The association of low birthweight and prematurity on outcomes in children and adults with nephrotic syndrome-a NEPTUNE cohort study.

BACKGROUND: In single-center studies, both preterm birth and low birth weight (LBW) are associated with worse outcomes in childhood nephrotic syndrome. Using the Nephrotic Syndrome Study Network (NEPTUNE) observational cohort, we tested the hypothesis that in patients with nephrotic syndrome, hypertension, proteinuria status, and disease progression would be more prevalent and more severe in subjects with LBW and prematurity singly or in combination (LBW/prematurity). METHODS: Three hundred fifty-nine adults and children with focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) and available birth history were included. Estimated glomerular filtration rate (eGFR) decline and remission status were primary outcomes, and secondary outcomes were kidney histopathology, kidney gene expression, and urinary biomarkers. Logistic regression was used to identify associations with LBW/prematurity and these outcomes. RESULTS: We did not find an association between LBW/prematurity and remission of proteinuria. However, LBW/prematurity was associated with greater decline in eGFR. This decline in eGFR was partially explained by the association of LBW/prematurity with APOL1 high-risk alleles, but the association remained after adjustment. There were no differences in kidney histopathology or gene expression in the LBW/prematurity group compared to normal birth weight/term birth. CONCLUSION: LBW and premature babies who develop nephrotic syndrome have a more rapid decline in kidney function. We did not identify clinical or laboratory features that distinguished the groups. Additional studies in larger groups are needed to fully ascertain the effects of (LBW) and prematurity alone or in combination on kidney function in the setting of nephrotic syndrome.

Effects of Percutaneous Endoscopic Gastrostomy in Patients with Esophageal Squamous Cell Carcinoma During Concurrent Chemoradiotherapy: a Prospective Study.

BACKGROUND AND AIMS: This prospective study aimed to compare the changes in nutritional status and complications among patients with esophageal squamous cell carcinoma(ESCC) who received enteral nutrition through oral intake, percutaneous endoscopic gastrostomy (PEG), and an enteral nasogastric tube (NG) during concurrent chemoradiotherapy (CCRT). METHODS: A total of 141 patients were included: 38, 74, and 29 patients were fed through oral intake, PEG, and NG, respectively. The clinical characteristics and baseline nutritional status of the three groups were recorded and analysed. The patient generated subjective global assessment score, skeletal muscle index, and quality of life were evaluated before and after CCRT; the incidence of adverse events during feeding using PEG and NG was also recorded. The correlations among the different nutritional pathways and the CCRT-related complications (e.g., radiation esophagitis and myelosuppression) were assessed. RESULTS: At baseline, the oral intake group had a significantly better nutritional status and lower disease stage than those in the PEG and NG groups. However, during the CCRT, the oral intake group exhibited the most significant decreases in weight and skeletal muscle index. The synchronous chemotherapy completion rate was the highest in the PEG group. Multivariate analysis showed that the planning tumour volume and the oral intake and NG feeding pathways were associated with ≥grade 2 radiation esophagitis. CONCLUSIONS: We found that PEG effectively maintains the body weight and skeletal muscle index of patients with esophageal cancer during CCRT. It also improves the synchronous chemotherapy completion rate and reduces the occurrence of ≥grade 2 radiation esophagitis.

Piezochromism in Dynamic Three-Dimensional Covalent Organic Frameworks.

Piezochromic materials with pressure-dependent photoluminescence tuning properties are important in many fields, such as mechanical sensors, security papers, and storage devices. Covalent organic frameworks (COFs), as an emerging class of crystalline porous materials (CPMs) with structural dynamics and tunable photophysical properties, are suitable for designing piezochromic materials, but there are few related studies. Herein, we report two dynamic three-dimensional COFs based on aggregation-induced emission (AIE) or aggregation-caused quenching (ACQ) chromophores, termed JUC-635 and JUC-636 (JUC=Jilin University China), and for the first time, study their piezochromic behavior by diamond anvil cell technique. Due to the various luminescent groups, JUC-635 has completely different solvatochromism and molecular aggregation behavior in the solvents. More importantly, JUC-635 with AIE effect exhibits a sustained fluorescence upon pressure increase (≈3 GPa), and reversible sensitivity with high-contrast emission differences (Δλem =187 nm) up to 12 GPa, superior to other CPMs reported so far. Therefore, this study will open a new gate to expand the potential applications of COFs as exceptional piezochromic materials in pressure sensing, barcoding, and signal switching.

Bone Cement Reperfusion Revision Surgery for Symptomatic Recurrence of Kümmell's Disease After Percutaneous Kyphoplasty.

STUDY DESIGN: Retrospective study. OBJECTIVES: To demonstrate that repeat Percutaneous vertebroplasty (PVP) performed for the same cemented vertebrae in Kümmell's disease can offer therapeutic benefit for patients with recurrent symptoms after initial percutaneous kyphoplasty (PKP) treatment. METHODS: From January 2019 to December 2021, we investigated 2932 patients with PKP. Among them, 191 patients were diagnosed Kümmell's disease. 33 patients upon presentation of recurrent symptoms underwent repeat PVP procedure. Radiologic outcomes and clinic indices were investigated. RESULTS: Bone cement reperfusion surgery was successfully completed in 33 patients. The average age was 73.5 ± 8.2 years old. The kyphosis angle showed significant correction from pre-operation to the final follow-up, descending from pre-operation (20.6 ± 11.1°) to final follow-up (15.4 ± 7.9°). The vertebral heights at different follow-up appointments were significantly higher than the pre-operative appointments. The VAS and ODI scores at final follow-up were respectively 1.2 ± .8 and 27.3 ± 5.4%, which were both significantly lower than those before operation. No complications such as cement leakage into the spinal canal or cement displacement occurred during follow-up. CONCLUSIONS: Bone cement reperfusion surgery can ameliorate kyphosis and restore vertebral height to some extent. Repeat PVP is a minimally invasive surgery that provides superior long-term results in clinical and radiological outcomes but is technically more difficult to perform.

Clinical feasibility and oncological safety of non-radioactive targeted axillary dissection after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: a prospective diagnostic and prognostic study.

BACKGROUND: Targeted axillary dissection (TAD) includes biopsy of clipped lymph node and sentinel lymph nodes. However, clinical evidence regarding clinical feasibility and oncological safety of non-radioactive TAD in a real-world cohort remains limited. METHODS: In this prospective registry study, patients routinely underwent clip insertion into biopsy-confirmed lymph node. Eligible patients received neoadjuvant chemotherapy (NACT) followed by axillary surgery. Main endpoints included the false-negative rate (FNR) of TAD and nodal recurrence rate. RESULTS: Data from 353 eligible patients were analyzed. After completion of NACT, 85 patients directly proceeded to axillary lymph node dissection (ALND), furthermore, TAD with or without ALND was performed in 152 and 85 patients, respectively. Overall detection rate of clipped node was 94.9% (95%CI, 91.3%-97.4%) and FNR of TAD was 12.2% (95%CI, 6.0%-21.3%) in our study, with FNR decreasing to 6.0% (95%CI, 1.7%-14.6%) in initially cN1 patients. During a median follow-up of 36.6 months, 3 nodal recurrences occurred (3/237 with ALND; 0/85 with TAD alone), with a three-year freedom-from-nodal-recurrence rate of 100.0% among the TAD-only patients and 98.7% among the ALND patients with axillary pathologic complete response (P=0.29). CONCLUSIONS: TAD is feasible in initially cN1 breast cancer patients with biopsy-confirmed nodal metastases. ALND can safely be foregone in patients with negativity or a low volume of nodal positivity on TAD, with a low nodal failure rate and no compromise of three-year recurrence-free survival.

Synthesis and Antineoplastic Activity of a Dimer, Spiroindolinone Pyrrolidinecarboxamide.

The mutation or function loss of tumour suppressor p53 plays an important role in abnormal cell proliferation and cancer generation. Murine Double Minute 2 (MDM2) is one of the key negative regulators of p53. p53 reactivation by inhibiting MDM2-p53 interaction represents a promising therapeutic option in cancer treatment. Here, to develop more effective MDM2 inhibitors with lower off-target toxicities, we synthesized a dimer, spiroindolinone pyrrolidinecarboxamide XR-4, with potent MDM2-p53 inhibition activity. Western blotting and qRT-PCR were performed to detect the impact of XR-4 on MDM2 and p53 protein levels and p53 downstream target gene levels in different cancers. Cancer cell proliferation inhibition and clonogenic activity were also investigated via the CCK8 assay and colony formation assay. A subcutaneous 22Rv1-derived xenografts mice model was used to investigate the in vivo anti-tumour activity of XR-4. The results reveal that XR-4 can induce wild-type p53 accumulation in cancer cells, upregulate the levels of the p53 target genes p21 and PUMA levels, and then inhibit cancer cell proliferation and induce cell apoptosis. XR-4 can also act as a homo-PROTAC that induces MDM2 protein degradation. Meanwhile, the in vivo study results show that XR-4 possesses potent antitumour efficacy and a favourable safety property. In summary, XR-4 is an interesting spiroindolinone pyrrolidinecarboxamide-derivative dimer with effective p53 activation activity and a cancer inhibition ability.

Dietary and supplemental intake of vitamins C and E is associated with altered DNA methylation in an epigenome-wide association study meta-analysis.

BACKGROUND: Dietary intake of antioxidants such as vitamins C and E protect against oxidative stress, and may also be associated with altered DNA methylation patterns. METHODS: We meta-analysed epigenome-wide association study (EWAS) results from 11,866 participants across eight population-based cohorts to evaluate the association between self-reported dietary and supplemental intake of vitamins C and E with DNA methylation. EWAS were adjusted for age, sex, BMI, caloric intake, blood cell type proportion, smoking status, alcohol consumption, and technical covariates. Significant results of the meta-analysis were subsequently evaluated in gene set enrichment analysis (GSEA) and expression quantitative trait methylation (eQTM) analysis. RESULTS: In meta-analysis, methylation at 4,656 CpG sites was significantly associated with vitamin C intake at FDR ≤ 0.05. The most significant CpG sites associated with vitamin C (at FDR ≤ 0.01) were enriched for pathways associated with systems development and cell signalling in GSEA, and were associated with downstream expression of genes enriched in the immune response in eQTM analysis. Furthermore, methylation at 160 CpG sites was significantly associated with vitamin E intake at FDR ≤ 0.05, but GSEA and eQTM analysis of the top most significant CpG sites associated with vitamin E did not identify significant enrichment of any biological pathways investigated. CONCLUSIONS: We identified significant associations of many CpG sites with vitamin C and E intake, and our results suggest that vitamin C intake may be associated with systems development and the immune response.

Blood lactate levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease in type 2 diabetes: a real-world study.

Aim: To investigate the association between blood lactate levels and metabolic dysfunction-associated fatty liver disease (MAFLD) in type 2 diabetes mellitus (T2DM). Methods: 4628 Chinese T2DM patients were divided into quartiles according to blood lactate levels in this real-world study. Abdominal ultrasonography was used to diagnosis MAFLD. The associations of blood lactate levels and quartiles with MAFLD were analyzed by logistic regression. Results: There were a significantly increased trend in both MAFLD prevalence (28.9%, 36.5%, 43.5%, and 54.7%) and HOMA2-IR value (1.31(0.80-2.03), 1.44(0.87-2.20), 1.59(0.99-2.36), 1.82(1.15-2.59)) across the blood lactate quartiles in T2DM patients after adjustment for age, sex, diabetic duration, and metformin use (all p<0.001 for trend). After correcting for other confounding factors, not only increased blood lactate levels were obviously associated with MAFLD presence in the patients with (OR=1.378, 95%CI: 1.210-1.569, p<0.001) and without taking metformin (OR=1.181, 95%CI: 1.010-1.381, p=0.037), but also blood lactate quartiles were independently correlated to the increased risk of MAFLD in T2DM patients (p<0.001 for trend). Compared with the subjects in the lowest blood lactate quartiles, the risk of MAFLD increased to 1.436-, 1.473-, and 2.055-fold, respectively, in those from the second to the highest lactate quartiles. Conclusions: The blood lactate levels in T2DM subjects were independently associated with an increased risk of MAFLD, which was not affected by metformin-taking and might closely related to insulin resistance. Blood lactate levels might be used as a practical indicator for assessing the risk of MAFLD in T2DM patients.

Effect of Cas9 Protein on the Seed-Target Base Pair of the sgRNA/DNA Hybrid Duplex.

CRISPR (clustered regularly interspaced short palindromic repeats)/CRISPR-associated protein (Cas9) has been widely used for gene editing. Not all guide RNAs can cleave the DNA efficiently remains a major challenge to CRISPR/Cas9-mediated genome engineering. Therefore, understanding how the Cas9 complex successfully and efficiently identifies specific functional targets through base-pairing has great implications for such applications. The 10-nt seed sequence at the 3' end of the guide RNA is critical to target recognition and cleavage. Here, through stretching molecular dynamics simulation, we studied the thermodynamics and kinetics of the binding-dissociation process of the seed base and the target DNA base with the Cas9 protein. The results showed that in the presence of Cas9 protein, the enthalpy change and entropy change in binding-dissociation of the seed base with the target are smaller than those without the Cas9 protein. The reduction of entropy penalty upon association with the protein resulted from the pre-organization of the seed base in an A-form helix, and the reduction of enthalpy change was due to the electrostatic attraction of the positively charged channel with the negative target DNA. The binding barrier coming from the entropy loss and the dissociation barrier resulting from the destruction of the base pair in the presence of Cas9 protein were lower than those without protein, which indicates that the seed region is crucial for efficiently searching the correct target by accelerating the binding rate and dissociating fast from the wrong target.

Evidence for a causal association between psoriasis and psychiatric disorders using a bidirectional Mendelian randomization analysis in up to 902,341 individuals.

BACKGROUND: The causal association between psoriasis and psychiatric disorders remains ambiguous. OBJECTIVES: This study aimed to investigate the causal relationship between psoriasis and common psychiatric disorders using bidirectional Mendelian randomization (MR) analysis. METHODS: Major depressive disorder (MDD) (N = 217,584), bipolar disorder (N = 51,710), schizophrenia (N = 77,096), and anxiety disorder (N = 218,792) were obtained as outcomes, and psoriasis (N = 337,159) were as exposure. Inverse variance weighting (IVW) was used as the main method, with other sensitivity methods as auxiliary methods. Sensitivity analysis and heterogeneity tests were performed to ensure the robustness of the results. We also performed a subgroup analysis of cases with psoriatic arthritis (PsA) (N = 213,879) by using the same testing methods. RESULTS: MR showed that the genetic risk of psoriasis was positively associated with bipolar disorder (odds ratio (OR) = 13.54, 95 % confidence interval (95%CI): 2.43-75.37, P = 0.002) and MDD (OR = 1.08, 95%CI: 1.01-1.15, P = 0.027), which indicated possible causal relationships between psoriasis and these two diseases. Schizophrenia (OR = 3.52, 95%CI: 0.22-55.71, P = 0.372) and anxiety disorders (OR = 0.65, 95%CI: 0.16-2.63, P = 0.546) indicated no significant causal association. No reverse causal effects of psychiatric disorders on psoriasis were found. Subgroup analysis also suggested causal association of PsA with the bipolar affective disorder (OR = 1.05, 95%CI: 1.01-1.08, P = 0.005). LIMITATIONS: Potential pleiotropic effects, restriction to European populations, and differences in diagnostic criteria. CONCLUSIONS: This study has supported the causal association of psoriasis with MDD and bipolar disorder, and the subtype PsA with bipolar disorder, which informed the intervention for mental illnesses in patients with psoriasis.

Preparation and Characterization of Soybean Protein Adhesives Modified with an Environmental-Friendly Tannin-Based Resin.

Soybean protein-based adhesives are limited in their application due to their poor wet bonding strength and poor water resistance. Herein, we prepared a novel, environmentally friendly soybean protein-based adhesive by adding tannin-based resin (TR) to improve the performance of water resistance and wet bonding strength. The active sites of TR reacted with the soybean protein and its functional groups and formed strong cross-linked network structures, which improved the cross-link density of the adhesives and then improved the water resistance. The residual rate increased to 81.06% when 20 wt%TR was added, and the water resistance bonding strength reached 1.07 MPa, which fully met the Chinese national requirements for plywood (Class II, ≥0.7 MPa). SEM observations were performed on the fracture surfaces of all modified SPI adhesives after curing. The modified adhesive has a denser and smooth cross-section. Based on the TG and DTG plots, the thermal stability performance of the TR-modified SPI adhesive was improved when TR was added. The total weight loss of the adhesive decreased from 65.13% to 58.87%. This study provides a method for preparing low-cost and high-performance, environmentally friendly adhesives.

Respiratory symptoms are common in stiff person syndrome spectrum disorders and are associated with number of body regions involved.

BACKGROUND AND PURPOSE: Stiff person syndrome (SPS) spectrum disorders (SPSSD) cause spasms and rigidity throughout different body regions and can be associated with apnea and acute respiratory failure. There are limited data on the prevalence and predictors of respiratory symptoms with spasms (RSwS) in SPSSD. We sought to characterize the spirometry patterns and the frequency and predictors of RSwS in a large SPSSD cohort. METHODS: Participants were recruited from the Johns Hopkins SPS Center between 1997 and 2021, as part of an ongoing, longitudinal observational study. Medical records were reviewed to assess demographics and clinical characteristics. Data were analyzed using descriptive statistics and multivariable logistic regression models. RESULTS: One-hundred ninety-nine participants (mean age = 53.4 ± 13.6 years, median time to diagnosis = 36 [IQR 66] months, 74.9% women, 69.8% White, 62.8% classic SPS phenotype) were included in final analyses; 35.2% of participants reported RSwS, of whom 24.3% underwent spirometry as part of routine clinical care. Obstructive (23.5%) and restrictive (23.5%) patterns were most commonly observed in those with SPSSD. An increasing number of body regions involved predicted the presence of RSwS (odds ratio [OR] = 1.95, 95% confidence interval [CI] = 1.50-2.53); those with ≥5 body regions involved (vs. ≤4) had higher odds (OR = 6.19, 95% CI = 2.81-13.62) of experiencing RSwS in adjusted models. Two patients died from SPSSD-associated respiratory compromise. CONCLUSIONS: RSwS are common in SPSSD and may be predicted by an increasing number of body regions involved by SPSSD. Close clinical monitoring and having a low threshold to obtain spirometry should be considered in people with SPSSD.

Different associations of anthropometric indices with diabetic retinopathy and diabetic kidney disease in chinese patients with type 2 diabetes mellitus.

AIMS: To investigate the associations of anthropometric indices, including body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), waist circumference (WC) and hip circumference (HC), with diabetic retinopathy (DR) and diabetic kidney disease (DKD) in Chinese patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This cross-sectional study evaluated 5226 Chinese participants with T2DM at three hospitals between 2005 and 2016. Logistic regression models and restricted cubic spline analysis were used to assess the associations of anthropometric indices with DR and DKD. RESULTS: A BMI of around 25 kg/m2 was related to a low risk of DR (OR based on the third fifth: 0.752, 95%CI: 0.615-0.920). Besides, HC had an inverse association with DR in men independently of BMI (OR based on the highest fifth: 0.495, 95%CI: 0.350-0.697). In the restricted cubic spline models, BMI, WHtR, WC, and HC showed J-shaped associations with DKD, while WHR showed an S-shaped association with DKD. Compared to the lowest fifth, the odds ratios (OR) based on the highest fifth of BMI, WHR, WHtR, WC and HC for DKD were 1.927 (1.572-2.366), 1.566 (1.277-1.923), 1.910 (1.554-2.351), 1.624 (1.312-2.012) and 1.585 (1.300-1.937) respectively in multivariable models. CONCLUSIONS: A median BMI and a large hip might be related to a low risk of DR, while lower levels of all the anthropometric indices were associated with a lower risk of DKD. Our findings suggested maintain a median BMI, a low WHR, a low WHtR and a large hip for prevention of DR and DKD.

Comparative three-dimensional genome architectures of adipose tissues provide insight into human-specific regulation of metabolic homeostasis.

Elucidating the regulatory mechanisms of human adipose tissues (ATs) evolution is essential for understanding human-specific metabolic regulation, but the functional importance and evolutionary dynamics of three-dimensional (3D) genome organizations of ATs are not well defined. Here, we compared the 3D genome architectures of anatomically distinct ATs from humans and six representative mammalian models. We recognized evolutionarily conserved and human-specific chromatin conformation in ATs at multiple scales, including compartmentalization, topologically associating domain (TAD), and promoter-enhancer interactions (PEI), which have not been described previously. We found promoter-enhancer interaction (PEI) are much more evolutionarily dynamic with respect to compartmentalization and topologically associating domain (TAD). Compared to conserved PEIs, human-specific PEIs are enriched for human-specific sequence and the binding motifs of their potential mediators (transcription factors) are less conserved. Our data also demonstrated that genes involved in the evolutionarily dynamics of chromatin organization have weaker transcriptional conservation than those associated with conserved chromatin organization. Furthermore, the genes involved in energy metabolism and the maintenance of metabolic homeostasis are enriched in human-specific chromatin organization, while housekeeping genes, health-related genes and genetic variations are enriched in evolutionarily conserved compared to human-specific chromatin organization. Finally, we showed extensively divergent human-specific 3D genome organizations among one subcutaneous and three visceral ATs. Together, these findings provide a global overview of 3D genome architecture dynamics between ATs from human and mammalian models, and new insights into understanding the regulatory evolution of human ATs.

Indicator displacement assay for freshness monitoring of green tea during storage.

Aging of green tea leads to reductions in its flavor and health value, yet in situ testing methods for green tea freshness are lacking. A novel sensitive indicator displacement assay (IDA) sensor was constructed and applied for monitoring of green tea freshness during storage. Low-cost pH dyes and metal ions were used as indicators and receptors, respectively, for the targeted detection of catechins in tea samples. The feasibility of the IDA reaction was verified using images and UV-vis spectroscopy, respectively. IDA combined with supervised algorithms achieved accurate identification of green tea freshness with an accuracy of 86.67%, and acceptable accuracies in the prediction of catechin monomers and total catechins with ratio of prediction to deviation values over 1.5. Thus, the developed IDA sensor is capable of qualitative and quantitative monitoring of the green tea freshness during storage, providing a new option for quality evaluation and control of green teas.

Topological Isomerism in Three-Dimensional Covalent Organic Frameworks.

Although isomerism is a typical and significant phenomenon in organic chemistry, it is rarely found in covalent organic framework (COF) materials. Herein, for the first time, we report a controllable synthesis of topological isomers in three-dimensional COFs via a distinctive tetrahedral building unit under different solvents. Based on this strategy, both isomers with a dia or qtz net (termed JUC-620 and JUC-621) have been obtained, and their structures are determined by combining powder X-ray diffraction and transmission electron microscopy. Remarkably, these architectures show a distinct difference in their porous features; for example, JUC-621 with a qtz net exhibits permanent mesopores (up to ∼23 Å) and high surface area (∼2060 m2 g-1), which far surpasses those of JUC-620 with a dia net (pore size of ∼12 Å and surface area of 980 m2 g-1). Furthermore, mesoporous JUC-621 can remove dye molecules efficiently and achieves excellent iodine adsorption (up to 6.7 g g-1), which is 2.3 times that of microporous JUC-620 (∼2.9 g g-1). This work thus provides a new way for constructing COF isomers and promotes structural diversity and promising applications of COF materials.

The activities and mechanisms of intestinal microbiota metabolites of TCM herbal ingredients could be illustrated by a strategy integrating spectrum-effects, network pharmacology, metabolomics and molecular docking analysis: Platycodin D as an example.

BACKGROUND: The intestinal microbiota plays a key role in understanding the mechanism of traditional Chinese medicine (TCM), as it could transform the herbal ingredients to metabolites with higher bioavailability and activity comparing to their prototypes. Nevertheless, the study of the activity and mechanism of microbiota metabolites reported by the published literature still lacks viable ways. Hence a new strategy is proposed to solve this issue. PURPOSE: A new strategy to study the activity and mechanism of intestinal microbiota metabolites of TCM herbal ingredients by integrating spectrum-effect relationship, network pharmacology, metabolomics analysis and molecular docking together was developed and proposed. METHOD: Platycodin D (PD) and its microbiota metabolites with antitussive and expectorant effect were selected as an example for demonstration. First, the PD and its microbiota metabolites with important contribution to antitussive and/or expectorant effects were screened through spectrum-effect relationship analysis. Second, network pharmacology and metabolomics analysis were integrated to identify the upstream key targets of PD and its microbiota metabolites as well as the downstream endogenous metabolites. Finally, the active forms of PD were further confirmed by molecular docking. RESULTS: Results showed that PD was an active ingredient with antitussive and/or expectorant effects, and the active forms of PD were its microbiota metabolites: 3-O-ß-d-glucopyranosyl platycodigenin, 3-O-ß-d-glucopyranosyl isoplatycodigenin, 7­hydroxyl-3-O-ß-d-glucopyranosyl platycodigenin, platycodigenin and isoplatycodigenin. In addition, those microbiota metabolites could bind the key targets of PAH, PLA2G2A, ALOX5, CYP2C9 and CYP2D6 to exert antitussive effects by regulating four metabolic pathways of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, glycerophospholipid metabolism and linoleic acid metabolism. Similarly, they could also bind the key targets of PLA2G1B, ALOX5, CYP2C9 and CYP2D6 to exert expectorant effect by regulating two pathways of glycerophospholipid metabolism and linoleic acid metabolism. CONCLUSION: The proposed strategy paves a new way for the illustration of the activities and mechanisms of TCM herbal ingredients, which is very important to reconcile the conundrums of TCM herbal ingredients with low oral bioavailability but high activity.

Building rural community disaster resilience in developing countries: insights from a Chinese NGO's Safe Rural Community Program.

As rural areas in developing countries are generally more vulnerable to disasters triggered by natural hazards than urban areas, it has become critical to strengthen rural community disaster resilience (CDR) to reduce the disaster risks. Using follow-up interviews, surveys, and secondary data, this study reviewed the "Safe Rural Community" (SRC) program implemented by One Foundation, a Chinese civilian NGO, after the 2013 Lushan earthquake in China. The study focused on five main key resilience elements; networks, infrastructure, institutions, capabilities, and culture. It was found that the SRC program successfully developed standardized, systematic, interrelated, and practical activities, such as local volunteer rescue teams, emergency supplies, disaster reduction training, community emergency plans, and regular emergency rescue drills. Third-party evaluations and a 2022 Lushan earthquake test revealed that this NGO-led, community-based, and team-oriented program had been effective. The SRC program in Lushan, therefore, provides some guidance on the development of effective CDR programs in rural communities in developing countries.

A Tailored Versatile and Efficient NHC-Based NNC-Pincer Manganese Catalyst for Hydrogenation of Polar Unsaturated Compounds.

The reactivity of metal-hydride complexes can be harnessed by the modification of ancillary ligands. With the aim of improving the hydride-donor ability of the key Mn-H intermediate and reducing steric hindrance, we herein report the rational design of a versatile and efficient NHC-based NNC-pincer Mn catalyst for hydrogenation reactions. This newly developed catalyst exhibited higher activity than the corresponding NNP-pincer Mn catalyst owing to its reduced steric hindrance and enhanced Mn-H σ-bonding orbital energy level through a π-antibonding interaction. Using this highly active NNC-pincer Mn catalyst, a rich array of polar unsaturated compounds (>80 examples) including esters, N-heteroarenes, amides, carbonates, and urea derivatives, were successfully hydrogenated under relatively mild conditions. This work represents a rare example of a general phosphine-free Mn-catalyzed hydrogenation system.

Structural characterization, in vivo toxicity and biological activity of two new pyro-type diterpenoid alkaloids derived from 3-acetylaconitine.

OBJECTIVE: The transformations that occur in diterpenoid alkaloids during the process of sand frying for Chinese herbal medicine preparation have yet to be clarified. This study investigated the structural changes that take place in 3-acetylaconitine during a simulation of heat-processing and evaluated the toxicity and biological activity of the pyrolysis products. METHODS: The diterpenoid alkaloid 3-acetylaconitine was heated at 180 °C for 15 min to simulate the process of sand frying. The pyrolysis products were separated using column chromatography, and their structures were investigated using high-resolution electrospray ionization mass spectroscopy and nuclear magnetic resonance spectroscopy. Further, in vivo cardiotoxicity and acute toxicity of 3-acetylaconitine and its pyrolysis products were compared, and the aconitine-induced arrhythmia model was employed to evaluate the antiarrhythmic effect of the pyrolysis products. RESULTS: Two new diterpenoid alkaloids, pyroacetylaconitine and 16-epi-pyroacetylaconitine, a pair of epimers at C-16, were isolated. After comparing the structures of these compounds, possible transformation pathways were proposed. Compared with the prototype compound, 3-acetylaconitine, the cardiotoxicity and acute toxicity of the heat-transformed products were significantly decreased. In the biological activity assay, the two pyrolysis products exhibited an effective increase in ventricular premature beat latency, a reduction in the occurrence of ventricular tachycardia, as well as an increase in the rate of arrhythmia inhibition, implying strong antiarrhythmic activity. CONCLUSION: Compared with 3-acetylaconitine, its pyrolysis products displayed lower toxicity and good antiarrhythmic effects; thus, they have potential for being developed into antiarrhythmic medicines. Please cite this article as: Wang YJ, Wang Y, Tao P. Structural characterization, in vivo toxicity and biological activity of two new pyro-type diterpenoid alkaloids derived from 3-acetylaconitine. J Integr Med. 2023; 21(3): 302-314.