Antihypertensive treatment during pregnancy induces long-term changes in gut microbiota and the behaviors of the attention deficit hyperactivity disorder offspring.

The pathogenesis of attention-deficit/hyperactivity disorder (ADHD) has not been fully elucidated. Gestational hypertension could double the probability of ADHD in the offspring, while the initial bacterial communication between the mother and offspring has been associated with psychiatric disorders. Thus, we hypothesize that antihypertensive treatment during pregnancy may abate the impairments in neurodevelopment of the offspring. To test this hypothesis, we chose Captopril and Labetalol, to apply to pregnant spontaneously hypertensive rat (SHR) dams and examined the outcomes in the male offspring. Our data demonstrated that maternal treatment with Captopril and Labetalol had long-lasting changes in gut microbiota and behavioral alterations, including decreased hyperactivity and increased curiosity, spatial learning and memory in the male offspring. Increased diversity and composition were identified, and some ADHD related bacteria were found to have the same change in the gut microbiota of both the dam and offspring after the treatments. LC-MS/MS and immunohistochemistry assays suggested elevated expression of brain derived neurotrophic factor (BDNF) and dopamine in the prefrontal cortex and striatum of offspring exposed to Captopril/ Labetalol, which may account for the improvement of the offspring's psychiatric functions. Therefore, our results support the beneficial long-term effects of the intervention of gestational hypertension in the prevention of ADHD.

Total Synthesis of Ganoderma Meroterpenoids Cochlearol B and Its Congeners Driven by Structural Similarity and Biological Homology.

Secondary metabolites that have the same biological origin must share some relationship in their biosynthesis. Exploring this relationship has always been a significant task for synthetic biologists. However, from the perspective of synthetic chemists, it is equally important to propose, prove, or refute potential biosynthetic pathways in order to elucidate and understand the biosynthesis of homologous secondary metabolites. In this study, driven by the high structural similarity between the homologous Ganoderma meroterpenoids cochlearol B and ganocin B, two chemically synthetic strategies were designed and investigated sequentially for the synthesis of cochlearol B from ganocin B. These strategies include intramolecular metal-catalyzed hydrogen atom transfer (MHAT) and intramolecular photochemical [2+2] cycloaddition. The aim was to reveal their potential biosynthetic conversion relationship using chemical synthesis methods. As a result, a highly efficient total synthesis of cochlearol B, cochlearol T, cochlearol F, as well as the formal total synthesis of ganocins A-B, and ganocochlearins C-D, has been achieved. Additionally, a novel synthetic approach for the synthesis of 6,6-disubstituted 6H-dibenzo[b,d]pyran and its analogues has been developed through palladium(II)-catalyzed Wacker-type/cross-coupling cascade reactions.

Synthesis of Multisubstituted 2,3-Allenamides via Palladium-Catalyzed Carbonylation of Propargylic Esters.

2,3-Allenamides are an important class of unsaturated group-substituted carbonyl compounds. A palladium-catalyzed aminocarbonylation of propargyl acetates with amines for the synthesized tri-/tetrasubstituted 2,3-allenamides has been developed. A broad range of tri-/tetrasubstituted 2,3-allenamides have been prepared from propargyl acetates in good to excellent yields. The reaction featured mild reaction conditions and good functional group tolerance. The applicability of this methodology was further highlighted by the late-stage modification of several natural products and pharmaceuticals.

Cooperative Cu/Pd-Catalyzed 1,5-Boroacylation of Cyclopropyl-Substituted Alkylidenecyclopropanes.

A Cu/Pd-cocatalyzed 1,5-boroacylation of cyclopropyl-substituted ACPs with B2pin2 and acid chlorides has been developed. Using cyclopropyl-substituted ACPs as the starting material, a broad range of 1,5-boroacylated products with multiple functional groups was prepared in good yields with excellent regio- and stereoselectively. Both aromatic and aliphatic acid chlorides were tolerated in this reaction.

A sandwich-type photoelectrochemical biosensor based on Ru(bpy)32+ sensitized In2S3 for aflatoxin B1 detection.

Aflatoxin B1 (AFB1), classified as a class I carcinogen, is a widespread mycotoxin that poses a serious threat to public health and economic development, and the food safety problems caused by AFB1 have aroused worldwide concern. The development of accurate and sensitive methods for the detection of AFB1 is significant for food safety monitoring. In this work, a sandwich-type photoelectrochemical (PEC) biosensor for AFB1 detection was constructed on the basis of an aptamer-antibody structure. A good photocurrent response was obtained due to the sensitization of In2S3 by Ru(bpy)32+. In addition, this sandwich-type sensor constructed by modification with the antibody, target detector, and aptamer layer by layer attenuated the migration hindering effect of photogenerated carriers caused by the double antibody structure. The aptamer and antibody synergistically recognized and captured the target analyte, resulting in more reliable PEC response signals. CdSe@CdS QDs-Apt were modified as a signal-off probe onto the sensor platform to quantitatively detect AFB1 with a "signal-off" response, which enhanced the sensitivity of the sensor. The PEC biosensor showed a linear response range from 10-12 to 10-6 g mL-1 with a detection limit of 0.023 pg mL-1, providing a feasible approach for the quantitative detection of AFB1 in food samples.

Quantitative Proteomics Provided Insights into the Protective Effects of Heat Acclimation on the Rat Hypothalamus after Exertional Heatstroke.

BACKGROUND: The effects of heat acclimation (HA) on the hypothalamus after exertional heatstroke (EHS) and the specific mechanism have not been fully elucidated, and this study aimed to address these questions. METHODS: In the present study, rats were randomly assigned to the control, EHS, HA, or HA + EHS groups (n = 9). Hematoxylin and eosin (H&E) staining was used to examine pathology. Tandem mass tag (TMT)-based proteomic analysis was utilized to explore the impact of HA on the protein expression profile of the hypothalamus after EHS. Bioinformatics analysis was used to predict the functions of the differentially expressed proteins. The differential proteins were validated by western blotting. An enzyme-linked immunosorbent assay was used to measure the expression levels of inflammatory cytokines in the serum. RESULTS: The H&E staining (n = 5) results revealed that there were less structural changes in hypothalamus in the HA + EHS group compared with the EHS group. Proteomic analysis (n = 4) revealed that proinflammatory proteins such as argininosuccinate synthetase (ASS1), high mobility group protein B2 (HMGB2) and vimentin were evidently downregulated in the HA + EHS group. The levels of interleukin (IL)-1ß, IL-1, and IL-8 were decreased in the serum samples (n = 3) from HA + EHS rats. CONCLUSIONS: HA may alleviate hypothalamic damage caused by heat attack by inhibiting inflammatory activities, and ASS1, HMGB2 and vimentin could be candidate factors involved in the exact mechanism.

Sucrose Transporter StSUT2 Affects Potato Plants Growth, Flowering Time, and Tuber Yield.

BACKGROUND: Sucrose transporters (SUTs) mediate sucrose phloem loading in source tissue and sucrose unloading into sink tissue in potatoes and higher plants, thus playing a crucial role in plant growth and development. In potatoes, the physiological function of the sucrose transporters StSUT1 and StSUT4 has been clarified, whereas the physiological role of StSUT2 is not yet fully understood. METHODS AND RESULTS: This study analyzed the relative expression of StSUT2 compared to that of StSUT1 and StSUT4 in different tissues from potatoes and its impact on different physiological characteristics by using StSUT2-RNA interference lines. Here, we report a negative effect of StSUT2-RNA interference on plant height, fresh weight, internodes number, leaf area, flowering time, and tuber yield. However, our data indicate that StSUT2 is not involved in carbohydrate accumulation in potato leaves and tubers. In addition, the data of the RNA-seq between the StSUT2-RNA interference line and WT showed that 152 genes were differentially expressed, of which 128 genes were upregulated and 24 genes were downregulated, and the GO and KEGG analyses revealed that differentially expressed genes were mainly related to cell wall composition metabolism. CONCLUSIONS: Thus, StSUT2 functions in potato plant growth, flowering time, and tuber yield without affecting carbohydrate accumulation in the leaves and tubers but may be involved in cell wall composition metabolism.

Urinary biomarkers for hepatocellular carcinoma: current knowledge for clinicians.

Hepatocellular carcinoma (HCC) is the most predominant primary liver cancer, causing many illnesses and deaths worldwide. The insidious clinical presentation, difficulty in early diagnosis, and the highly malignant nature make the prognosis of HCC extremely poor. The complex and heterogeneous pathogenesis of HCC poses significant challenges to developing therapies. Urine-based biomarkers for HCC, including diagnostic, prognostic, and monitoring markers, may be valuable supplements to current tools such as serum α-fetoprotein (AFP) and seem promising for progress in precision medicine. Herein, we reviewed the major urinary biomarkers for HCC and assessed their potential for clinical application. Molecular types, testing platforms, and methods for building multimolecule models in the included studies have shown great diversity, thus providing abundant novel tools for future clinical transformation and applications.

Palladium-Catalyzed Intramolecular Heck/Aminocarbonylation of Alkene-Tethered Iodobenzenes with Nitro Compounds: Synthesis of Carbamoyl-Substituted Benzoheterocycles.

A palladium-catalyzed intramolecular Heck/aminocarbonylation of alkene-tethered iodobenzenes with nitro compounds has been developed for the synthesis of carbamoyl-substituted benzoheterocycles. Using Mo(CO)6 as a solid CO source, no external reductant or additives were needed in this procedure. Both nitroarenes and nitroalkanes were well tolerated. A range of carbamoyl-substituted dihydrobenzofurans and indolines were prepared in moderate to high yields.

Palladium Catalyzed Annulation of o-Iodo-Anilines with Propargyl Alcohols: Synthesis of Substituted Quinolines.

A palladium catalyzed annulation of o-iodo-anilines with propargyl alcohols for the synthesis of substituted quinolines has been developed. The reaction tolerates diverse functional groups under mild conditions, providing direct access to 2,4-disubstituted quinolines from easily available starting materials. A broad range of 2,4-disubstituted quinolines were efficiently prepared in good to excellent yields.

An electrochemiluminescence aptasensor based on highly luminescent silver-based MOF and biotin-streptavidin system for mercury ion detection.

In this study, for the first time, a silver-based metal-organic framework (Ag-MOF) was synthesized and used as the electrochemiluminescence (ECL) emitter for building an ECL sensor. After modification with chitosan (CS) and gold nanoparticles (Au NPs), the ECL stability of Ag-MOF was improved. To detect mercury ions, a biosensor was constructed using the mercury ion aptamer and steric effect of streptavidin. First, the capture strand (cDNA) with terminal-modified sulfhydryl group was attached to the electrode surface by the Au-S bond. Then, the mercury-ion aptamer (Apt-Hg) modified with biotin was anchored to the electrode by complementary pairing with cDNA. Streptavidin (SA) could be fixed on the electrode by linking with biotin, thereby reducing the ECL signal. However, in the presence of mercury ions, the aptamer was removed and streptavidin could not be immobilized on the electrode. Hence, the ECL signal of the sensor increased with the concentration of mercury ions, which was linear in the range from 1 µM to 300 fM. The detection limit could reach 66 fM (S/N = 3). The sensor provided a new method for the detection of mercury ions.

Divergent synthesis of bis(indolyl)methanes via FeIII-catalysed regioselective dehydrogenative coupling reactions: a biomimetic approach to 6,6'-bis-(debromo)-gelliusine F.

The divergent dehydrogenative coupling reactions of tryptamines with the catalysis of nontoxic FeIII salts in the presence of DDQ as the co-oxidant have been developed. Remarkably, the transformations feature a rapid and regioselective assembly of diverse 2,8'- and N1,8'-bis(indolyl) methane derivatives from readily-available starting materials by simply changing the FeIII salt and reaction temperature. Besides, the fast reaction rate, mild reaction conditions, low catalyst cost and easy operations make this methodology quite useful. The synthetic utility was further demonstrated in the biomimetic synthesis of 6,6'-bis-(debromo)-gelliusine F.

PACAP/PAC1-R activation contributes to hyperalgesia in 6-OHDA-induced Parkinson's disease model rats via promoting excitatory synaptic transmission of spinal dorsal horn neurons.

Pain is a common annoying non-motor symptom in Parkinson's disease (PD) that causes distress to patients. Treatment for PD pain remains a big challenge, as its underlying mechanisms are elusive. Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1-R play important roles in regulating a variety of pathophysiological processes. In this study, we investigated whether PACAP/PAC1-R signaling was involved in the mechanisms of PD pain. 6-hydroxydopamine (6-OHDA)-induced PD model was established in rats. Behavioral tests, electrophysiological and Western blotting analysis were conducted 3 weeks later. We found that 6-OHDA rats had significantly lower mechanical paw withdrawal 50% threshold in von Frey filament test and shorter tail flick latency, while mRNA levels of Pacap and Adcyap1r1 (gene encoding PAC1-R) in the spinal dorsal horn were significantly upregulated. Whole-cell recordings from coronal spinal cord slices at L4-L6 revealed that the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in dorsal horn neurons was significantly increased, which was reversed by application of a PAC1-R antagonist PACAP 6-38 (250 nM). Furthermore, we demonstrated that intrathecal microinjection of PACAP 6-38 (0.125, 0.5, 2 µg) dose-dependently ameliorated the mechanical and thermal hyperalgesia in 6-OHDA rats. Inhibition of PACAP/PAC1-R signaling significantly suppressed the activation of Ca2+/calmodulin-dependent protein kinase II and extracellular signal-regulated kinase (ERK) in spinal dorsal horn of 6-OHDA rats. Microinjection of pAAV-Adcyap1r1 into L4-L6 spinal dorsal horn alleviated hyperalgesia in 6-OHDA rats. Intrathecal microinjection of ERK antagonist PD98059 (10 µg) significantly alleviated hyperalgesia in 6-OHDA rats associated with the inhibition of sEPSCs in dorsal horn neurons. In addition, we found that serum PACAP-38 concentration was significantly increased in PD patients with pain, and positively correlated with numerical rating scale score. In conclusion, activation of PACAP/PAC1-R induces the development of PD pain and targeting PACAP/PAC1-R is an alternative strategy for treating PD pain.

Targeting proteasomal deubiquitinases USP14 and UCHL5 with b-AP15 reduces 5-fluorouracil resistance in colorectal cancer cells.

5-Fluorouracil (5-FU) is the first-line treatment for colorectal cancer (CRC) patients, but the development of acquired resistance to 5-FU remains a big challenge. Deubiquitinases play a key role in the protein degradation pathway, which is involved in cancer development and chemotherapy resistance. In this study, we investigated the effects of targeted inhibition of the proteasomal deubiquitinases USP14 and UCHL5 on the development of CRC and resistance to 5-FU. By analyzing GEO datasets, we found that the mRNA expression levels of USP14 and UCHL5 in CRC tissues were significantly increased, and negatively correlated with the survival of CRC patients. Knockdown of both USP14 and UCHL5 led to increased 5-FU sensitivity in 5-FU-resistant CRC cell lines (RKO-R and HCT-15R), whereas overexpression of USP14 and UCHL5 in 5-FU-sensitive CRC cells decreased 5-FU sensitivity. B-AP15, a specific inhibitor of USP14 and UCHL5, (1-5 µM) dose-dependently inhibited the viability of RKO, RKO-R, HCT-15, and HCT-15R cells. Furthermore, treatment with b-AP15 reduced the malignant phenotype of CRC cells including cell proliferation and migration, and induced cell death in both 5-FU-sensitive and 5-FU-resistant CRC cells by impairing proteasome function and increasing reactive oxygen species (ROS) production. In addition, b-AP15 inhibited the activation of NF-κB pathway, suppressing cell proliferation. In 5-FU-sensitive and 5-FU-resistant CRC xenografts nude mice, administration of b-AP15 (8 mg·kg-1·d-1, intraperitoneal injection) effectively suppressed the growth of both types of tumors. These results demonstrate that USP14 and UCHL5 play an important role in the development of CRC and resistance to 5-FU. Targeting USP14 and UCHL5 with b-AP15 may represent a promising therapeutic strategy for the treatment of CRC.

Anti-α-Glucosidase, SAR Analysis, and Mechanism Investigation of Indolo[1,2-b]isoquinoline Derivatives.

To find potential α-glucosidase inhibitors, indolo[1,2-b]isoquinoline derivatives (1-20) were screened for their α-glucosidase inhibitory effects. All derivatives presented potential α-glucosidase inhibitory effects with IC50 values of 3.44 ± 0.36~41.24 ± 0.26 µM compared to the positive control acarbose (IC50 value: 640.57 ± 5.13 µM). In particular, compound 11 displayed the strongest anti-α-glucosidase activity, being ~186 times stronger than acarbose. Kinetic studies found that compounds 9, 11, 13, 18, and 19 were all reversible mix-type inhibitors. The 3D fluorescence spectra and CD spectra results revealed that the interaction between compounds 9, 11, 13, 18, and 19 and α-glucosidase changed the conformational changes of α-glucosidase. Molecular docking and molecular dynamics simulation results indicated the interaction between compounds and α-glucosidase. In addition, cell cytotoxicity and drug-like properties of compound 11 were also investigated.

K2CO3-Promoted oxy-Michael Addition/Cyclization of α,ß-Unsaturated Carbonyl Compounds with Naphthols: Synthesis of Naphthopyrans.

A potassium carbonate promoted tandem oxy-Michael addition/cyclization of α,ß-unsaturated carbonyl compounds with naphthol derivatives for the synthesis of 2-substituted naphthopyrans was developed. Using the readily available, inexpensive potassium carbonate as the promoter, a range of different substituted naphthopyrans were prepared.

Comparison of robotic camera holders with human assistants in endoscopic surgery: a systematic review and meta-analysis.

BACKGROUND: Robotic camera holders can overcome the shortcomings of human assistants, such as shaking and accidental rotation in endoscopic surgery. Robotic camera holder is not affected by the operation time and surgical position and reduces the size of the team. However, there is still controversy over the practicality of robotic camera holders. MATERIAL AND METHODS: We searched PubMed, Web of Science, Embase, Cochrane Library PubMed, Embase, Cochrane Library and Web of Science. The last database search was performed on 30 April 2022. Two reviewers independently reviewed the studies. RESULTS: A total of eight studies (n = 698, 354 controls and 344 robotic camera holders) were included in our analysis. The results showed that the robotic camera holder significantly outperformed human assistants on the frequency of lens cleaning (SMD, -0.48; 95% CI, -0.90 to -0.05) and inappropriate movements (MD, -3.57; 95% CI, -4.93 to -2.21). There was no difference in total operation time (MD, 6.99; 95% CI, -2.47 to 16.72), preparation time (MD, 2.43; 95% CI, -0.32 to 5.18) or blood loss (MD, 34.47; 95% CI, -8.05 to 76.98) between the robotic camera holder and human assistant. However, the robotic camera holder was significantly slower in the core operation (MD, 5.06; 95% CI, 1.18 to 8.94), and surgeons had mixed reviews of robotic systems. CONCLUSIONS: The robotic camera holder provided the surgeon with a highly stable environment. Although the robotic camera holder will not increase the total time, it still needs to improve the core operation time. There is much room for improvement in robotic camera holders. Further development of devices with intuitive control systems and a greater range of motion will be required to accommodate more complex surgeries.

[Systematic identification of chemical forms of key terpene synthase in Cinnamomum camphora].

Cinnamomum camphora is an important economic tree species in China. According to the type and content of main components in the volatile oil of leaf, C. camphora were divided into five chemotypes, including borneol-type, camphor-type, linalool-type, cineole-type, and nerolidol-type. Terpene synthase(TPS) is the key enzyme for the formation of these compounds. Although several key enzyme genes have been identified, the biosynthetic pathway of(+)-borneol, which has the most economic value, has not been reported. In this study, nine terpenoid synthase genes CcTPS1-CcTPS9 were cloned through transcriptome analysis of four chemical-type leaves. After the recombinant protein was induced by Escherichia coli, geranyl pyrophosphate(GPP) and farnesyl pyrophosphate(FPP) were used as substrates for enzymatic reaction, respectively. Both CcTPS1 and CcTPS9 could catalyze GPP to produce bornyl pyrophosphate, which could be hydrolyzed by phosphohydrolase to obtain(+)-borneol, and the product of(+)-borneol accounted for 0.4% and 89.3%, respectively. Both CcTPS3 and CcTPS6 could catalyze GPP to generate a single product linalool, and CcTPS6 could also react with FPP to generate nerolidol. CcTPS8 reacted with GPP to produce 1,8-cineol(30.71%). Nine terpene synthases produced 9 monoterpene and 6 sesquiterpenes. The study has identified the key enzyme genes responsible for borneol biosynthesis in C. camphora for the first time, laying a foundation for further elucidating the molecular mechanism of chemical type formation and cultivating new varieties of borneol with high yield by using bioengineering technology.

Total Synthesis of Metaphanine and Oxoepistephamiersine.

Herein, we report a concise and divergent synthesis of the complex hasubanan alkaloids metaphanine and oxoepistephamiersine from commercially available and inexpensive cyclohexanedione monoethylene acetal. Our synthesis features a palladium-catalyzed cascade cyclization reaction to set the tricyclic carbon framework of the desired molecules, a regioselective Baeyer-Villiger oxidation followed by a MeNH2 triggered skeletal reorganization cascade to construct the benzannulated aza[4.4.3]propellane, and a strategically late-stage regio-/diastereoselective oxidative annulation of sp3 C-H bond to form the challenging THF ring system and hemiketal moiety in a single step. In addition, a highly enantioselective alkylation of cyclohexanedione monoethylene acetal paved the way for the asymmetric synthesis of target molecular.

A Nomogram to Predict Individual Survival of Patients with Liver-Limited Metastases from Gastroenteropancreatic Neuroendocrine Neoplasms: A US Population-Based Cohort Analysis and Chinese Multicenter Cohort Validation Study.

INTRODUCTION: Although gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) with liver metastasis encompass a wide variety of clinical conditions with various prognosis, no statistical model for predicting the prognosis of these patients has been established. We sought to establish a more elaborative and individualized nomogram to predict survival of patients with liver-limited metastatic GEP-NENs. In addition, this nomogram was validated by both the Surveillance, Epidemiology, and End Results (SEER) database and a Chinese multicenter cohort. METHODS: Patients diagnosed with GEP-NENs with liver-limited metastasis between 2010 and 2016 were identified from the SEER database. Kaplan-Meier survival analysis was performed to analyze survival outcomes. A nomogram was established based on the independent prognostic variables identified from univariate and multivariate Cox regression analyses. The nomogram was evaluated in both an internal validation SEER dataset and an external validation dataset composed of patients from the Chinese multicenter cohort. RESULTS: A total of 1,474 patients from the SEER database and 192 patients from the multicenter cohort were included. Age, tumor size, differentiation, primary tumor resection, and liver metastasis resection were identified as independent prognostic factors by univariate and multivariate Cox analyses and were verified by Kaplan-Meier survival analysis (all p < 0.0001). A nomogram was developed and validated by calibration curves and areas under the curve of the external validation cohort, which showed good consistency and veracity in predicting overall survival. CONCLUSION: A nomogram was developed for the first time to predict the survival of patients with liver-limited metastases from GEP-NENs. Both internal and external validation demonstrated excellent discrimination and calibration of our nomogram. Based on this prognostic model, clinicians could develop more personalized treatment strategies and surveillance protocols.