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Background Objective Methods Results Conclusions Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited neurodegenerative disorder for which there is currently no cure, nor effective treatment strategy.Our aim was to investigate the safety and efficacy of high‐dose ganglioside GM1 (ganglioside‐monosialic acid) pulse treatment in patients with SCA3.Patients were randomly allocated to receive either high‐dose GM1 (400 mg on the first day followed by 200 mg/day), low‐dose GM1 (40 mg/day), or placebo (normal saline) for 4 weeks. The primary outcome, assessed by measuring the change in the Scale for the Assessment and Rating of Ataxia (SARA) scores from baseline to 12 weeks post‐treatment, is central to evaluating treatment efficacy. Secondary outcomes included changes in the International Cooperative Ataxia Rating Scale (ICARS) score, Barthel Index of Activities of Daily Living (ADL), and plasma and cerebrospinal fluid (CSF) GABA levels. Safety was assessed in all treated patients.A total of 48 patients with SCA3 were enrolled in this study. After 12 weeks, data from 43 patients were included in the efficacy analysis (intention‐to‐treat analysis). The least‐squares mean change in the SARA score from baseline to 12 weeks post‐treatment was −3.80 (standard error [SE], 0.39; 95% confidence interval [CI], −4.58 to −3.02) in the high‐dose GM1 group, 0.34 (SE, 0.40; 95% CI, −0.46 to 1.13) in the low‐dose GM1 group, and 0.73 (SE, 0.40; 95% CI, −0.07 to 1.52) in the placebo group, respectively. Secondary outcomes showed improvements in the ICARS score, Barthel Index of ADL, and plasma and CSF GABA levels in the high‐dose GM1 group compared to the low‐dose GM1 and placebo groups. All treatments were well‐tolerated and safe.High‐dose GM1 treatment significantly ameliorated ataxic symptoms in patients with SCA3. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

C25H34O7, monoclinic, P21 (no. 4), a = 9.24730(10) Å, b = 9.9061(2) Å, c = 12.5907(2) Å, β = 101.264(2)°, V = 1131.15(3) Å3, Z = 2, Rgt(F) = 0.0380, wRref(F2) = 0.1025, T = 173 K.

Three new abietane and two new tigliane diterpenoids were isolated from the roots Euphorbia fischeriana. Their structures were elucidated by spectroscopic methods and quantum chemical calculation. Compounds 4 and 5 exhibited the inhibitory activities against human cancer cells HeLa and HepG2, with IC50 ranging from 3.54 to 11.45 µM. [ABSTRACT FROM AUTHOR]

Chemical investigation of the aerial parts of Mikania micrantha led to the isolation of eight sesquiterpenoids and ten diterpenoids, including five cadinane sesquiterpenoids (1−5), three bisabolene sesquiterpenoids (6 − 8), nine ent-kaurane diterpenoids (9–17), and an abietane diterpenoid (18). Among them, 1 − 3 are new and feature a rare lactone or furan ring derived from C-6 isopropyl group side chain. Compound 18 was isolated from genus Mikania for the first time, and was also the first example of abietane-type diterpenoids from this plant. Their structures were elucidated on the basis of extensive spectroscopic analyses (1D and 2D NMR, HRESIMS, and ECD). All compounds were examined for their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophage cells, and compound 18 exhibited pronounced inhibition on NO production (IC50 = 11.04 µM), being comparable to the positive control, quercetin (IC50 = 11.15 µM). [ABSTRACT FROM AUTHOR]

C25H34O7, monoclinic, P21 (no. 4), a = 9.24730(10) Å, b = 9.9061(2) Å, c = 12.5907(2) Å, β = 101.264(2)°, V = 1131.15(3) Å3, Z = 2, Rgt(F) = 0.0380, wRref(F2) = 0.1025, T = 173 K. [ABSTRACT FROM AUTHOR]

Marsilea quadrifolia is an edible aquatic medicinal plant used as a traditional health food in Asia. Four new polyphenols including kaempferol 3-O-(2″-O-E-caffeoyl)-β-d-glucopyranoside (1), kaempferol 3-O-(3″-O-E-caffeoyl)-α-l-arabinopyranoside (3), 4-methy-3′-hydroxypsilotinin (4) and (±)-(E)-4b-methoxy-3b,5b-dihydroxyscirpusin A (18) together with 14 known ones (2, 5–17) were isolated from the ethanol extract of M. quadrifolia. Structures of the new compounds were elucidated by extensive spectroscopic analyses. In DPPH and oxygen radical absorbance capacity antioxidant assays, some compounds showed stronger antioxidant activities and quercetin (9) was the most potent antioxidant in both assays. In a restraint-induced oxidative stress model in mice, quercetin significantly attenuated the increase in plasma ALT and AST levels as well as liver MDA content of restrained mice. Liver SOD activity was also significantly increased by quercetin, indicating a significant in vivo antioxidant activity. As a rich source of polyphenols with strong antioxidant activities, M. quadrifolia may be developed to a product for relieving oxidative stress. [ABSTRACT FROM AUTHOR]

Twelve new bufadienolides ( 1 – 12 ), along with fourteen known analogues ( 13 – 26 ) were isolated from the skins of Bufo bufo gargarizans Cantor. Their chemical structures were elucidated on the basis of NMR, HRESIMS and X-ray diffraction analysis. Compound 1 was an unusual bufadienolide with 3,19-epoxy moiety and A/B trans ring junction. Compounds 2 – 4 were rare bufadienolides possessing 10-H or 10-carboxyl units. All the isolated compounds were tested for their cytotoxic effects on HepG2, A549 and HeLa cells. Six new compounds ( 2 , 3 , 5 , 6 , 10 and 12 ) displayed significant anti-proliferative activities with IC 50 values ranging from 0.049 to 1.856 μM. Arenobufagin ( 24 ) exhibited the most potent cytotoxic activity with IC 50 value 0.011 μM. In addition, the present data provided more insight into the structure–activity relationships of bufadienolides. [ABSTRACT FROM AUTHOR]

To investigate the chemical constituents of medicinal plant Uncaria hirsuta, three new monoterpenoid alkaloids, named hirsutanines A–C (1–3), were isolated. Their structures with absolute configurations were elucidated by means of NMR, X-ray diffraction and CD analysis. Compound 3 was the first dimeric monoterpenoid alkaloid obtained from genus Uncaria. [ABSTRACT FROM AUTHOR]

Background: Natural products present in low quantity in herb medicines constitute an important source of chemical diversity. However, the isolation of sufficient amounts of these low abundant constituents for structural modification has been a challenge for several decades and subsequently halts research on the utilization of this important source of chemical entities for drug discovery and development. And, pro-angiogenic therapies are being explored as options to treat cardio-cerebral vascular diseases and wound healing recently. The present study investigates the pro-angiogenic potential of tanshinone derivatives produced by one-pot synthesis using zebrafish model. Methodology/Principal Findings: In order to address the difficulty of chemical modification of low abundant constituents in herb medicines, a novel one-pot combinatorial modification was used to diversify a partially purified tanshinone mixture from Salvia miltiorrhiza. This led to the isolation of ten new imidazole-tanshinones (Compounds 1–10) and one oxazole-tanshinone (Compound 11), the structures of which were characterized by spectroscopic methods in combination with single-crystal X-ray crystallographic analysis. The angiogenesis activities of the new tanshinone derivatives were determined in an experimental model of chemical-induced blood vessels damage in zebrafish. Of all the tested new derivatives, compound 10 exhibited the most potent vascular protective and restorative activity with an EC50 value of 0.026 µM. Moreover, the mechanism underlying the pro-angiogenesis effect of 10 probably involved the VEGF/FGF-Src-MAPK and PI3K-P38 signalling pathways by gene expression analysis and a blocking assay with pathways-specific kinase inhibitors. Conclusions/Significance: Taken together, our study demonstrated the more distinctive pro-angiogenic properties of 10 than other tanshinones and revealed 10 has potential for development as a pro-angiogenic agent for diseases associated with insufficient angiogenesis. Our results highlighted the great potential of adopting a newly modified one-pot approach to enhance the chemical diversity and biological activities of constituents from natural products regardless of their abundances. [ABSTRACT FROM AUTHOR]

Two new bufadienolide glycosides (1 and 2) with an A/B trans ring fusion together with nine known compounds (3–11) were isolated from the rhizomes of Helleborus thibetanus. The structures of new compounds were elucidated by extensive spectroscopic analyses in combination with single-crystal X-ray diffraction. The bufadienolides 1 and 3–6 exhibited potent cytotoxic activities against the prostate cancer cells. [ABSTRACT FROM AUTHOR]

Bufalin possesses a strong anti-cancer effect, but the cardiac toxicity targeting the Na+, K+-ATPase limits its application. Here, two bufalin derivatives, bufadienolactam (1) and secobufalinamide (2), were synthesised by treating bufalin with ammonium acetate in dimethylformamide solution. Their structures were elucidated by extensive spectroscopic methods. The structure of compound 2 was further confirmed by single-crystal X-ray diffraction analysis. Compounds 1 and 2 expressed strong inhibitory activities against androgen-dependent prostate cancer cells (IC50 values about 10 μM), but only weak inhibition on Na+, K+-ATPase (Ki about 70 μM), indicating that they might be potential anti-prostate cancer agents without severe cardiac toxicity. [ABSTRACT FROM AUTHOR]

Two new vinblastine-type N-oxide alkaloids, 17-desacetoxyvinblastine -oxide (1) and 20′-deoxyvinblastine -oxide (2), were isolated from the leaves of Catharanthus roseus. The structures of 1 and 2 were established by the analysis of their nuclear magnetic resonance and HR-ESI-MS spectroscopic data. All alkaloids were evaluated for their cytotoxic activities against the human hepatocellular carcinoma (HepG2) cell line, human colorectal carcinoma (Lovo) cell line and human breast carcinoma (MCF-7) cell line by the MTT method in vitro, respectively. The results showed that cytotoxic activities of alkaloids 1 and 2 exhibited moderate inhibitory activity on the proliferation of three cancer cells. [ABSTRACT FROM AUTHOR]

Abstract: A new diketosteroid, (E)-stigmasta-24(28)-en-3,6-dione (1), along with three known steroids (2–4) was isolated from marine alga Tydemania expeditionis collected in China Sea. Their structures were elucidated by extensive spectroscopic methods. Comparison of the chemical constituents revealed significant diversity among different locations. The biological activities of 1, 3 and 4 were evaluated on the prostate cancer cell lines and androgen receptor. Compound 1 exhibited moderate inhibitory activities against the prostate cancer cells DU145, PC3 and LNCaP with IC50 values of 31.27±1.50, 40.59±3.10 and 19.80±3.84μM, respectively. Compound 3 showed more potent activities with IC50 values of 12.38±2.47, 2.14±0.33 and 1.38±0.07μM, respectively. However, compound 4 showed only weak inhibitory activities on LNCaP cells and was inactive on DU145 and PC3 cells. A competitive binding assay showed that compound 1 exhibited significant affinity to the androgen receptor with an IC50 value of 7.19±0.45μM, while 3 and 4 were inactive. The fact that the inhibitory properties of 1 and 3 against the prostate cancer cells were inconsistent with their affinities to the androgen receptor suggested that there might be other mechanism of action involved in the cytotoxic activity. [Copyright &y& Elsevier]

Toad venom (venenum bufonis, also called Chan'su) has been widely used for centuries in China to treat different diseases, especially for cancer. Bufadienolides are mainly responsible for the anti-cancer effects of toad venom. However, systematic chemical composition and cytotoxicity as well as key pharmacophores of these bufadienolides from toad venom have not yet been defined clearly. To enrich the understanding of the diversity of bufadienolides and to find bufadienolides with better activities from toad venom. This study was carried out to isolate chemical constituents, research their anti-tumor effects and mechanisms by MTT assay, flow cytometry and Western blotting, and develop a CoMFA and CoMSIA quantitative structure-activity relationship (QSAR) model for illustrating the vital relationship between the chemical structures and cytotoxicities. Among 47 natural bufadienolides, most of bufadienolides (21 compounds isolated in this study and 26 compounds isolated previously) could significantly inhibit the proliferation of cancer cells, and compounds 1 , 8 , 12 , 18 and 19 showed the most potent inhibitory activity against four types of human tumor cells. Compound 18 induced G 2 /M cell cycle arrest and apoptosis. Moreover, 3D contour maps generated from CoMFA and CoMSIA identified several pharmacophores of bufadienolides responsible for the anti-tumor activities. Our study might provide reliable information for future structure modification and rational drug design of bufadienolides with anticancer activities in medical chemistry. Unlabelled Image [ABSTRACT FROM AUTHOR]