Correction and removal of expression of concern: Total synthesis of tubulysin U and N14-desacetoxytubulysin H.

Correction and removal of expression of concern for 'Total synthesis of tubulysin U and N14-desacetoxytubulysin H' by Bohua Long et al., Org. Biomol. Chem., 2020, 18, 5349-5353, https://doi.org/10.1039/D0OB01109F.

Unprecedented nor-seco-diterpene lactones inhibited osteogenic differentiation of valve interstitial cells.

The first examples of ent-atisane and ent-isopimarane diterpene lactones with an unusual 2,3-seco-2-nor-tetrahydro-2H-pyran-2-one nucleus, eufislactones A (1) and B (2), were isolated from the roots of Euphorbia fischeriana, together with a new (3) and fifteen known biosynthetic congeners (4-18). Their structures incorporating absolute configurations were elucidated via the comprehensive spectroscopic analyses, electronic circular dichroism (ECD) calculation, and single-crystal X-ray diffraction analyses. Biogenetically, compounds 1 and 2 were constructed by the plausible monomeric precursors, ent-atis-16-ene-3,14-dione (6) and ent-isopimara-8(14),15-dien-3-one (17), respectively, via key Baeyer-Villiger oxidation, decarboxylation, and semi-acetalization reactions to create a unique 2,3-seco-2-nor-tetrahydro-2H-pyran-2-one core. Our bioassays have revealed that eufislactone A (EFA, 1) displayed significant inhibitory effect on the osteogenic differentiation of human valvular interstitial cells (VICs), highlighting its potential as a preventive agent against the progression of human calcific aortic valve disease (CAVD).

Pair-Density-Wave and Chiral Superconductivity in Twisted Bilayer Transition Metal Dichalcogenides.

We theoretically explore possible orders induced by weak repulsive interactions in twisted bilayer transition metal dichalcogenides (e.g., WSe_{2}) in the presence of an out-of-plane electric field. Using renormalization group analysis, we show that superconductivity survives even with the conventional van Hove singularities. We find that topological chiral superconducting states with Chern number N=1, 2, 4 (namely, p+ip, d+id, and g+ig) appear over a large parameter region with a moiré filling factor around n=1. At some special values of applied electric field and in the presence of a weak out-of-plane Zeeman field, spin-polarized pair-density-wave (PDW) superconductivity can emerge. This spin-polarized PDW state can be probed by experiments such as spin-polarized STM measuring spin-resolved pairing gap and quasiparticle interference. Moreover, the spin-polarized PDW could lead to a spin-polarized superconducting diode effect.

Concise Enantioselective Total Synthesis of Isopavine Alkaloids.

Herein, we report a concise asymmetric total synthesis of isopavine alkaloids, which feature a special azabicyclo[3.2.2]nonane tetracyclic skeleton. The key steps include iridium-catalyzed asymmetric hydrogenation of unsaturated carboxylic acids, Curtius rearrangement, and Eschweiler-Clarke methylation, which enable an enantioselective approach to isopavine alkaloids in 6-7 linear steps. Furthermore, for the first time, isopavine alkaloids, especially (-)-reframidine (3), are found to display effective antiproliferative effects on various cancer cell lines.

Correction: Formal synthesis of cyclotheonellazole A.

Correction for 'Formal synthesis of cyclotheonellazole A' by Bohua Long et al., Org. Biomol. Chem., 2023, https://doi.org/10.1039/d3ob00038a.

Expression of concern: Total synthesis of tubulysin U and N14-desacetoxytubulysin H.

Expression of concern for 'Total synthesis of tubulysin U and N14-desacetoxytubulysin H' by Bohua Long et al., Org. Biomol. Chem., 2020, 18, 5349-5353, https://doi.org/10.1039/D0OB01109F.

Formal synthesis of cyclotheonellazole A.

A convergent procedure for the formal synthesis of cyclotheonellazole A in high yields and excellent stereoselectivity has been developed. This synthesis features an efficient preparation of O-pivaloyl-protected α-hydroxy-ß-amino amides and a one-pot process to introduce the challenging thiazole moiety. The overall synthesis is very efficient and paves the way for the preparation of analogues for drug development.

Discovery of two ent-atisane diterpenoid lactones with AChE inhibitory activity from the roots of Euphorbia fischeriana.

Euphorlactone A (1), a rare rearranged ent-atisane norditerpenoid with an undescribed 3-nor-2,4-olide-ent-atisane scaffold, and euphorlactone B (2), a new ent-atisane diterpenoid with an unprecedented seven-membered lactone ring C, were isolated from the roots of Euphorbia fischeriana. Their planar structures with absolute configurations were extensively elucidated by analysis of 1D and 2D NMR data, electronic circular dichroism (ECD) calculations, Rh2(OCOCF3)4-induced ECD curves, and single-crystal X-ray diffraction. Euphorlactone A (ELA) showed a remarkable AChE (acetylcholinesterase) inhibitory activity (IC50 = 2.13 ± 0.06 µM and Ki = 0.058 µM), which was five times stronger than that of the positive control (rivastigmine, IC50 = 12.46 ± 0.82 µM), and further in vitro enzyme inhibition kinetic analysis and molecular docking studies were performed to investigate the AChE inhibitory mechanism.

Asymmetric total synthesis and anti-hepatocellular carcinoma profile of enantiopure euphopilolide and jolkinolide E.

A flexible asymmetric synthesis of both enantiomers of euphopilolide (1) and jolkinolide E (2) [(+)-and (-)-1, (+)-and (-)-2] has been accomplished. This synthesis features an intramolecular oxa-Pauson-Khand reaction (o-PKR) to expeditiously construct the challenging tetracyclic [6.6.6.5] abietane-type diterpene framework, elegantly showcasing the complexity-generating features of o-PKR synthetic methodology leveraging on a judiciously chosen suitable chiral pool scaffold. Furthermore, the anti-hepatocellular carcinoma (HCC) activity of synthetic (-)-euphopilolide (1), (-)-jolkinolide E (2) and their analogues was evaluated. We found that (-)-euphopilolide (1) and (-)-jolkinolide E (2) inhibited the proliferation and induced apoptosis in HCC cells. These findings lay a good foundation for further pharmacology studies of abietane lactone derivatives and provide valuable insight for the development of anti-HCC small molecule drug of natural product origin.

Three Neolignan Glycosides from the Root of Nothopanax davidii.

Three neolignan glycosides, including a new compound (7S,8R)-dihydro-3'-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1'-benzofuranpropanol-9-O-ß-D-xylopyranoside (1), were isolated from the root of Nothopanax davidii. Their structures were determined by extensive spectroscopic analyses, particularly NMR, HR-ESI-MS, and ECD experiments, and the absolute configuration of 2 was first definitively determined. The anti-tumor activity was assessed on four tumor cells by MTT assay, the anti-inflammatory activity was determined by inhibition of NO production in LPS reduced RAW264.7 cells, and the interaction with iNOS was predicted by molecular docking. At the dose of 100 µM, the three neolignan glycosides showed no cytotoxic activity against HepG2, HCT116, HeLa and A549 human tumor cells, but significantly inhibited LPS induced NO generation in RAW264.7 cells with inhibition rates of 31.53 %, 23.95 %, and 20.79 %, respectively, showing weak anti-inflammatory activity, possibly due to their binding to key residues of iNOs involved in inhibitor binding.

Traditional Chinese medicine for dementia.

In Western medicine, dementia refers to a spectrum of diseases affecting cognition, mental health, and physical abilities. Ancient medical literatures of traditional Chinese medicine (TCM) also recorded dementia-like symptoms, but described the disease from a totally distinct theoretical point of view. The earliest records of memory loss in ancient China can be traced back 2000 years earlier. In TCM, dementia can be attributed mainly to the Brain dystrophy, Spleen-Kidney weakness, Blood stasis, and Phlegm stagnation. Of interest, ancient Chinese physicians have proposed that dementia manifests as not only cognitive but also noncognitive symptoms including psychiatric disorders and sleep disturbance, which have been investigated widely nowadays in Western medicine. Various TCM prescriptions, herbal medicines, and acupunctures have also been proposed for dementia prevention and therapy. Some of these strategies are still used in current clinical practice. Reviewing and highlighting the unique TCM recognition of treating dementia may shed light on future dementia research.

Application of a Pseudotargeted MS Method for the Quantification of Glycated Hemoglobin for the Improved Diagnosis of Diabetes Mellitus.

Proteins in a human body continuously undergo glycation reactions with reducing sugars, forming early as well as advanced glycation end-products (AGEs) which are highly disease-relevant. Specifically, N-1-(deoxyfructosyl) valine of ß-hemoglobin (HbA1c) has been considered as a marker of diabetes, but the exact map of glycated Hb peptides corelated with diabetes in different stages is poorly studied. Here, the pseudotargeted parallel reaction monitoring (PRM) method combined with relative retention time (iRT) endogenous peptides was proposed for exploring the roles of deoxyfructosyl (DF-), carboxymethyl (CM-), and carboxyethyl (CE-) based Hb modifications in clinical prognosis and diagnosis of type 2 diabetes mellitus (T2DM) and its complication. For building the pseudotargeted list, data-dependent acquisition (DDA) combined with multiple enzyme digestion was employed for the comprehensive identification of the three types of modification in vitro Hb and in vivo Hb. The introduction of the endogenous iRT peptides during PRM analysis facilitates being able to obtain accurate quantitative results. When applying this new strategy to quantify the three kinds of glycated Hb peptides in clinical samples, patients with T2DM in different pathophysiological conditions were fully distinguished from the controls, indicating the necessity of adopting multiple glycation types for the improved diagnosis of T2DM. Taken together, the newly developed pseudotargeted PRM method not only expands the horizons of glycated Hb by reliably assessing the actual status of T2DM but also reveals that endogenous iRT might be a viable option for label-free quantitative analysis.

Total synthesis of tubulysin U and N14-desacetoxytubulysin H.

A concise and efficient procedure for the total synthesis of tubulysin U and N14-desacetoxytubulysin H has been developed with high stereoselectivity on a gram scale. This synthesis features an elegant cascade one-pot process to install the challenging thiazole moiety and the employment of stereoselective reductions and a series of high-yield mild reactions to ensure the requisite stereochemistry, reaction scale, and yield and to avoid the vexing epimerization occurring during peptide formation.

CT2-3, a novel magnolol analogue suppresses NSCLC cells through triggering cell cycle arrest and apoptosis.

Magnolol, a major bioactive component found in Magnolia officinalis with anti-inflammation and anti-oxidation activities as well as minimized cytotoxic effects. Although magnolol has a wide range of clinical applications, the anti-tumor activity of magnolol is not efficient. Herein, we reported the synthesis and anti-cancer activities of three novel magnolol analogues CT2-1, CT2-2, CT2-3, among which CT2-3 revealed more efficient anti-non-small cell lung cancer (NSCLC) activity than magnolol. Our data showed that CT2-3 could significantly inhibit the proliferation of human NSCLC cells in a dose-dependent manner. In addition, we revealed CT2-3 could induce cell cycle arrest through down-regulating mRNA expression of CDK4, CDK6 and cyclin D1. Moreover, we verified that CT2-3 could cause ROS generation, leading to apoptosis of human NSCLC cells. Further more, we also provided strong evidences that CT2-3 down-regulates the expression of c-Myc and topoisomerases, and contributes to the apoptosis of human NSCLC cells. Taken together, the current study is the first to report a promising new chemotherapeutic drug candidate CT2-3 that can efficiently eliminate human NSCLC cells through triggering cell cycle arrest as well as ROS-mediated and c-Myc/topoisomerases-mediated apoptosis.

Design, synthesis and evaluation of a baicalin and berberine hybrid compound as therapeutic agent for ulcerative colitis.

Structural modification of active natural compoundswhichwereoriginated fromTraditional Chinese Medicine (TCM) have showedgreat advantagesin thedevelopmentof new drugs. In TCM, "Huangqin-Huanglian" is a classic "medicine couple"thathas been used to treat intestinal diseases for thousands ofyears, while baicalinand berberine are the major active compoundsof Huangqin and Huanglianrespectively. Based onthis"medicine couple",wedesignedand synthesizeda newbaicalin and berberine hybrid compound (BBH).Its molecular structure wasconfirmedby spectroscopy.The antibacterial activity of BBH was detected in vitro.Results indicatedthat the new hybrid compound exhibited the best antibacterial activity forproteobacteria as compared with its original synthetic materials (baicalin andberberine). In vivo, the effect of BBHon ulcerative colitiswas alsoinvestigated.BBH treatment significantly ameliorated the disease symptoms andpreventedthe colon damage of ulcerative colitis. Furthermore, BBH showed asignificant anti-inflammatory effect through regulating activities of SOD, MPOandexpressions of pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6) in colontissue. Data also suggested that BBH was more superior than baicalin and berberine inameliorating colonic damage. This indicated that the new hybrid compound BBHshowed enhanced efficacy in treating ulcerative colitis.

A novel metformin derivative showed improvement of lipid metabolism in obese rats with type 2 diabetes.

In this study, we investigated the lipid metabolism regulatory activity of a novel metformin derivative (MD568) and its potential mechanism of action in obese rats with type 2 diabetes mellitus (T2 DM). Previous gene chip analysis of 3T3-L1 cells have shown that MD568 regulates the transcription of genes involved in the peroxisome proliferator-activated receptor (PPAR) signalling pathway, fatty acid metabolism, and glycerolipid metabolism. In this study, obese T2 DM rats were treated with MD568 (200 mg/kg) for 8 weeks. Results showed that MD568 significantly reduced the body weight gain, plasma glucose, insulin, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels. MD568 treatment also improved the insulin resistance of obese T2 DM model rats. In particular, in white adipose tissue, MD568 inhibited the excessive volume increment of adipose cells by down-regulating the protein levels of CCAAT/enhancer-binding protein-α (C/EBP-α) and PPAR-γ, as well as the transcription of their target lipid metabolism-related genes. In the liver, MD568 inhibited hepatic fatty lesions and interfered with hepatic gluconeogenesis by regulating the expression of lipid metabolism-related genes and glycogen-related kinases. In conclusion, our results suggest that the newly synthesized MD568 affects the maintenance of lipid homeostasis in obese type 2 diabetic rats.

Development of a fluorescent DNA nanomachine for ultrasensitive detection of Salmonella enteritidis without labeling and enzymes.

A capture probe complex containing a specific Salmonella enteritidis (S. enteritidis) aptamer and partly hybridized signal trigger sequence was designed with the ability to directly detect viable S. enteritidis. In the presence of the target S. enteritidis, single-stranded trigger sequences were liberated and in turn reacted with hairpins I, II, and III to initiate the triple strand migration reaction; this in turn produced numerous hairpin I·II·III complexes with scaffolds of copper nanoparticles (CuNPs) and replaced the trigger sequence which initiated the next cycle of triple migration reaction. Cyclically, the reuse of the trigger sequences and the successive, cascading production of scaffolds of CuNPs achieved the synthesis of highly fluorescent CuNPs, thus providing significantly enhanced fluorescent signals to achieve ultrasensitive detection of live S. enteritidis as low as 25 CFU/mL with a linear range of detection from 50 to 104 CFU/mL with an emission wavelength at 590 nm. By integrating the triple cascade strand migration amplification with recyclable trigger sequences, aptamer-based target recognition, and self-protection mediated by CuNPs hairpin scaffolds, this is the first report on a non-labeled, non-enzymatic, modification-free, and DNA extraction-free ultrasensitive fluorescent biosensor for the direct detection of live Salmonella, which is distinguished from dead Salmonella. It also provides a new strategy to detect viable bacteria by applying the CuNPs, thus extending the application of metal nanoparticles. Graphical abstract.

A liver-chip-based alcoholic liver disease model featuring multi-non-parenchymal cells.

Non-parenchymal cells play a key role in the occurrence and development of alcoholic liver disease. However, this cellular behaviour has not been fully characterized, and it is inconvenient to observe in traditional in vitro alcoholic liver disease (ALD) models and animal models. Herein we developed a demountable liver-on-chip device for investigation of pathophysiological process of individual non-parenchymal cells in alcohol induced ALD. This liver-device comprised of HepG2, LX-2, EAhy926 and U937 cells, which were ordered in a physiological distribution under perfuse. This device allows improved HepG2 cells activities and maintained high liver functions which including albumin synthesis and urea secretion. This novel liver-device is able to recreate the damage process of hepatic non-parenchymal cell lines induced by alcohol, and to understand the intercellular communication between different types of hepatic cells during ALD by measuring multiple biomarkers of each types of hepatic non-parenchymal cell lines, including Ve-cadherin, eNOS, VEGF and α-SMA. The proposed liver-device is able to further studies of pathological analysis and drug- and toxicity-screening.

Rapid and simple detection of ascorbic acid and alkaline phosphatase via controlled generation of silver nanoparticles and selective recognition.

Ascorbic acid (AA) and alkaline phosphatase (ALP) serve as an important coenzyme and enzyme in multiple biological metabolism reactions, respectively, and abnormal levels of these substrates have been associated with several diseases. Herein, a new and simple fluorescence strategy has been developed for AA and ALP sensing by exploiting CdTe quantum dots (QDs) as an effective signal indicator. This method is mainly based on the selective fluorescence-quenching reaction between Ag+ and CdTe QDs, as opposed to silver nanoparticles (Ag NPs); Ag+ can be reduced to Ag NPs by AA. Furthermore, by taking advantage of AA as a mediator, this strategy is further exploited for ALP assay given that ALP can cause the hydrolysis of l-ascorbic acid-2-phosphate (AAP), which yields AA. Under optimal conditions, controlled generation of Ag NPs and the selective recognition-based sensing system exhibit high sensitivity toward AA and ALP with limits of detection (LODs) of 3 µM and 0.25 U L-1 and linear ranges of detection from 0 to 800 µM and 1 to 1000 U L-1, respectively. Moreover, the sensor was successfully used for assaying AA in fruit juice and ALP in human serum. The results demonstrate that the proposed fluorescence strategy has significant advantages, such as its simplicity, cost-effectiveness, and rapid runtime, and the operational convenience of this label-free method further demonstrates its potential for constructing effective sensors with biochemical and clinical applications.

Artemether Attenuates the Progression of Non-small Cell Lung Cancer by Inducing Apoptosis, Cell Cycle Arrest and Promoting Cellular Senescence.

Lung cancer is the most common cause of cancer death, approximately 85% of which are non-small cell lung cancer (NSCLC). Here we found that artemether (ART), a natural derivative of artemisinin, significantly inhibits the proliferation of NSCLC cells in a dose- and time-dependent manner. We also demonstrated that high concentration of ART induces apoptosis in NSCLC cells through down-regulating the level of anti-apoptotic protein B-cell lymphoma-2 (Bcl-2), cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein 2 (cIAP2). While low concentration of ART inhibits the mRNA level of cell cycle related genes including cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 6 (CDK6), cyclin A2, cyclin B1 and cyclin D1, leading to cell cycle arrest in NSCLC cells. Moreover, we confirmed that low concentration of ART induces DNA double-stranded breaks (DSBs), as well as promoting cellular senescence in NSCLC cells by up-regulating the mRNA and protein level of p16. Taken together, ART represents a promising new anti-NSCLC drug candidate that could attenuate progression of NSCLC cells in a p53-independent manner through inducing apoptosis, cell cycle arrest and promoting cellular senescence.