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N-Acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) therapies have received approval for treating both orphan and prevalent diseases. To improve in vivo efficacy and streamline the chemical synthesis process for efficient and cost-effective manufacturing, we conducted this study to identify better designs of GalNAc-siRNA conjugates for therapeutic development. Here, we present data on redesigned GalNAc-based ligands conjugated with siRNAs against angiopoietin-like 3 (ANGPTL3) and lipoprotein (a) (Lp(a)), two target molecules with the potential to address large unmet medical needs in atherosclerotic cardiovascular diseases. By attaching a novel pyran-derived scaffold to serial monovalent GalNAc units before solid-phase oligonucleotide synthesis, we achieved increased GalNAc-siRNA production efficiency with fewer synthesis steps compared to the standard triantennary GalNAc construct L96. The improved GalNAc-siRNA conjugates demonstrated equivalent or superior in vivo efficacy compared to triantennary GalNAc-conjugated siRNAs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: To study the effect of Apelin-13/APJ system on intervertebral disc degeneration and its mechanism., Patients and Methods: This study detected the expression of APJ in human intervertebral disc tissue with varying degrees of degeneration. IL-1β is used to stimulate the degeneration of nucleus pulposus cells. We used recombinant human Apelin-13 and Ala13 to activate and inhibit the APJ receptor, respectively. The inhibitor LY294002 was used to inhibit the PI3K/AKT signaling pathway. We studied the effects of Apelin-13/APJ system on nucleus pulposus cells and its mechanism by Western blot, RT-PCR, and so on., Results: APJ is lowly expressed in the nucleus pulposus of patients with a high degree of degeneration. IL-1β stimulates the nucleus pulposus cells and reduces the expression of APJ in nucleus pulposus cells. Recombinant human Apelin-13 reduces the degradation of nucleus pulposus extracellular matrix, promotes proliferation, and reduces the levels of apoptosis and inflammation. In addition, the Apelin-13/APJ system increases the expression of PI3K and AKT and activates the PI3K/AKT signaling pathway., Conclusions: Apelin-13/APJ system activates PI3K/AKT signaling pathway activity, reduces the degradation of nucleus pulposus extracellular matrix, promotes proliferation, and reduces the level of apoptosis and inflammation, thus delaying the degeneration of the intervertebral disc.

Background: Isolated gastrointestinal venous malformations (GIVMs) are extremely rare congenital developmental abnormalities of the venous vasculature. Because of their asymptomatic nature, the diagnosis is often quite challenging. However, as symptomatic GIVMs have nonspecific clinical manifestations, misdiagnosis is very common. Here, we report a case of isolated diffuse GIVMs inducing mechanical intestinal obstruction. A literature review was also conducted to summarize clinical features, diagnostic points, treatment selections and differential diagnosis in order that doctors may have a comprehensive understanding of this disease., Case Summary: A 50-year-old man presented with recurrent painless gastrointestinal bleeding for two months and failure to pass flatus and defecate with nausea and vomiting for ten days. Digital rectal examination found bright red blood and soft nodular masses 3 cm above the anal verge. Computed tomography showed that part of the descending colon and rectosigmoid colon was thickened with phleboliths in the intestinal wall. Colonoscopy exhibited bluish and reddish multinodular submucosal masses and flat submucosal serpentine vessels. Endoscopic ultrasonography showed anechoic cystic spaces within intestinal wall. The lesions were initially thought to be isolated VMs involving part of the descending colon and rectosigmoid colon. Laparoscopic subtotal proctocolectomy, pull-through transection and coloanal anastomosis and ileostomy were performed. Histopathology revealed intact mucosa and dilated, thin-walled blood vessels in the submucosa, muscularis, and serosa involving the entire colorectum. The patient recovered with complete symptomatic relief during the 52-mo follow-up period., Conclusion: The diagnosis of isolated GIVMs is challenging. The information presented here is significant for the diagnosis and management of symptoms., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflicts of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Herein, highly branched Pt@Ag core-shell nanoparticles (Pt@Ag NPs) were fabricated by a facile one-pot wet-chemical approach, where poly(ethyleneimine) (PEI) served as structure-directing and capping agents. Their structure, morphology and composition were mainly characterized by a set of techniques. And their growth mechanism was discussed in some detail. The prepared catalyst exhibited remarkable enhancement in catalytic activity of 4-nitrophenol (4-NP) reduction as a proof-of-concept application, surpassing commercial Pt black and home-made Ag NPs catalysts. Also, the as-obtained catalyst showed superior stability without sacrificing the catalytic activity. These observations endow the catalyst possibility for practical applications in nitrophenols environmental remediation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Hybridization of different pharmacophores from various bioactive substances into a single molecule is the potential weapon to prevent the drug resistance since this strategy can provide new leads with complimentary activities and/or multiple pharmacological targets. Fluoroquinolone and isatin are common pharmacophores, and their derivatives possess various biological activities. Obviously, hybridization of these two pharmacophores into one molecule may result in novel candidates with broader spectrum, higher efficiency, lower toxicity as well as multiple mechanisms of action. Therefore, fluoroquinolone-isatin hybrids have the potential for clinical deployment in the control and eradication of various diseases. This review covers the recent advances of fluoroquinolone-isatin hybrids as potential anti-bacterial, anti-tubercular, anti-viral and anti-cancer agents. The structure-activity relationship is also discussed to pave the way for the further rational development of this kind of hybrids., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Pt-based bimetallic nanocrystals are feasible to dramatically improve the catalytic performances in fuel cells via morphology- and composition-engineering. Herein, bimetallic platinum 69 -cobalt 31 nanosheet nanoassemblies (Pt 69 Co 31 NSNSs) were facilely synthesized through a one-pot co-reduction solvothermal strategy in oleylamine (OAm), using cetyltrimethylammonium chloride (CTAC) and allantoin as the directing agents. The current synthesis highly depended on the critical concentrations of Pt and Co precursors, the combined use of allantoin to OAm as the co-reductant, and the use of proper allantoin concentration. The obtained nanocatalyst exhibited largely enhanced electrocatalytic activity and durable ability towards ethylene glycol oxidation reaction (EGOR) and oxygen reduction reaction (ORR) relative to home-made Pt 85 Co 15 nanoparticles (NPs), Pt 19 Co 81 NPs and Pt black catalysts due to its much larger electrochemically active surface area than the contrasts., (Copyright © 2018 Elsevier Inc. All rights reserved.)

To realize the efficient and complete removal of organic pollutants in waste water, it is highly urgent for scalable synthesis of either self-supported bimetallic nanocatalysts or anchored on carbon-based materials. In this study, a simple one-pot coreduction method was developed for preparing well-dispersed AgPd alloyed nanoclusters uniformly dispersed on reduced graphene oxide (AgPd NCs/rGO) at room temperature by utilizing 5-azacytosine as the capping agent. The nanocomposites were characterized by a set of physical characterizations. The formation mechanism and catalytic mechanism were discussed in some details. Moreover, the prepared AgPd NCs/rGO exhibited dramatically increased catalytic properties towards the reduction of 4-nitrophenol (4-NP) in the presence of NaBH 4 when compared to commercial Pd/C (20 wt.%)., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The emergence and wide-spread of drug-resistant bacteria including multi-drug resistant and pan-drug resistant pathogens which are associated with considerable mortality, represent a significant global health threat. 4-Quinolones which are exemplified by fluoroquinolones are the second largest chemotherapy agents used in clinical practice for the treatment of various bacterial infections. However, the resistance of bacteria to 4-quinolones develops rapidly and spreads widely throughout the world due to the long-term, inappropriate use and even abuse. To overcome the resistance and improve the potency, several strategies have been developed. Amongst them, molecular hybridization, which is based on the incorporation of two or more pharmacophores into a single molecule with a flexible linker, is one of the most practical approaches. This review aims to summarize the recent advances made towards the discovery of 4-quinolone hybrids as potential antibacterial agents as well as their structure-activity relationship (SAR). The enriched SAR may pave the way for the further rational development of 4-quinolone hybrids with excellent potency against both drug-susceptible and drug-resistant bacteria., (Copyright © 2017. Published by Elsevier Masson SAS.)

One-third of the world's population infected tuberculosis (TB), and more than 1 million deaths annually. The co-infection between the mainly pathogen Mycobacterium tuberculosis (MTB) and HIV, and the incidence of drug-resistant TB, multi-drug resistant TB, extensively drug-resistant TB as well as totally drug-resistant TB have further aggravated the mortality and spread of this disease. Thus, there is an urgent need to develop novel anti-TB agents against both drug-susceptible and drug-resistant TB. The wide spectrum of biological activities and successful utilization of pyrazole-containing drugs in clinic have inspired more and more attention towards this kind of heterocycles. Numerous of pyrazole-containing derivatives have been synthesized for searching new anti-TB agents, and some of them showed promising potency and may have novel mechanism of action. This review aims to outline the recent achievements in pyrazole-containing derivatives as anti-TB agents and their structure-activity relationship., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Twelve novel 1H-1,2,3-triazole-tethered gatifloxacin (GTFX) isatin conjugates 5a-l with greater lipophilicity compared with GTFX were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against M. tuberculosis (MTB) H 37 Rv and MDR-TB as well as cytotoxicity. The preliminary results showed that all the targets (MIC: 0.10-8 μg/mL) exhibited excellent inhibitory activity against MTB H 37 Rv and MDR-TB, but eight of them (CC 50 : 7.8-62.5 μg/mL) were much more toxic than the parent GTFX (CC 50 : 125 μg/mL). Among them, 5g (MIC: 0.10 μg/mL) was 4-8 times more potent in vitro than the references GTFX (MIC: 0.78 μg/mL) and RIF (MIC: 0.39 μg/mL) against MTB H 37 Rv, but less active than INH (MIC: 0.05 μg/mL). The most potent 5g and 5h (MIC: 0.25 μg/mL) were 4->512 times more active than the three references (MIC: 1.0->128 μg/mL) against MDR-TB. Unfortunately, both of the two hybrids (CC 50 : 7.8 μg/mL) were much more cytotoxic than the other derivatives, need to be further optimized., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Tuberculosis (TB) remains one of the most widespread and leading deadliest diseases, threats one-third of the world's population. Although numerous efforts have been undertaken to develop new anti-TB agents, only a handful of compounds have entered human trials in the past 5 decades. Triazoles including 1,2,3-triazole and 1,2,4-triazole are one of the most important classes of nitrogen containing heterocycles that exhibited various biological activities. Triazole derivatives are regarded as a new class of effective anti-TB candidates owing to their potential anti-TB potency. Thus, molecules containing triazole moiety may show promising in vitro and in vivo anti-TB activities and might be able to prevent the drug resistant to certain extent. This review outlines the advances in the application of triazole-containing hybrids as anti-TB agents, and discusses the structure-activity relationship of these derivatives., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Tuberculosis (TB) is a lift-threatening chronic deadliest infectious disease caused predominantly by Mycobacterium tuberculosis (MTB) which affects primarily the lungs (pulmonary TB) apart from other vital organs. The emergence of drug-resistant TB (DR-TB), multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB) and the recently cases of totally drug resistant (TDR) towards currently accessible standard drugs was increased up to alarming level in the recent decades. In pursuit of searching new anti-TB agents, numerous of derivatives have been synthesized and screened for their anti-TB activity. Coumarins are one of the most important classes of natural products that exhibited various biological activities, and their derivatives regarded as a new class of effective anti-TB candidates owing to their potential anti-TB activity. Thus, coumarin skeleton has attracted great interest in the development of new anti-TB agents. This review outlines the advances in the application of coumarin-containing derivatives as anti-TB agents and the critical aspects of design and structure-activity relationship of these derivatives., (Published by Elsevier Masson SAS.)

A series of novel 8-OMe ciprofloxacin (CPFX)-hydrazone/azole hybrids were designed, synthesized, and evaluated for their in vitro biological activities. Our results reveal that all of the hydrozone-containing hybrids (except for 7 ) show potency against Mycobacterium tuberculosis (MTB) H 37 Rv (minimum inhibitory concentration (MIC): <0.5 μM), which is better than the parent drug CPFX, and comparable to moxifloxacin and isoniazid, some of the tested Gram-positive strains (MIC: 0.06-4 μg/mL), and most Gram-negative strains (MIC: ≤0.03-4 μg/mL)., Competing Interests: The authors declare no conflict of interest.

Tuberculosis (TB), which has been a scourge of humanity for thousands of years, is a worldwide pandemic disease caused mainly by Mycobacterium tuberculosis (MTB). The emergence of drug-resistant TB (DR-TB), multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB) and totally drug-resistant TB (TDR-TB) increase the challenges to eliminate TB worldwide. Isoniazid (INH), a critical frontline anti-TB drug, is one of the most effective drugs used to treatment of TB infection for more than 60 years. Unfortunately, bacterial strains resistant to INH are becoming common which mainly due to the long-term widely use even abuse. Therefore, there is an urgent need to develop novel anti-TB agents. Numerous efforts have been undertaken to develop new anti-TB agents, but no new drug has been introduced for more than 5 decades. It has been suggested that the incorporation of lipophilic moieties into the framework of INH can increase permeation of the drug into bacterial cells, thereby enhancing the anti-TB. Therefore, INH derivatives with greater lipophilicity are emerging as one of the most potential anti-TB agents. Indeed, the INH derivative LL-3858 is in initial stages of phase II clinical trial for the treatment of TB and may be approved to treat TB in the near future. This review aims to summarize the recent advances made towards the discovery anti-TB agents holding INH as a nucleus including INH hybrids and INH hydrazide-hydrazone derivatives., (Copyright © 2017. Published by Elsevier Masson SAS.)

Aim: The study aimed to determine whether Helicobacter pylori infection is associated with colorectal adenocarcinoma and to quantify the extent of the risk., Method: A literature search was performed to identify studies published between 1995 and 2012 for relevant risk estimates. Fixed and random effect meta-analytical techniques were conducted for colorectal adenocarcinoma and adenomatous polyp., Results: Twenty-seven case-controlled studies involving 3450 adenocarcinoma patients, 1304 adenomatous polyp patients and more than 4000 controls were included. Helicobacter pylori was associated with an increased risk of colorectal adenocarcinoma and adenomatous polyp [odds ratio (OR) 1.24, 95% CI 1.12-1.37, P = 0.66; OR 1.87, 95% CI 1.53-2.28, P = 0.81]. There was a significant association between the CagA-positive strain and adenocarcinoma risk (OR 1.22, 95% CI 1.08-1.37, P = 0.05). In addition, there was an increased risk of tubular adenoma and villous adenoma formation (OR 3.06, 95% CI 1.98-4.73, P = 0.14; OR 2.05, 95% CI 0.84-4.97, P = 0.86)., Conclusion: The meta-analysis suggests a promoting effect of Helicobacter pylori on the risk of adenocarcinoma. It also suggests that Helicobacter infection might have its influence at the start of the adenomatous polyp disease sequence., (Colorectal Disease © 2013 The Association of Coloproctology of Great Britain and Ireland.)

The incidence of esophageal adenocarcinoma has markedly increased in the last few decades and Barrett's esophagus is regarded as the precursor lesion of this cancer. The aim of the study was to quantify the adenocarcinoma risk associated with nonsteroidal anti-inflammatory drug use and to determine at which stage chemoprevention with this drug is the most effective in esophageal inflammation - Barrett's esophagus - adenocarcinoma sequence. A literature search was performed to identify studies published between 1998 and 2009 for relevant risk estimates. Fixed and random effect meta-analytical techniques were conducted for aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, and all nonsteroidal anti-inflammatory drugs. Four cohort and 10 case-control studies were included. Use of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs in normal population was associated with a reduced risk of adenocarcinoma (odds ratio [OR]: 0.73, 95% confidence interval [CI]: 0.65-0.83; OR: 0.84, 95% CI: 0.72-0.98, respectively). The use of all nonsteroidal anti-inflammatory drugs was associated with a reduced risk of adenocarcinoma (relative risk [RR]: 0.64, 95% CI: 0.42-0.96) in Barrett's esophagus patients. However, no obvious dose-effect relationships were found. In addition, we discovered a reverse association between drugs use and adenocarcinoma risk in people without a history of upper gastrointestinal tract disorders (OR: 0.57, 95% CI: 0.43-0.77, P= 0.12). Our meta-analyses suggest a protective effect of nonsteroidal anti-inflammatory drugs on the risk of adenocarcinoma. Our results also suggest that the drugs might act after the formation of Barrett's epithelium in the esophageal inflammation - Barrett's esophagus - adenocarcinoma sequence., (© 2010 Copyright the Authors. Journal compilation © 2010, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.)

Extrapontine myelinolysis and pure word deafness are very uncommon disorders. Here, we report a case of a 19-year-old woman who suffered from osmotic demyelination syndrome with coincidence of typical pure word deafness. As a consequence of rapid correction of hyponatremia, the patient demonstrated an initial onset of cortical deafness, and then progressed to generalized auditory agnosia, which eventually developed into confined verbal auditory agnosia (pure word deafness). Bilateral extrapontine myelinolysis was confirmed using brain magnetic resonance imaging. This case suggests that verbal and nonverbal stimuli may involve separate thalamocortical pathways.

As an important organic compound, chiral alcohols are the key chiral building blocks to many single enantiomer pharmaceuticals. Asymmetric reduction of the corresponding prochiral ketones to produce the chiral alcohols by biocatalysis is one of the most promising routes. Asymmetric reduction of different kinds of non-natural prochiral ketones catalyzed by various plants tissue was studied in this work. Acetophenone, 4'-chloroacetophenone and ethyl 4-chloroacetoacetate were chosen as the model substrates for simple ketone, halogen-containing aromatic ketone and beta-ketoesters, respectively. Apple (Malus pumila), carrot (Daucus carota), cucumber (Cucumis sativus), onion (Allium cepa), potato (Soanum tuberosum), radish (Raphanus sativus) and sweet potato (Ipomoea batatas) were chosen as the biocatalysts. It was found that these kinds of prochiral ketoness could be reduced by these plants tissue with high enantioselectivity. Both R- and S-form configuration chiral alcohols could be obtained. The e.e. and chemical yield could reach about 98 and 80% respectively for acetophenone and 4'-chloroacetophenone reduction reaction with favorable plant tissue. And the e.e. and yield for ethyl 4-chloroacetoacetate reduction reaction was about 91 and 45% respectively.