutrition, immediate smoking cessation, and optimisation of an operative plan for the reduction of surgical duration were feasible measures for DSSI prevention following ORIF of ankle fractures.

Novel, highly potent systemic glucokinase activators for the treatment of Type 2 Diabetes Mellitus.

Glucokinase (GK, hexokinase IV) is a unique hexokinase that plays a central role in mammalian glucose homeostasis. Glucose phosphorylation by GK in the pancreatic ß-cell is the rate-limiting step that controls glucose-stimulated insulin secretion. Similarly, GK-mediated glucose phosphorylation in hepatocytes plays a major role in increasing hepatic glucose uptake and metabolism and possibly lowering hepatic glucose output. Small molecule GK activators (GKAs) have been identified that increase enzyme activity by binding to an allosteric site. GKAs offer a novel approach for the treatment of Type 2 Diabetes Mellitus (T2DM) and as such have garnered much attention. We now report the design, synthesis, and biological evaluation of a novel series of 2,5,6-trisubstituted indole derivatives that act as highly potent GKAs. Among them, Compound 1 was found to possess high in vitro potency, excellent physicochemical properties, and good pharmacokinetic profile in rodents. Oral administration of Compound 1 at doses as low as 0.03mg/kg led to robust blood glucose lowering efficacy in 3week high fat diet-fed mice.

Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus.

Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic ß-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose-lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine-2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6. GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses ⩾10mpk, with ⩾70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia.

Reversal of muscle atrophy by Zhimu and Huangbai herb pair via activation of IGF-1/Akt and autophagy signal in cancer cachexia.

PURPOSE: Muscle atrophy is the prominent clinical feature of cancer-induced cachexia. Zhimu and Huangbai herb pair (ZBHP) has been used since ancient China times and have been phytochemically investigated for constituents that might cause anti-cancer, diabetes, and their complication. In this study, the effects and mechanisms of ZBHP on reversal of muscle atrophy were explored. METHODS: C57BL/6 mice implanted with colon-26 adenocarcinoma were chosen to develop cancer cachexia for evaluating the effects of ZBHP on reversal of muscle atrophy. The body weight, survival time, inflammatory cytokines, and pathological changes of muscle were monitored. In addition, IGF-1/Akt and autophagy pathway members were analyzed to interpret the mechanism of drug response. RESULTS: The function and morphology of skeletal muscle in cachexia model were significantly disturbed, and the survival time was shortened. Consistently, inflammatory cytokines and muscle atrophy-related atrogin-1, MuRF1, and FOXO3 were significantly increased, and IGF-1/Akt and autophagy signal pathways were depressed. Treatment with ZBHP significantly alleviated tumor-free body weight reduction and cachexia-induced changes in cytokines and prolonged survival. ZBHP treatment not only inhibited the muscle atrophy-related genes but also activated the IGF-1/Akt and autophagy signal pathways to facilitate the protein synthesis. CONCLUSIONS: The results revealed that ZBHP treatment could inhibit the muscle atrophy induced by cancer cachexia and prolong the survival time, and ZBHP may be of value as a pharmacological alternative in treatment of cancer cachexia.

A novel series of indazole-/indole-based glucagon receptor antagonists.

A novel, potent series of glucagon receptor antagonists (GRAs) was discovered. These indazole- and indole-based compounds were designed on an earlier pyrazole-based GRA lead MK-0893. Structure-activity relationship (SAR) studies were focused on the C3 and C6 positions of the indazole core, as well as the benzylic position on the N-1 of indazole. Multiple potent GRAs were identified with excellent in vitro profiles and good pharmacokinetics in rat. Among them, GRA 16d was found to be orally active in blunting glucagon induced glucose excursion in an acute glucagon challenge model in glucagon receptor humanized (hGCGR) mice at 1, 3 and 10mg/kg (mpk), and significantly lowered acute glucose levels in hGCGR ob/ob mice at 3 mpk dose.

Genome-wide comparative analysis of NBS-encoding genes between Brassica species and Arabidopsis thaliana.

BACKGROUND: Plant disease resistance (R) genes with the nucleotide binding site (NBS) play an important role in offering resistance to pathogens. The availability of complete genome sequences of Brassica oleracea and Brassica rapa provides an important opportunity for researchers to identify and characterize NBS-encoding R genes in Brassica species and to compare with analogues in Arabidopsis thaliana based on a comparative genomics approach. However, little is known about the evolutionary fate of NBS-encoding genes in the Brassica lineage after split from A. thaliana. RESULTS: Here we present genome-wide analysis of NBS-encoding genes in B. oleracea, B. rapa and A. thaliana. Through the employment of HMM search and manual curation, we identified 157, 206 and 167 NBS-encoding genes in B. oleracea, B. rapa and A. thaliana genomes, respectively. Phylogenetic analysis among 3 species classified NBS-encoding genes into 6 subgroups. Tandem duplication and whole genome triplication (WGT) analyses revealed that after WGT of the Brassica ancestor, NBS-encoding homologous gene pairs on triplicated regions in Brassica ancestor were deleted or lost quickly, but NBS-encoding genes in Brassica species experienced species-specific gene amplification by tandem duplication after divergence of B. rapa and B. oleracea. Expression profiling of NBS-encoding orthologous gene pairs indicated the differential expression pattern of retained orthologous gene copies in B. oleracea and B. rapa. Furthermore, evolutionary analysis of CNL type NBS-encoding orthologous gene pairs among 3 species suggested that orthologous genes in B. rapa species have undergone stronger negative selection than those in B .oleracea species. But for TNL type, there are no significant differences in the orthologous gene pairs between the two species. CONCLUSION: This study is first identification and characterization of NBS-encoding genes in B. rapa and B. oleracea based on whole genome sequences. Through tandem duplication and whole genome triplication analysis in B. oleracea, B. rapa and A. thaliana genomes, our study provides insight into the evolutionary history of NBS-encoding genes after divergence of A. thaliana and the Brassica lineage. These results together with expression pattern analysis of NBS-encoding orthologous genes provide useful resource for functional characterization of these genes and genetic improvement of relevant crops.

Truncated monocyte chemoattractant protein-1 can alleviate cardiac injury in mice with viral myocarditis via infiltration of mononuclear cells.

BALB/c mice inoculated intraperitoneally with coxsackievirus group B type 3 (CVB3) were allocated to five groups; namely, a viral myocarditis group infected with CVB3 alone (control group), an antibody intervention group that received intracardiac anti-MCP-1, an antibody intervention control group that received goat IgG, a tMCP-1 intervention group that received plasmid pVMt expressing tMCP-1, and a tMCP-1 intervention control group that received plasmid pVAX1. There was also a normal control group. The ratio of murine heart weight to body weight, pathological score of myocardial tissue, serum creatine kinase-MB titers and CVB3 loading of myocardial tissue were assessed. The cardiac lesions in mice that received 20, 40 or 60 µg pVMt (P < 0.05) were less severe than those in control mice with untreated viral myocarditis. In addition, fewer mononuclear cells had infiltrated the myocardium of mice who received 40 or 60 µg pVMt intramyocardially (P < 0.01), whereas there was no difference in mononuclear cell infiltration between mice with viral myocarditis and those that received 20 µg pVMt (P > 0.05). There was also no difference between mice that received anti-MCP-1 antibody and those that received 40 µg pVMt in ratio of HW/BW, serum CK-MB titers and pathological score (P > 0.05). This study showed that tMCP-1 can alleviate cardiac lesions and cardiac injury in mice with viral myocarditis via infiltration of mononuclear cells. Thus, tMCP-1 may be an alternative to anti-MCP-1 antibody treatment of viral myocarditis. Further research is required.