Biologically active franchetine-type diterpenoid alkaloids: Isolation, synthesis, anti-inflammatory, agalgesic activities, and molecular docking.

In this study, four franchetine-type diterpenoid alkaloids (1-4) were isolated from Aconitum sinoaxillare, and fourteen diverse franchetine analogs (5-18) were synthesized. Compounds 1, 2, 7 and 16 exhibited stronger inhibitory effects on NO production when compared to celecoxib. Among them, compound 1 had the best inhibitory effect on iNOS and COX-2 inflammatory proteins. The in vitro studies displayed that the anti-inflammatory effect of the most active compound 1 was ascribed to the inhibition of the TLR4-MyD88/NF-κB/MAPKs signalling pathway. Consequently, this led to a inhibition in the expression of inflammatory factors or mediators including NO, ROS, TNF-α, IL-6, IL-1ß, iNOS, and COX-2. Additionally, compound 1 had low toxicity (LD50 > 20 mg/kg) in mice, and it had notable analgesic effects on acetic acid-induced visceral pain (ED50 = 2.15 ± 0.07 mg/kg). Moreover, compound 1 exhibited a distinct reduction in the NaV1.7 and NaV1.8 channel currents during both resting and half-inactivated states at 50 µM. The present study enriches the pharmacological activities of franchetine derivatives and provides valuable insights for the development of novel anti-inflammatory and analgesic agents.

Diterpenoid alkaloids from Delphinium sherriffii.

Three new diterpenoid alkaloids (1, 2, 3) and seventeen known (4-20) compounds were isolated from the whole plant of Delphinium sherriffii Munz (Ranunculaceae). Their structures were elucidated by various spectroscopic analyses, including IR, HR-ESI-MS, 1D and 2D NMR spectra. All compounds were evaluated for the inhibitory activity of Sf9 cells and compound 5 exhibited the strongest cytotoxicity (IC50 = 8.97 µM) against Sf9 cell line.

Diterpenoid alkaloids from Delphinium trichophorum.

The ethanol extract of the whole plant of Delphinium trichophorum Franch was subjected to a phytochemical study, leading to the isolation of ten unprecedented diterpenoid alkaloids, including nine delnudine-type C20-diterpenoid alkaloids named trichophodines A-I and one kusnezoline-type C20-diterpenoid alkaloid named trichophozine A. Additionally, seven known compounds were also identified. Their structures were elucidated on the basis of extensive spectroscopic analysis, including HSQC, HMBC, 1H-1H COSY, NOESY and X-ray crystallographic analysis. Most isolated compounds were screened for inhibitory activities against LPS-induced NO production in RAW 264.7 macrophage cells and acetylcholinesterase inhibitory effects. Guan-fu base V exhibited potent inhibitory activity against acetylcholinesterase, demonstrating an inhibitory rate of 53.81% at a concentration of 40 µM.

Diagnostic efficiency of conventional ultrasound, shear wave elastography, and superb microvascular imaging in evaluating ulnar neuropathy at the elbow.

INTRODUCTION/AIMS: The current diagnosis of ulnar neuropathy at the elbow (UNE) relies mainly on the clinical presentation and nerve electrodiagnostic (EDX) testing, which can be uncomfortable and yield false negatives. The aim of this study was to investigate the diagnostic value of conventional ultrasound, shear wave elastography (SWE), and superb microvascular imaging (SMI) in diagnosing UNE. METHODS: We enrolled 40 patients (48 elbows) with UNE and 48 healthy volunteers (48 elbows). The patients were categorized as having mild, moderate or severe UNE based on the findings of EDX testing. The cross-sectional area (CSA) was measured using conventional ultrasound. Ulnar nerve (UN) shear wave velocity (SWV) and SMI were performed in a longitudinal plane. RESULTS: Based on the EDX findings, UNE severity was graded as mild in 4, moderate in 10, and severe in 34. The patient group showed increased ulnar nerve CSA and stiffness at the site of maximal enlargement (CSA mean at the site of max enlargement [CSAmax] and SWV mean at the site of max enlargement [SWVmax]), ulnar nerve CSA ratio, and stiffness ratio (elbow-to-upper arm), compared with the control group (p < .001). Furthermore, the severe UNE group showed higher ulnar nerve CSAmax and SWVmax compared with the mild and moderate UNE groups (p < .001). The cutoff values for diagnosis of UNE were 9.5 mm2 for CSAmax, 3.06 m/s for SWVmax, 2.00 for CSA ratio, 1.36 for stiffness ratio, and grade 1 for SMI. DISCUSSION: Our findings suggest that SWE and SMI are valuable diagnostic tools for the diagnosis and assessment of severity of UNE.

Antitumor effects of Cypaliuruside F from Cyclocarya paliurus on HepG2 cells.

An undescribed dammarane triterpenoid saponin Cypaliuruside F was isolated from the leaves of Cyclocarya paliurus in our preliminary study. The MTT assay, flow cytometry, cell scratch, and DAPI staining were used to detect the antitumor effects of Cypaliuruside F on HepG2 cells. Subsequently, network pharmacology and molecular docking analysis were used to analyse the key targets of Cypaliuruside F against HCC. In addition, a Western blot was performed to determine the effects of Cypaliuruside F on the expression of key proteins in HepG2 cells. The experimental results indicated that the damarane triterpenoid saponin Cypaliuruside F from Cyclocarya paliurus inhibits the proliferation of HepG2 cells by inducing apoptosis and cell cycle arrest. These changes may promote the apoptosis of HepG2 cells by inhibiting the expression of mTOR, STAT3, and Bcl-2 while activating Bax.

Norditerpenoid alkaloids from Aconitum refractum var. circinatum as autophagy inducers.

A total of twenty-two diterpenoid alkaloids, including ten unprecedented ones, namely refractines C-L, were isolated from the roots of Aconitum refractum (Finet et Gagnep.) Hand.-Mazz. Refractine C was the first example of a natural diterpenoid alkaloid wherein C-19 is linked to N position by an oxaziridine ring. Refractine L was a rare glycosidic diterpenoid alkaloid with fructofuranoside. Most of the isolated compounds obtained from a previous study were screened for their anti-inflammatory and myocardial protective activities. The autophagy-inducing effects of some of these compounds on RAW 264.7 cells were evaluated by assessing the expression of microtubule-associated protein 1 light chain 3 (LC3-II/LC3-I). Results revealed that some compounds exerted varying levels of inhibitory effects on the proliferative activity of RAW 264.7 cells.

Synthesis and biological evaluation of lycoctonine derivatives with cardiotonic and calcium channels inhibitory activities.

In our previous study, a screening of a variety of lycotonine-type diterpenoid alkaloids were screened for cardiotonic activity revealed that lycoctonine had moderate cardiac effect. In this study, a series of structurally diverse of lycoctonine were synthesized by modifying on B-ring, D-ring, E-ring, F-ring, N-atom or salt formation on lycoctonine skeleton. We evaluated the cardiotonic activity of the derivatives by isolated frog heart, aiming to identify some compounds with significantly enhanced cardiac effects, among which compound 27 with a N-isobutyl group emerged as the most promising cardiotonic candidate. Furthermore, the cardiotonic mechanism of compound 27 was preliminarily investigated. The result suggested that the cardiotonic effect of compound 27 is related to calcium channels. Patch clamp technique confirmed that the compound 27 had inhibitory effects on CaV1.2 and CaV3.2, with inhibition rates of 78.52 % ± 2.26 % and 79.05 % ± 1.59 % at the concentration of 50 µM, respectively. Subsequently, the protective effect of 27 on H9c2 cells injury induced by cobalt chloride was tested. In addition, compound 27 can alleviate CoCl2-induced myocardial injury by alleviating calcium overload. These findings suggest that compound 27 was a new structural derived from lycoctonine, which may serve as a new lead compound for the treatment of heart failure.

Diterpenoid Alkaloids from Delphinium liangshanense.

Two new C19-diterpenoid alkaloids of the lycoctonine-type (liangshanine A and liangshanine B) and nineteen known compounds (3-21) were isolated from the whole plant of Delphinium liangshanense W. T. Wang, and all the compounds were identified by different spectroscopic analyses, such as IR, HR-ESI-MS and NMR. All the compounds were isolated from this plant for the first time and tested for the anti-proliferation effects on MH7 A and SF9 cells to figure their anti-rheumatoid arthritis and anti-insect activity, but none of them showed remarkable activity.

In vitro and in†vivo biological evaluation of Lappaconitine derivatives as potential anti-inflammatory agents.

Natural products and their derivatives are a precious treasure in the pursuit of potent anti-inflammatory drugs. In this work, we measured the toxicity of 78 LA derivatives at 20 µM using MTT, then we evaluated the NO release of compounds without obvious toxicity in LPS-induced RAW.264.7 by Griess reagent, we identified three compounds, namely compounds 6, 19, 70, which exhibited promising anti-inflammatory potential. These compounds exhibited IC50 values of 10.34±2.05 µM, 18.18±4.80 µM and 15.66±0.88 µM. In addition, through ELISA kits, compounds 6, 19, 70 significantly reduce the production of inflammatory factors (TNF-α, IL-6, IL-1ß). Real-time PCR and western blot analysis showed that compounds 6, 19, 70 inhibited the mRNA and protein expression of iNOS and COX-2. Notably, compound 6 exhibited the most potent inhibitory activity. In vitro, it inhibits LPS-induced phosphorylation of NF-κB p65, IκBα, ERK1/2, JNK, and p38 MAPKs in RAW264.7 cells. In vivo, compound 6 potently inhibits the secretion of inflammatory mediators and neutrophil activation in ALI mice. Our findings suggest that compound 6 may be a potential anti-inflammatory drug.

Value of Intrauterine Autologous Platelet-Rich Plasma Therapy on Endometrial Receptivity: A Literature Review.

Endometrial receptivity is an important factor that influences embryo implantation. Thus, it is important to identify an applicable approach to improve endometrial receptivity in women undergoing assisted reproductive technology. Recently, growing evidence has indicated that intrauterine platelet-rich plasma (PRP) infusion is an effective method to obtain a satisfactory reproductive outcome by increasing endometrial thickness and improving endometrial receptivity. Therefore, the present review aims to outline the possible mechanisms of PRP on endometrial receptivity and summarize the present literature on the effects of PRP therapy in improving endometrial receptivity.

Design, Synthesis, and Biological Activity of Donepezil: Aromatic Amine Hybrids as Anti-Alzheimerss Drugs.

In this study, benzylpiperidine, the active group of donepezil (DNP), was connected with the neurotransmitter phenylethylamine by square amide, in which the fat chain of phenylethylamine was reduced and the benzene rings were substituted. A series of multifunctional hybrid compounds, including DNP-aniline hybrids (1-8), DNP-benzylamine hybrids (9-14), and DNP-phenylethylamine hybrids (15-21) were obtained and their cholinesterase inhibitory activity and neuroprotection of the SH-SY5Y cell line were determined. Results showed that compound 3 exhibited excellent acetylcholinesterase inhibitory activity with an IC50 value of 4.4 µM, higher than that of positive control DNP and significant neuroprotective effects against H2O2-induced oxidative damage in SH-SY5Y cells with 80.11% viability rate at 12.5 µM, much higher than that of the model group (viability rate = 53.1%). The mechanism of action of compound 3 was elucidated by molecular docking, reactive oxygen species (ROS), and immunofluorescence analysis. The results suggest that compound 3 could be further explored as a lead compound for the treatment of Alzheimer's disease. In addition, molecular docking research indicated that the square amide group formed strong interactions with the target protein. Based on the above analysis, we believe that square amide could be an interesting construction unit in anti-AD agents.

Diagnostic performance of endorectal ultrasound combined with shear wave elastography for rectal tumors staging.

OBJECTIVE: This study aims to analyze the performance of endorectal ultrasound (ERUS) combined with shear wave elastography (SWE) for rectal tumor staging. METHODS: Forty patients with rectal tumors who had surgery were enrolled. They underwent ERUS and SWE examinations before surgery. Pathological results were used as the gold standard for tumor staging. The stiffness values of the rectal tumor, peritumoral fat, distal normal intestinal wall, and distal perirectal fat were analyzed. The diagnostic accuracy of ERUS stage, tumor SWE stage, ERUS combined with tumor SWE stage, and ERUS combined with peritumoral fat SWE stage were compared and evaluated by receiver operating characteristic (ROC) curve to select the best staging index. RESULTS: From T1 to T3 stage, the maximum elasticity (Emax) of the rectal tumor increased gradually (p < 0.05). The cut-off values of adenoma/T1 and T2, T2 and T3 tumors were 36.75 and 85.15kPa, respectively. The diagnostic coincidence rate of tumor SWE stage was higher than that of ERUS stage. Overall diagnostic accuracy of ERUS combined with peritumoral fat SWE Emax restaging was significantly higher than that of ERUS. CONCLUSIONS: ERUS combined with peritumoral fat SWE Emax for tumor restaging can effectively distinguish between stage T2 and T3 rectal tumors, which provides an effective imaging basis for clinical decisions.

C19-diterpenoid alkaloids from Aconitum refractum var. circinatum.

Two unprecedented aconitine-type C19-diterpenoid alkaloids, refractines A-B (1-2), along with 12 known compounds (3-14) were isolated from the roots of Aconitum refractum (Finet et Gagnep.) Hand. -Mazz. Their structures were elucidated based on extensive spectroscopic analyses, including 1D and 2D NMR, IR, and HR-ESI-MS data. All compounds were tested for inhibitory activities against NO production in LPS induced RAW 264.7 macrophages, compounds 10 and 14 had slight inhibited NO production with rate of 29.4% and 22.1% at the concentration of 30 µM, respectively.

Adenophorone, An Unprecedented Sesquiterpene from Eupatorium adenophorum: Structural Elucidation, Bioinspired Total Synthesis and Neuroprotective Activity Evaluation.

(-)-Adenophorone (1), a caged polycyclic sesquiterpene featuring an unprecedented tricyclo[4.3.1.05,9 ]decane skeleton, was isolated from Eupatorium adenopharum Spreng. The structure of 1 was unambiguously established by a combination of spectroscopic analysis, X-ray crystallography, and bioinspired total synthesis. Key synthetic features include a sequential Reformatsky/oxidation/regio- and stereoselective hydrogenation, and subsequent merged MBH-Tsuji-Trost cyclization. The concise synthetic sequence efficiently constructs the bicyclic skeleton of cadinene sesquiterpene (+)-euptox A (2) in 8 steps from commercially available monoterpene (-)-carvone (6), with outstanding performance on diastereocontrol. The bioinspired synthesis of 1 was achieved from 2, a plausible biogenetic precursor, via transannular Michael addition. This work provides experimental evidence of our proposed biosynthetic hypothesis of 1. Additionally, compound 1 showed potent neuroprotective activity in H2 O2 -treated SH-SY5Y and PC12 cells.

Design, synthesis and anti-inflammatory activity of diterpenoid alkaloids and non-steroidal anti-inflammatory drug hybrids based on molecular hybridization strategy.

Molecular hybridization is a widely employed approach in pharmaceutical chemistry for modifying drugs with the aim of improving pharmacological efficacy and reducing adverse effects. A prime example of this is the case of benorylate, which was created by combining aspirin and acetaminophen, two non-steroidal anti-inflammatory drugs (NSAIDs). Diterpenoid alkaloids, which exhibit potent anti-inflammatory activity, have limitations in their application due to their toxicity and side effects. Thus, we aimed to design new anti-inflammatory lead compounds through the molecular hybridization of the anti-inflammatory active skeletons (lappaconitine, aconorine, and bulleyaconitine A) of diterpenoid alkaloids with classical NSAIDs. In this study, we synthesized 25 diterpenoid alkaloid derivatives with NSAIDs, organized into four series. Among these derivatives, lappaconitine derivative 1e demonstrated the strongest inhibition of lipopolysaccharide (LPS)-induced NO production in RAW 264.7 cells with minimal cytotoxicity. Additionally, 1e effectively suppressed the inflammatory response induced by carrageenan in vivo, with a swelling rate of only 1%. This anti-inflammatory potency was found to be significantly superior to that of naproxen. The molecular docking analysis revealed that the binding affinity of 1e was scored as -10.3 kcal/mol, suggesting that it forms a stable complex with cyclooxygenase-2 (COX-2). Therefore, compound 1e holds potential as a lead anti-inflammatory compound that could be further developed.

Diterpenoid alkaloids from Delphinium trichophorum.

Three new hetisine type C20-diterpenoid alkaloids, named as trichophorines A-C (1-3), were isolated from Delphinium trichophorum, together with nine known alkaloids (4-12). Their structures were elucidated on the basis of spectroscopic data (1D, 2D NMR, single-crystal X-ray, and HR-ESI-MS). All compounds were evaluated for the inhibitory activities against LPS induced NO production in RAW 264.7 macrophage cells, and none of them showed considerable inhibitory activity.

Synthesis and biological evaluation of esculetin derivatives as potential anti-HBV agents.

Previous in vivo and in vitro studies revealed that esculetin (Fig. 1) has anti-hepatitis B virus (anti-HBV) activity as well as a protective effect on liver damage caused by duck hepatitis B virus. We designed and synthesized a series of esculetin derivatives, introduced side chains containing various amino groups into site 7 of the parent structure, and synthesized C-4 and C-8 substituted derivatives with the goal of investigating their anti-HBV activities. In vitro anti-HBV activity was performed against HepG2.2.15 cells by using Enzyme-Linked Immunosorbent Assay(ELISA) kit and cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay with lamivudine as the positive control. The results demonstrated that several compounds showed moderate anti-HBV activity, while the introduction of morpholine groups could significantly inhibit the expression of hepatitis B e antigen (HBeAg) and the introduction of the 2-methylimidazole group could significantly inhibit the expression of Hepatitis B surface antigen (HBsAg). Among all tested compounds, compound 4a demonstrated the best anti-HBeAg activity (IC50 = 15.8 ± 4.2 µM), while compound 6d demonstrated the best anti-HBsAg activity (IC50 = 21.4 ± 2.8 µM). Compounds 6b and 6c showed moderate anti-HBV activity and HBsAg inhibition. Compounds 4b showed moderate anti-HBV activity and an inhibitory effect on HBeAg. In addition, compounds 4a, 4c, 4d, 6b, 6c and 6d showed improved metabolic stability. This study provides useful guidance for the discovery of anti-HBV drugs, which merits further investigation.

Four New C19 -Diterpenoid Alkaloids from Aconitum nagarum Stapf.

Four new aconitine-type C19 -diterpenoid alkaloids, were isolated from the roots of Aconitum nagarum Stapf which were named as nagarutines A-D (1-4), together with eleven known compounds (5-15). The structures of the compounds were identified by IR, HR-ESI-MS, 1D and 2D NMR spectra. All compounds were tested for the inhibitory effect on LPS induced NO production in RAW 264.7 macrophages, compound 7 showed moderate anti-inflammatory activity effect and Inhibition rate is about 44.50%.

Compounds isolated from the pericarp of Zanthoxylum bungeanum and inhibitory activity against LPS-induced NO production in RAW264.7.

Seventeen compounds were isolated and identified from the ethyl acetate part of Zanthoxylum bungeanum Maxim., including one new compound 18-acetyloxyneocryptotanshinone (1) and 16 known compounds (2-17). Their structures were elucidated by extensive spectroscopy. The absolute configuration of 1 was confirmed by electronic circular dichroism (ECD). All compounds were evaluated for the inhibition of LPS-induced nitric oxide (NO) production in RAW264.7 macrophages, of which 1 and 10 exhibited the most significant inhibitory effect, with IC50 of 17.29 and 10.27 µM, respectively.

Photochemical Selective Oxidation of Benzyl Alcohols to Aldehydes or Ketones.

Using Eosin Y as a metal-free photocatalyst and O2 as an oxidant, the present study reports a new photochemical protocol that enables efficient aerobic oxidation of various benzyl alcohols to the corresponding aldehydes or ketones in excellent yields under mild reaction conditions. The catalyst system presents good functional-group tolerance and exquisite chemoselectivity, which also can easily be scaled-up to gram scale. Moreover, the methodological applications in practical synthesis of several organic molecules and the primary reaction mechanism were also discussed.