Effect of electroacupuncture on Nrf2/NLRP3/Caspase-1 pathway mediated-pyroptosis in mice with Parkinson's disease. / ç”µé’ˆå¯¹å¸•é‡‘æ£®ç— å°é¼ Nrf2/NLRP3/Caspase-1通路介导的细胞焦亡的影响.

OBJECTIVES: To observe the effect of electroacupuncture (EA) on nuclear transcription factor E2 related factor 2 (Nrf2)/NOD-like receptor family pyrin domain-containing protein 3 (NLRP3)/cysteine aspartic acid specific protease-1 (Caspase-1) pathway in the substantia nigra (SN) of mice with Parkinson's disease (PD), so as to explore the neuroprotective mechanism of EA. METHODS: Forty C57BL/6 male mice were randomly divided into 4 groups, namely, control, PD model, EA and sham-EA groups, with 10 mice in each group. The PD mouse model was established by gavage of rotenone for 4 weeks. Mice in the EA group were given EA stimulation (1 mA, 2 Hz) at "Fengfu" (GV36), bilateral "Taichong" (LR3) and "Zusanli" (ST36) for 30 min, once daily for 2 consecutive weeks. And mice in the sham-EA group were given acupuncture at the subcutaneous areas of the same acupoints without EA stimulation. The open-field test was used for assessment of mouse behavior. The levels of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) in the serum were detected by enzyme-linked immunosorbent assay . The positive expression of tyrosine hydroxylase (TH) in SN was determined by immunohistochemistry. The mRNA expression levels of Nrf2, NLRP3, Caspase-1, gasdermin D(GSDMD), IL-1ß, IL-18 and the protein expression levels of Nrf2, NLRP3, Caspase-1 and GSDMD in the SN were detected by quantitative real-time PCR and Western blot, separately. RESULTS: After modeling, compared with the control group, the behavioral score was increased (P<0.01), the total exercise time, the total distance and the average speed were decreased (P<0.01), and the positive expression of TH and the mRNA and protein expression levels of Nrf2 in the SN were decreased (P<0.01), while the contents of IL-1ß and IL-18 in serum, the mRNA and protein expression levels of NLRP3, Caspase-1 and GSDMD and the mRNA expression levels of IL-1ß and IL-18 in the SN were up-regulated (P<0.01) in the PD model group. Following EA intervention, the behavioral score was decreased(P<0.01), the total exercise time, total distance and average speed were increased (P<0.01), the positive expression of TH and the mRNA and protein expressions of Nrf2 in SN were up-regulated (P<0.01, P<0.05), while the contents of IL-1ß and IL-18 in serum, the mRNA and protein expression levels of NLRP3, Caspase-1 and GSDMD as well as the mRNA expression levels of IL-1ß and IL-18 in the SN were down-regulated (P<0.01, P<0.05) in the EA group relative to the PD model and sham-EA groups. There were no significant differences in the above indicators between the PD model and sham-EA groups. CONCLUSIONS: EA stimulation of GV36, LR3 and ST36 can improve motor deficits, reduce the loss of dopamine neurons in the SN, and inhibit neuroinflammatory responses in mice with PD, which may be related to its effects in regulating the Nrf2/NLRP3/Caspase-1 pathway mediated pyroptosis.

UPLC-Q-Orbitrap-MS/MS-Guided Isolation of Bioactive Withanolides from the Fruits of Physalis angulata.

Physalis angulata Linn. is an exotic Amazonian fruit that is commonly recognized as wild tomato, winter cherry, and gooseberry. While its fruit is known to contain many nutrients, such as minerals, fibers, and vitamins, few papers have investigated withanolide derivatives from its fruits. UPLC-Q-Orbitrap-MS/MS, which produces fragmentation spectra, was applied for the first time to guide the isolation of bioactive withanolide derivatives from P. angulata fruits. As a result, twenty-six withanolide derivatives, including two novel 1,10-secowithanolides (1 and 2) and a new derivative (3), were obtained. Compounds 1 and 2 are rare rearranged 1,10-secowithanolides with a tetracyclic 7/6/6/5 ring system. All structures were assigned through various spectroscopic data and quantum chemical calculations. Nine withanolide derivatives exhibited significant inhibitory effects on three tumor cell lines with IC50 values of 0.51-13.79 µM. Moreover, three new compounds (1-3) exhibited potential nitric oxide inhibitory effects in lipopolysaccharide-stimulated RAW264.7 cells (IC50: 7.51-61.8 µM). This investigation indicated that fruits of P. angulata could be applied to treat and prevent cancer and inflammatory-related diseases due to their potent active withanolide derivatives.

Effects of electroacupuncture on the intestinal thioredoxin interaction protein/Nod-like receptor 3 signaling pathway in mice with Parkinson's disease. / ç”µé’ˆå¯¹å¸•é‡‘æ£®ç— å°é¼ è‚ é“ç¡«æ°§è¿˜è›‹ç™½äº’ä½œè›‹ç™½/NODæ ·å—ä½“3信号通路的影响.

OBJECTIVES: To observe the effects of electroacupuncture (EA) at "Fengfu" (GV16), "Taichong" (LR3) and "Zusanli" (ST36) on α-synuclein (α-syn), Occludin, Claudin-1, thioredoxin interaction protein (TXNIP) and Nod-like receptor 3 (NLRP3) in Parkinson's disease (PD) mice, so as to investigate the mechanisms of EA on intestinal barrier function and inflammation in PD mice. METHODS: Thirty six C57BL/6 mice were randomly divided into control, model and EA groups, with 12 mice in each group. PD mice model was induced by rotenone intragastric administration for 28 days. Mice in the EA group were treated with EA (2 Hz, 1 mA) at GV16, LR3 and ST36 for 30 min, once a day for 14 days. The behavioral scores were observed. The total distance of autonomic movement was measured by open field test. The expression level of α-syn in substantia nigra and colon tissue was determined by immunohistochemistry. The colonic morphology and goblet cell distribution were observed by Alcian blue staining. The expression levels of Occludin, Claudin-1, TXNIP and NLRP3 mRNA in colon tissue were detected by real-time fluorescence quantitative PCR. RESULTS: Compared with the control group, the behavioral scores of rats were increased (P<0.01)；the total distance of autonomous movement was decreased (P<0.01)；the positive expression level of α-syn in the substantia nigra and colon was increased (P<0.01)；the goblet cells and crypts in colon tissue were reduced, and the muscular layer was thinner；the expression levels of Occludin and Claudin-1 mRNAs in colon tissue were decreased (P<0.01) while TXNIP and NLRP3 mRNAs were increased (P<0.01) in the model group. Compared with the model group, the surface villi of colon tissue was more complete, the goblet cells and crypts were increased, and the muscular layer was thickened；the other indexes were reversed (P<0.01, P<0.05) in the EA group. CONCLUSIONS: EA at GV16, LR3 and ST36 can reduce the abnormal accumulation of α-syn in the substania nigra and colon tissue of PD mice, alleviate the damage of intestinal barrier, regulate TXNIP/NLRP3 signaling pathway, so as to delay the occurrence and development of PD.

[Regularities of acupoint compatibility and application characteristics of methods of needling and moxibustion in the treatment of ankle sprain based on complex network analysis].

OBJECTIVE: To analyze the compatibility regularities of acupoints and the application characteristics of needling-moxibustionmethods in the treatment of ankle sprain by using complex network technology, so as to provide the basis and treatment ideas. METHODS: The clinical research articles on acupuncture treatment of ankle joint sprain published from November 2011 to November 2021 were retrieved from databases of CNKI, Wanfang Data knowledge service platform, VIP information Chinese journal service platform and PubMed by using key words of "acupuncture""moxibustion" "acupuncture and moxibustion" "ankle injury" "ankle sprain" "injured ankle" and "syndesmotic injuries". After screening these articles according to our inclusion and exclusion criteria, a database of acupuncture treatment of ankle sprain was established. Then, analysis on the occurrence frequency of acupoints and their related meridians, and methods of needling manipulation, and the association rule analysis (quantitative analysis) about the closeness between acupoints, and the degree of support and confidence coefficient were conducted for acquiring the acupoint combinations with higher correlation in the compatibility using Apriori algorithm after modeling (with IBM SPSS Modeler18.0 software). Gephi 0.9.2 software was used to make complex network analysis, for which "k-core hierarchical analysis" and "community analysis" were used as the methods to analyze the network structure of acupoints, and the confidence value was used as the index to measure the importance of acupoints. RESULTS: A total of 201 articles meeting the criteria were collected, including 196 articles in Chinese and 5 in English. A total of 236 acupuncture prescriptions were extracted, involving 61 acupoints, with a total frequency of occurrence being 846. The top 10 acupoints were Ashi point, Kunlun (BL60), Jiexi (ST41), Qiuxu (GB40), Shenmai (BL62), Yanglingquan (GB34), Taixi (KI3), Zhaohai (KI6), Xuanzhong (GB39) and Shangqiu (SP5), with the occurrence frequency being 109, 79, 70, 68, 63, 59, 53, 52, 37 and 34, respectively. The results of descriptive analysis showed that the top 5 meridians were Gallbladder Meridian of Foot-shaoyang, Bladder Meridian of Foot-taiyang, Kidney Meridian of Foot-shaoyin, Stomach Meridian of Foot-yangming and Spleen Meridian of Foot-taiyin, with the frequency being 181, 153, 116, 105 and 53, respectively. Complex network analysis displayed that after "k-core hierarchical analysis" and "Community division", two communities were reserved, mainly involving 15 core acupoints such as Ahshi point, GB40, ST14, BL62, GB34, KI6, BL60, KI3, GB39, Zusanli (ST36), SP5; Taichong (LR3), Zulinqi (GB41), Sanyinjiao (SP6) and Rangu (KI2). The results of association rule analysis showed that the most relevant acupoint combination is "BL60-ST41" (support degree 34.83％), followed by "BL60-KI3" (support degree 26.37%), reflecting the principle of selection of local acupoint for ankle sprain. The therapeutic methods are filiform needle acupuncture, and the reducing technique and uniform reinforcing and reducing manipulation are the most commonly used approaches, but the reinforcing method is rarely used. CONCLUSION: In the treatment of ankle sprain, local acupoints and Ashi points are mainly used, in combination with reducing or uniform reinforcing and reducing manipulations, as well as the method of needling and moxibustion, which provides a good reference for clinical practice.

Hyperpatone A, a polycyclic polyprenylated acylphloroglucinol with a rare 8/6/5/6/5 pentacyclic skeleton from Hypericum patulum.

Hyperpatone A (1), a highly oxidated polycyclic polyprenylated acylphloroglucinol (PPAP), along with a biosynthesized related PPAP (2) was isolated from Hypericum patulum under the guidance of LC-MS investigation. Architecturally, compound 1 represents the first PPAP with an unprecedented 8/6/5/6/5 pentacyclic skeleton and an intramolecular peroxy bridge, which might be derived from the [3.3.1]-type bicyclic polyprenylated acylphloroglucinol via the critical Baeyer-Villiger oxidation, decarboxylation, and intramolecular cyclization. The structures were established by extensive spectroscopic analysis, ACD software calculation, and quantum chemical computations. A plausible biogenetic pathway of 1 and 2 was also proposed. Importantly, both compounds exhibited moderate cytotoxic activities against the HEL cell line with the IC50 values ranging from 10.2 to 19.2 µM. Moreover, compound 1 showed an inhibitory effect on NO production in lipopolysaccharide-stimulated RAW264.7 cells at a lower concentration of 5 or 1 µM.

Targets and mechanisms of Alpinia oxyphylla Miquel fruits in treating neurodegenerative dementia.

The dried and ripe fruits of Alpinia oxyphylla and ripe fruits of Alpinia oxyphylla Miquel (AO) have the effects of tonifying kidney-essence and nourishing intelligence and thus have been widely used in treating dementia. Alzheimer's disease (AD) is a typical form of neurodegenerative dementia with kidney-essence deficiency in Traditional Chinese Medicine (TCM). So far, there is a lack of systematic studies on the biological basis of tonifying kidney-essence and nourishing intelligence and the corresponding phytochemicals. In this study, we investigated the targets of AO in tonifying kidney-essence and nourishing intelligence based on the key pathophysiological processes of neurodegenerative dementia. According to ultra-high-performance liquid chromatography with triple quadrupole mass spectrometry data and Lipinski's rule of five, 49 bioactive phytochemicals from AO were identified, and 26 of them were found to target 168 key molecules in the treatment of neurodegenerative dementia. Nine phytochemicals of AO were shown to target acetylcholinesterase (ACHE), and 19 phytochemicals were shown to target butyrylcholinesterase (BCHE). A database of neurodegenerative dementia with kidney-essence deficiency involving 731 genes was constructed. Furthermore, yakuchinone B, 5-hydroxy-1,7-bis (4-hydroxy-3-methoxyphenyl) heptan-3-one (5-HYD), oxyhylladiketone, oxyphyllacinol, butyl-ß-D-fructopyranoside, dibutyl phthalate, chrysin, yakuchinone A, rhamnetin, and rhamnocitrin were identified as the key phytochemicals from AO that regulate the pathogenesis of neurodegenerative dementia in a multitargeted manner. The approach of studying the pharmacological mechanism underlying the effects of medicinal plants and the biological basis of TCM syndrome may be helpful in studying the translation of TCM.

[Visual analysis of the acupoint prescription characteristics of acupuncture and moxibustion in treatment of rheumatoid arthritis].

Using the complex network technology, the characteristics of the core acupoint prescriptions and the application of acupuncture-moxibustion techniques were analyzed in treatment of rheumatoid arthritis (RA) so as to provide the evidences for acupoint selection and therapeutic methods for RA treated with acupuncture and moxibustion. The articles of acupuncture and moxibustion for treatment of RA in recent 20 years were collated and imported, and the database of the acupoint prescriptions was developed. Using Cytoscape 3.9.2 software, the acupoints in the prescriptions were visualized for the common occurrence network analysis. The association rule analysis was performed with IBM SPSS Modeler 18.0 software and the complex network analysis was by Gephi 0.9.2 software. A total of 798 articles were screened, in which, 3 258 prescriptions were extracted with 253 acupoints involved. The analysis of acupoint selection was conducted in terms of syndrome/pattern differentiation, acupoint locations and main acupoints, and therapeutic methods. The results showed that the most common TCM syndromes of RA included painful bi syndrome, wandering bi syndrome, fixed bi syndrome and bi syndrome due to wind, damp and heat. Regarding the core combination of acupoints, painful bi syndrome: Guanyuan (CV 4) and Shenshu (BL 23); fixed bi syndrome: Yinlingquan (SP 9), Sanyinjiao (SP 6), Zusanli (ST 36), Pishu (BL 20) and Fenglong (ST 40); wandering bi syndrome: Fengchi (GB 20), Geshu (BL 17), Fengmen (BL 12), Xuehai (SP 10) and Waiguan (TE 5); bi syndrome due to wind, damp and heat: Dazhui (GV 14), Quchi (LI 11) and Hegu (LI 4). Regarding the acupoint locations, the acupoints located in the upper limbs, lower limbs and spinal region were generally selected. Quchi (LI 11) was one of the main acupoints in prescriptions with the highest use frequency. Zusanli (ST 36) and Shenshu (BL 23) presented the highest co-occurrence intensity, while Zusanli (ST 36) and Quchi (LI 11) indicated the highest correlation. The treatment of acupuncture-moxibustion for RA is generally complied with the principle as "the synthesis of main acupoints, supplementary acupoints in local affected area and those based on syndrome differentiation". Warm needling and the combination of acupuncture and herbal medication are the most common therapeutic methods for RA.

[Identification of metabolites of imperatorin in rats: based on UHPLC-Q-Exactive Orbitrap MS].

This study aims to identify and analyze the metabolites of imperatorin in rats by UHPLC-Q-Exactive Orbitrap MS. Specifically, after rats were treated(ig) with imperatorin, the plasma, urine, and feces were collected, and the samples were processed by solid phase extraction. Then, UHPLC-Q-Exactive Orbitrap MS was performed. In MS, 0.1% formic acid water(A)-acetonitrile(B) was applied as mobile phase for gradient elution and the data of MS in both positive and negative ion modes were collected. The metabolites of imperatorin in blood, urine, and feces of rats were analyzed to explore the metabolic pathways of imperatorin in rats. According to accurate molecular weight, multistage MS data, MS fragmentation rule of the standard substance, and previous reports, a total of 51 metabolites were identified, with 35, 40, and 16 from plasma, urine, and feces, separately. The main metabolic pathways were oxidization, glucuronidation, isopentenyl removal, sulphation, carboxylation, among others. The conclusion in this study is expected to serve as a reference for the further development and the further pharmacodynamics study of imperatorin.

Hypersampones A-C, Three Nor-Polycyclic Polyprenylated Acylphloroglucinols with Lipid-Lowering Activity from Hypericum sampsonii.

Hypersampones A-C (1-3), three unprecedented nor-polycyclic polyprenylated acylphloroglucinols (PPAPs), were isolated from Hypericum sampsonii. These compounds represent the first nor-PPAPs with an unexpected tetracyclic 6/5/5/6 ring system. Their structures were assigned through the analysis of detailed spectroscopic data, X-ray crystallography, and electronic circular dichroism calculations. Compound 1 significantly inhibited the accumulation of lipid in an oleic acid-treated HepG2 cell model by suppressing the protein expression of FAS and ACACA at 5 µM.

Mapping thalamic-anterior cingulate monosynaptic inputs in adult mice.

The anterior cingulate cortex (ACC) is located in the frontal part of the cingulate cortex, and plays important roles in pain perception and emotion. The thalamocortical pathway is the major sensory input to the ACC. Previous studies have show that several different thalamic nuclei receive projection fibers from spinothalamic tract, that in turn send efferents to the ACC by using neural tracers and optical imaging methods. Most of these studies were performed in monkeys, cats, and rats, few studies were reported systematically in adult mice. Adult mice, especially genetically modified mice, have provided molecular and synaptic mechanisms for cortical plasticity and modulation in the ACC. In the present study, we utilized rabies virus-based retrograde tracing system to map thalamic-anterior cingulate monosynaptic inputs in adult mice. We also combined with a new high-throughput VISoR imaging technique to generate a three-dimensional whole-brain reconstruction, especially the thalamus. We found that cortical neurons in the ACC received direct projections from different sub-nuclei in the thalamus, including the anterior, ventral, medial, lateral, midline, and intralaminar thalamic nuclei. These findings provide key anatomic evidences for the connection between the thalamus and ACC.

Three New Aglain Derivatives from Aglaia odorata Lour. and Their Cytotoxic Activities.

Three new aglain derivatives (1-3), one known aglain derivative (4), two known rocaglamide derivatives (5 and 6), four known triterpenoids (7-10), and three steroids (11-13) were isolated from Aglaia odorata Lour. Their structures were established through the analysis of detailed spectroscopic data and electronic circular dichroism calculations. Five compounds (1 and 4-7) exhibited cytotoxic activities on human leukemia cells (HEL) and human breast cancer cells with IC50 values in the range of 0.03-8.40 µM. In particular, the cytotoxicity of compound 5 was six times stronger than that of the positive control (adriamycin) in HEL cell lines.

Chemical constituents from the flowers of Hypericum monogynum L. with COX-2 inhibitory activity.

Hypericum monogynum L. (Hypericaceae) has been used as a folk Chinese medicine for the treatment of inflammatory related diseases. Cyclooxygenase-2 (COX-2) is a crucial target for the development of agents to treat inflammation. To search for anti-inflammatory compounds from traditional Chinese medicines, a chemical constituent study along with COX-2 inhibitory activity analysis was performed for this plant. In this study, sixteen chemical monomers, including three undescribed oxidative degradation polycyclic polyprenylated acylphloroglucinols (PPAPs, hypemoins C-E), two undescribed PPAPs (hypemoins A and B), and 11 known compounds, were identified from the flowers of H. monogynum. Their structures were characterized by HRESIMS, NMR techniques, ECD, and single crystal X-ray diffraction. Four flavonoid derivatives showed remarkable COX-2 inhibitory activities, with IC50 values ranging from 0.220 ± 0.006 to 1.655 ± 0.098 µM. Among these compounds, the possible recognition mechanism between quercetin 3-(6″-O-caffeoyl)-ß-3-D-galactoside and COX-2 was predicted by molecular docking analysis. Moreover, the multidrug resistance reversal activities for the selected compounds were evaluated.

Two New Cytotoxic Maytansinoids Targeting Tubulin from Trewia nudiflora.

Two new maytansinoids, N-methyltreflorine (1: ) and methyltrewiasine (2: ), were isolated from the dried fruits of Trewia nudiflora, together with three known congeners (3:  - 5: ). Their structures were elucidated by spectroscopic methods, and the absolute configuration of 1: and 2: was determined by X-ray crystallographic analysis. Compounds 1:  - 5: exhibited strong cytotoxicity against human tumor cell lines, including HeLa, MV-4 - 11, and MCF-7, with IC50 values ranging from 0.12 to 11 nM. Compounds 1: and 4: also showed inhibitory activity against the MCF-7/ADR cell line with IC50 values of 13 and 28 nM, respectively. Compounds 1: and 2: significantly inhibited tubulin polymerization in vitro with IC50 values of 3.6 and 3.2 µM, respectively.

[Electroacupuncture improves behavioral activities by suppressing neuroinflammation and TLR4/NF-κB signaling in substantia nigra of midbrain in Parkinson's disease rats].

OBJECTIVE: To observe the effect of electroacupuncture(EA) at "Fengfu" (GV16) and "Taichong"(LR3) on the expression of tyrosine hydroxylase (TH), α-synuclein (α-syn) and microglial-related microglial (MG), Toll-like receptor 4（TLR4）/nuclear factor kappa B （NF-κB） signaling pathway in the substantia nigra (SN) of midbrain in Rotenone-induced Parkinson's disease (PD) rats, so as to explore its mechanisms underlying improvement of PD. METHODS: SD male rats were randomly divided into normal control, PD model and EA groups (n=12 in each group). The PD model was established by subcutaneous injection of rotenone (1 mg/kg) at the back of neck. EA (2 Hz, 1 mA) was applied to bilateral GV16 and LR3, once daily for 2 weeks. The rats' behavior(hair color, reaction capacity, locomotion and gait state)scores (0-10 points) were given and the autonomic movement state (trajectory of autonomous motion, total distance, average speed and duration of motion in 8 min) was detected by using open field tests. The immunoactivity of TH and α-syn in the SN tissue were determined by using immunohistochemistry staining, and the number of Iba-1-labelled microglia (MG) was detected by using immunofluorescence staining. The expression levels of TLR4 and NF-κB P65 proteins in the SN were detected by Western blot, and the contents of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the SN were determined by using enzyme-linked immunosorbent assay. RESULTS: In comparison with the normal group, the behavioral score, α-syn immunoactivity, number of Iba-1 labelled microglia, expression of TLR4 and NF-κB P65 proteins and the contents of TNF-α and IL-6 in the SN were significantly increased (P<0.01), whereas the total distance, average speed, duration of motion of the autonomic movement in 8 min, and the TH immunoactivity were remarkably decreased in the model group (P<0.01). After EA intervention, compared with the model group, the increase of the behavioral score, α-syn immunoactivity, number of Iba-1-labelled microglia, expression of TLR4 and NF-κB P65 proteins, the contents of TNF-α and IL-6 in the SN, and the decrease of the total distance, average speed, duration of motion of the autonomic movement in 8 min, and the TH immunoactivity were reversed (P<0.05, P<0.01). CONCLUSION: EA can improve the behavioral manifestations of PD rats, which may be associated with its functions in down-regulating the abnormal accumulation of pathological α-syn, TLR4/NF-κB signaling, inhibiting activities of microglia and in up-regulating the expression of TH in the SN of midbrain.

Hymoins A-D: Two Pairs of Polyprenylated Acylphloroglucinols from Hypericum monogynum and Their Light-Induced Transformation.

Hymoins A-D (1-4), two pairs of light-induced transformative polyprenylated acylphloroglucinols with an unprecedented pentacyclic skeleton, were isolated from the flowers of Hypericum monogynum. The first decarbonylative ring contraction of complex natural products was investigated by light irradiation. Their structures were elucidated by nuclear magnetic resonance analysis, X-ray crystallography, and electronic circular dichroism calculations. In addition, compound 3 showed moderate inhibition efficacy of the platelet-activating-factor-induced aggregation of rabbit platelets.

Hypermoins A-D: Rearranged Nor-Polyprenylated Acylphloroglucinols from the Flowers of Hypericum monogynum.

Hypermonins A-D (1-4), four rearranged nor-polycyclic polyprenylated acylphloroglucinols (PPAPs) with unprecedented skeletons, together with two new biosynthesis related PPAPs (5 and 6) were isolated and identified from the flowers of Hypericum monogynum. Hypermoins A-D represented the first examples of highly modified norPPAPs characterized by a rare 7/6/6/5-tetracyclic system. From the biogenic synthesis pathway analysis, all isolates shared the same biosynthetic intermediate, and the addition of two methyls or one methyl to this intermediate through methyltranferase could generate different types of PPAPs (1-7). Their planner structures as well as absolute configuration were confirmed via spectroscopic analysis, ECD calculation, and X-ray crystallography. All isolates potentially reversed multidrug resistance (MDR) activity in both two cancer cells, HepG2/ADR and MCF-7/ADR. Specifically, hypermoin E (5) and hyperielliptone HA (7) were found to be the best MDR modulators with the reversal fold ranging from 41 to 236, which is higher than the positive control verapamil.

Existing knowledge on Euphorbia fischeriana Steud. (Euphorbiaceae): Traditional uses, clinical applications, phytochemistry, pharmacology and toxicology.

ETHNOPHARMACOLOGICAL RELEVANCE: Euphorbia fischeriana Steud. (Euphorbiaceae) is a perennial herb distributed in grassland, hill slopes or gravel hillside, with average altitude of 100-600 m. The whole grass of E. fischeriana is toxic with roots used as folk medicine to treat Zhushui, dyspepsia, abdominal distension, abdominal pain, cough, as well as external applications such as cure of scabies and tuberculosis of lymph nodes. AIM OF THE REVIEW: This systematic review aims to provide a detailed and in-depth summary about the reported advances in traditional uses, clinical applications, phytochemistry, pharmacology and toxicity of E. fischeriana, so as to offer fresh ideas and broader vision and insights for subsequent studies. MATERIALS AND METHODS: Various scientific data bases such as CNKI, Elsevier, Google Scholar, Pubmed, Science Direct, SciFinder Scholar and Web of Science were searched to collect information about E. fischeriana. Other relevant literatures were searched in 'Flora of China Editorial Committee', ancient books, Ph.D and Masters' Dissertation to get more data of E. fischeriana. RESULTS: A total of 241 chemical constituents have been identified from the roots of E. fischeriana, including diterpenoids, triterpenoids, meroterpenoids, acetophenones, flavonoids, coumarins, steroids, phenolic acids, tannins, etc. Various pharmacological activities have been demonstrated, especially anti-tumor, antibacterial, anti-inflammatory, antiviral and anti-leukemia activities. Moreover, different investigations about clinical uses and toxicology of E. fischeriana indicated that attention should be paid to its usage and dosage. CONCLUSION: The researches of E. fischeriana are excellent, but gap still remains. As a poisonous traditional Chinese medicine, there are not enough studies on the toxicity of E. fischeriana. In addition, scholars' research on the pharmacological mechanism of E. fischeriana focuses more on the anti-tumor activity, which can be broadened in the future. Presumably, chemical constituents and biological activities of diterpenoids and trace meroterpenoids in E. fischeriana deserve further research in-depth in the future, in order to provide low toxicity and high efficiency lead compounds. Meanwhile, further studies on other medicinal aspects may lay a foundation for the comprehensive development and utilization of E. fischeriana.

Discovery and synthesis of rocaglaol derivatives inducing apoptosis in HCT116 cells via suppression of MAPK signaling pathway.

Six rocaglaol derivatives were isolated from Dysoxylum gotadhora, and those compounds showed good cytotoxic activity with IC50 values ranging from 10 to 350 ng/mL against five different cancer cells. Obviously, further total synthesis of rocaglaol derivatives for medical chemistry study is of great significance. Then, twenty six rocaglaol derivatives including 25 new compounds were designed, synthesized, and evaluated for their cytotoxic activities against three human cancer cell lines: human colon cancer cells (HCT116), colorectal cancer stem cells (P6C), and human red leukocyte leukemia cells (HEL), using MTT assay. Most of derivatives showed good cytotoxic activities, with the lowest IC50 being 3.2 nM for HEL cells, which was 169 times stronger than that of the positive control (doxorubicin). Further mechanism study indicated that 11k could significantly suppress MAPK pathway in HCT116 cells, which may responsible for induction of apoptosis and cell cycle arrest.

Two new seco-polycyclic polyprenylated acylphloroglucinol from Hypericum sampsonii.

Hypsampsone A (1) and hyperhexanone F (2), two novel seco-polycyclic polyprenylated acylphloroglucinols, were isolated from Hypericum sampsonii. Hypsampsone A (1) features the first spirocyclic system fused with 5/6/5/5 tetracyclic skeleton. Hyperhexanone F (2) represents the second novel 1,2-seco-bicyclo[3.3.1]-PPAP skeleton. Their structures were established by extensive spectroscopic analysis, computer-assisted structure elucidation software, and calculated electronic circular dichroism spectra. A plausible biogenetic pathway of 1 was also proposed. Compounds 1 and 2 showed moderate multidrug resistance reversal activity to adriamycin (ADR) resistant cancer cell lines, HepG2/ADR and MCF-7/ADR, with the fold-reversals ranging from 16 to 38 at noncytotoxic concentration of 10 µM.

Derivatives of Deoxypodophyllotoxin Induce Apoptosis through Bcl-2/Bax Proteins Expression.

BACKGROUND: Deoxypodophyllotoxin, isolated from the Traditional Chinese Medicine Anthriscus sylvestris, is well-known because of its significant anti-tumor activity with strong toxicity in vitro and in vivo. OBJECTIVE: In this article, a series of deoxypodophyllotoxin derivatives were synthesized and their anti-tumor effectiveness was evaluated. METHODS: The anti-tumor activity of deoxypodophyllotoxin derivatives was investigated by the MTT assay method. Apoptosis percentage was measured by flow cytometer analysis using Annexin-V-FITC. RESULTS: The derivatives revealed obvious cytotoxicity in the MTT assay by decreasing the number of late cancer cells. The decrease of Bcl-2/Bax could be observed in MCF-7, HepG2, HT-29, and MG-63 using Annexin V-FITC. The ratio of Bcl-2/Bax in the administration group was decreased, which was determined by the ELISA kit. CONCLUSION: The derivatives of deoxypodophyllotoxin could induce apoptosis in tumor cell lines by influencing Bcl-2/Bax.