Phenolics and terpenoids with good anti-inflammatory activity from the fruits of Amomum villosum and the anti-inflammatory mechanism of active diterpene.

The fruits of Amomum villosum are often considered a medicinal and food homologous material and have been found to have therapeutic effects in chronic enteritis, gastroenteritis, and duodenal ulcer. The aim of this study is to discover the anti-inflammatory active ingredients from dried ripe fruits of A. villosum and to elucidate the molecular mechanisms. We verified that the inhibitory activity of the ethyl acetate extract was superior to Dexamethasone (Dex), so we ultimately chose to study the ethyl acetate extract from the fruits of A. villosum. A total of 33 compounds were isolated from its ethyl acetate extract, including nine known diterpenoids (compounds 1-9), twelve known sesquiterpenoids (compounds 10-21), ten known phenolics (compounds 22, 23, 25-29, 31-33) and two new phenolics (24 and 30). On the basis of chemical evidences and spectral data analysis (UV, ECD, Optical rotation data, 1D and 2D-NMR, HR-ESI-MS, NMR chemical shift calculations), the structures of new compounds were elucidated. Among these compounds, isocoronarin D (5) was found to have good anti-inflammatory activity. Further research has found that isocoronarin D can down-regulate the protein levels of COX2 and NOS2, activate Nrf2/Keap1 and suppress NF-κB signaling pathway in LPS-induced RAW264.7 cells. In addition, isocoronarin D inhibited inflammasome assembly during inflammasome activation by hampering the binding of NLRP3 and ASC. Further evidence revealed that isocoronarin D suppressed the assembly of the NLRP3 inflammasome via blocking the formation of ASC specks. From these results, isocoronarin D may be the important bioactive compound of A. villosum and exhibits anti-inflammatory effects by regulating the NF-κB/Nrf2/NLRP3 axis in macrophages.

Antioxidant aromatic compounds from Amomum villosum and target prediction of active ingredients.

The dried fruit of Amomum villosum is an important spice and medicinal plant that has received great attention in recent years due to its high content of bioactive components and its potential for food additives and drug development. However, the stems and leaves of A. villosum are usually disposed of as waste. Based on the study of the fruits of A. villosum, we also systematically studied its stems and leaves. Fourteen aromatic compounds (1-14) were isolated and identified from A. villosum, including five new compounds (1-5) and nine known compounds (6-14). Among them, compounds 2-5, 8-10, 12-13 were obtained from the fruits of A. villosum, and compounds 1, 6-7,11, 14 were isolated from the stems and leaves of A. villosum. Based on chemical evidence and spectral data analysis (UV, ECD, Optical rotation data, 1D and 2D-NMR, and HR-ESI-MS), the structures of new compounds were elucidated. Furthermore, all compounds were tested for their effects on the survival rate of BV-2 cells in the presence of hydrogen peroxide. Among them, compound 5 showed antioxidant effects. Through network pharmacology screening and the cell thermal shift assay (CETSA), the Phosphoglycerate Mutase 5 (PGAM5) protein was identified as the antioxidant target of compound 5. Molecular docking results showed that compound 5 maintains binding to PGAM5 by forming hydrogen bond interactions with Lys93 and Agr214. In summary, A. villosum had potential medicinal and food values due to the diverse bioactive components.

Coumarins and flavones with anti-inflammatory activity isolated from the branches and leaves of Daphne retusa.

In this study, two new (1, 13) and fourteen known (2-12, 14-16) compounds were isolated from the branches and leaves of Daphne retusa. On the basis of chemical evidence and spectral data analysis (UV, ECD NMR, and HR-ESI-MS), the structures of new compounds were elucidated. Furthermore, all compounds have been tested for their inhibitory effects on NO production in LPS-induced RAW 264.7 cells, and compound 3 showed obvious inhibitory effect. Through target screening and molecular docking technology, potential binding targets for compound 3 to exert anti-inflammatory effects have been predicted.

Synthesis of Lathyrol PROTACs and Evaluation of Their Anti-Inflammatory Activities.

Lathyrol is a core scaffold structure of many lathyrane diterpenoids with potent anti-inflammatory activity isolated from Euphorbia lathyrism. It was chosen as a framework to design and synthesize a series of proteolysis targeting chimeras. A total of 15 derivatives were obtained. Compound 13 exhibited inhibitory activity on LPS-induced NO production in RAW264.7 cells (IC50 = 5.30 ± 1.23 µM) with low cytotoxicity. Furthermore, compound 13 significantly degraded v-maf musculoaponeurotic fibrosarcoma oncogene homologue F (MAFF) protein, a target of lathyrane diterpenoid, concentration- and time-dependently. The mechanism of action of 13 is related to activating the Keap1/Nrf2 pathway. It also inhibited the expression of NF-κB, blocked the nuclear translocation of NF-κB, and activated autophagy in LPS-induced RAW264.7 cells. Based on the results obtained, compound 13 might be a promising anti-inflammatory agent.

Chemical constituents from the stems and leaves of Amomum villosum Lour. and their anti-inflammatory and antioxidant activities.

Amomum villosum Lour. is a medicinal and edible plant, whose medicinal parts are dried and mature fruits, and its stems and leaves are always treated as waste. HPLC-MS/MS analysis showed that the chemical components contained in the stems/leaves of A. villosum and those in fruits are quite different. To discover potential active ingredients from the stems/leaves of A. villosum, phytochemical evaluation of the stems/leaves of A. villosum was conducted to isolate and identify-four undescribed compounds (1, 2a, 2b, and 3) along with 41 known ones (4a, 4b, 5a, 5b, and 6-42). All isolated compounds were assessed for their anti-inflammatory and antioxidant activities. Among them, compounds 5b, 33, 34, and 38 exhibited anti-inflammatory activity, and compounds 1, 4a, 4b, 6, 7, 15, 33, 35, 37, and 41 showed antioxidant effects. Among them, the new compound 1 showed a significant antioxidant effect via activation of NRF2/HO-1 pathways. Therefore, the leaves and stems of A. villosum may be served as a potential medicine or dietary supplement for preventing and treating diseases resulting from inflammation and oxidative stress.

Research progress of plant-derived natural alkaloids in central nervous system diseases.

Central nervous system (CNS) disease is one of the most important causes of human death. Because of their complex pathogenesis, more and more attention has been paid to them. At present, drug treatment of the CNS is the main means; however, most drugs only relieve symptoms, and some have certain toxicity and side effects. Natural compounds derived from plants can provide safer and more effective alternatives. Alkaloids are common nitrogenous basic organic compounds found in nature, which exist widely in many kinds of plants and have unique application value in modern medicine. For example, Galantamine and Huperzine A from medicinal plants are widely used drugs on the market to treat Alzheimer's disease. Therefore, the main purpose of this review is to provide the available information on natural alkaloids with the activity of treating central nervous system diseases in order to explore the trends and perspectives for the further study of central nervous system drugs. In this paper, 120 alkaloids with the potential effect of treating central nervous system diseases are summarized from the aspects of sources, structure types, mechanism of action and structure-activity relationship.

Xanthones and Phenylpropanoids from the Whole Herb of Swertia pseudochinensis and Their Anti-Inflammatory Activity.

An undescribed xanthone dimer, 1,3,5,8-tetrahydroxy-7-(1',5',8'-trihydroxy-3'-methoxy-2'-xanthonyl)xanthone (1) was separated together with eleven known compounds (2-12) from the dried whole herb of Swertia pseudochinensis. It was the first time that the compounds 8-12 were isolated from the Swertia genus. The structure of compound 1 was illuminated based on chemical evidence and spectral data analysis (UV, 1D and 2D-NMR, HR-ESI-MS). Moreover, the inhibitory effects of all compounds on NO production in LPS-induced RAW 264.7 cells were tested, compounds 8, 9, 10, 11 and 12 showing significant inhibition. The IC50 value of compound 12 was 3.05±1.10 µM. Using target screening and molecular docking, we hypothesized that compound 12 may bind neutrophil elastase to exert its anti-inflammatory effects.

Three New Labdane-Type Diterpenoids from the Fruits of Amomum villosum and Their Anti-Inflammatory Activities.

Three new labdane-type diterpenoids, calcaratarin E, villosumtriol, and 12-epi-villosumtriol (1-3) were isolated from the fruits of Amomum villosum, along with seven known diterpenoids (4-10). Through comprehensive analysis of chemical evidence and spectral data including UV, 1D and 2D NMR, HR-ESI-MS, IR, and X-ray crystallography, the structures of these novel compounds were successfully determined. Additionally, the inhibitory effects of compounds 2-10 on NO production in lipopolysaccharide (LPS)-induced RAW264.7 cells were evaluated. Notably, compound 6 exhibited the most significant inhibitory effect with an IC50 value of 1.74±0.69 µM.

[The application study of Electrophysiological appropriate technology in perioperative nursing of patients undergoing microdissection testicular sperm extraction].

Obstract: To explore the application of electrophysiological appropriate technology in perioperative nursing of patients undergoing microdissection testicular sperm extraction. METHODS: A retrospective analysis was conducted on the medical records of 108 patients who underwent testicular incision and sperm extraction under a microscope at our center from May 2022 to June 2023. Among them, 51 patients received routine care and 57 patients received electrophysiological treatment. Evaluate the perioperative nursing effects of appropriate electrophysiological techniques through VAS pain score, Self Rating Anxiety Scale (SAS) score, Pittsburgh Sleep Quality Score, and Kolcaba Comfort Scale. RESULT: Patients who received appropriate electrophysiological interventions had lower VAS pain scores (2.36 ± 1.37 vs 4.16 ± 1.38, P<0.001) than the control group, and higher KOLCABA comfort scale scores than the control group (70.73 ± 19.46 vs 52.06 ± 17.50, P<0.001); There was no statistically significant difference in the Self Rating Anxiety Scale (SAS) score and Pittsburgh Sleep Quality Score. CONCLUSION: Electrophysiological techniques can effectively improve postoperative pain and comfort in patients undergoing testicular incision and sperm extraction under a microscope, and have clinical application value.

[Nursing cooperation in surgical collection of testis tissues from prepubertal male patients for cryopreservation: A study of 4 cases].

OBJECTIVE: To explore nursing cooperation in surgical collection of the testis tissue from prepubertal male patients for cryopreservation. METHODS: We retrospectively analyzed the methods and effects of perioperative nursing in surgical collection of the testis tissue from 4 prepubertal male patients for cryopreservation in our Center of Reproductive Medicine. Before, during and after operation, we took strict measures in making sterilized ice containers, intraoperative nursing cooperation, protection of the isolated testis tissues and transferring of the samples. RESULTS: Testis tissues were successfully collected from all the 4 prepubertal males, 31, 31, 20 and 34 samples from each case respectively, well protected and subjected to slow cryopreservation after standard processing in the embryo laboratory. CONCLUSION: In surgical collection of the testis tissue for cryopreservation, preparation of sterilized ice containers, intraoperative nursing cooperation and protection and transferring of the samples are essential for standard processing and cryopreservation of the testis tissue in the embryo laboratory.

SIRT6 mediates multidimensional modulation to maintain organism homeostasis.

As a member of the silent information regulators (sirtuins) family, SIRT6 can regulate a variety of biological processes, including DNA repair, glucose and lipid metabolism, oxidative stress and lifespan, and so forth. SIRT6 maintains organism homeostasis in a variety of phenotypes by mediating epigenetic regulation and posttranslational modification of functional proteins. In this review, we outline the structural basis of SIRT6 enzyme activity and its mechanism of maintaining organism homeostasis in a variety of phenotypes, with an emphasis on the upstream that regulates SIRT6 expression and the downstream substrates. And how SIRT6 achieves multidimensional coordination to maintain organism homeostasis and even extend lifespan. We try to understand the regulatory mechanism of SIRT6 in different phenotypes from the perspective of protein interaction.

Kynurenine-3-monooxygenase (KMO): From its biological functions to therapeutic effect in diseases progression.

Kynurenine-3-monooxygenase (KMO) is a mitochondrial enzyme involved in the eukaryotic kynurenine pathway (KP), which is the major catabolic route of tryptophan. KMO can convert the substrate kynurenine into the neurotoxin 3-hydroxykynurenine and quinolinic acid, which promote the production of toxic metabolites and formation of free radical in the blood, while decrease the neuroprotective metabolite kynurenic acid. As a result of branch point, KMO is predicted as an attractive drug target for several diseases, especially neurodegenerative diseases, psychosis, and cancer. This review mainly pays attention to KMO structure and the research of mechanisms and functions, with a particular emphasis on the roles of KMO in the pathogenesis of various conditions. Furthermore, we also summarized important KMO inhibitors to supporting their effects on these diseases, indicating the prospect to find novel KMO inhibitors for diseases therapy.

Synthesis of lathyrane diterpenoid nitrogen-containing heterocyclic derivatives and evaluation of their anti-inflammatory activities.

As our ongoing work on lathyrane diterpenoid derivatization, three series of lathyrane diterpenoid derivatives were designed and synthesized based combination principles, including pyrazole, thiazole and furoxan moieties. Biological evaluation indicated that compound 23d exhibited excellently inhibitory activity on LPS-induced NO production in RAW264.7 cells (IC50 = 0.38 ± 0.18 µM). The preliminary structure-activity relationships (SARs) suggested that phenylsulfonyl substituted furoxan moiety had the strongest ability to improve anti-inflammatory activity of lathyrane diterpenoids. Furthermore, compound 23d significantly reduced the level of ROS. Its molecular mechanism was related to inhibiting the transcriptional activation of Nrf2/HO-1 pathway. Based on these considerations, 23d might be a promising anti-inflammatory agent, which is noteworthy for further exploration.

A review on natural products with cage-like structure.

Natural products with diverse structures and significant biological activities are essential sources of drug lead compounds, and play an important role in the research and development of innovative drugs. Cage-like compounds have various structures and are widely distributed in nature, especially caged xanthones isolated from Garcinia genus, paeoniflorin and its derivatives isolated from Paeonia lactiflora Pall, tetrodotoxin (TTX) and its derivatives, and so on. In recent years, the development and utilization of cage-like compounds have been a research hotspot in chemistry, biology and other fields due to their special structures and remarkable biological activities. In this review, we mainly summarized the cage-like compounds with various structures found and isolated from natural drugs since 1956, summarized its broad biological activities, and introduced the progress in the biosynthesis of some compounds, so as to provide a reference for the discovery of more novel compounds, and the development and application of innovative drugs.

Diterpenoids from the whole plant of Euphorbia wallichii and their protective effects on H2O2-induced BV-2 microglial cells injury.

Thirteen undescribed diterpenoids, including an ent-isopimarane (1), ten ent-atisanes (2-8 and 15-17), and two ingenanes (20 and 21) and ten known compounds, were separated from the whole plant of E. wallichii. The structures and absolute stereochemistry of these compounds were delineated by 1D and 2D NMR, mass spectrometry, pyridine-induced solvent shifts, and X-ray diffraction analyses. Euphwanoid A (1) is elucidated as an ent-16­norisopimarane type diterpenoid featuring a C-8-O-C-15 lactone fragment. And euphwanoid B (2) represents a rare ent-atisane type tetranorditerpene possessing a tetrahydrofuran moiety. In addition, all these isolated compounds were assayed for their protective effects on H2O2-induced BV-2 microglial cells damage. And representative compound 1 could protect BV-2 cells against oxidative damage via the NRF2/HO-1 signaling pathway.

Alkaloids of Delphinium grandiflorum and their implication to H2O2-induced cardiomyocytes injury.

Three new diterpenoid alkaloids (1-3), and eight known alkaloids (4-11) were isolated from the aerial parts of Delphinium grandiflorum. Grandifline A (1) represents an unprecedented diterpenoid alkaloid ring system featuring a C-7NC17 hemiaminal moiety and a lactone fragment through the linkage of C-17OC19 unit. And we named this newly-discovered class of rearranged C19-diterpenoid alkaloid scaffold as grandiflodines (B-12). Grandifline B (2) is the first naturally-occurring 7,17-secolycoctonine diterpenoid alkaloid with a C-7OC17 unit forming a hemiacetal. Their structures were elucidated via spectroscopic data and single-crystal X-ray diffraction analysis. The protective effects of compounds 1-11 on H2O2-induced cardiomyocytes injury were assayed. And compounds 6 and 10 showed significant protective effects, with IC50 values of 1.881 ± 0.680 µM and 1.904 ± 0.750 µM, respectively. Further, compound 6 could reduce oxidative damage by inhibiting cell death via the AMPK/AKT/mTOR signaling pathway in H2O2-induced H9C2 cells.

Withanolides from dietary tomatillo suppress HT1080 cancer cell growth by targeting mutant IDH1.

Isocitrate dehydrogenase (IDH) is one key rate-limiting enzyme in the tricarboxylic acid cycle, which is related to various cancers. Tomatillo (Physalis ixocarpa), a special tomato, is widely consumed as nutritious vegetable in Mexico, USA, etc. As a rich source for withanolides, the fruits of P. ixocarpa were investigated, leading to the isolation of 11 type-A withanolides including 4 new ones (1 is an artificial withanolide). All these withanolides were evaluated for their inhibition on mutant IDH1 enzyme activity. Among them, physalin F (11) exhibited potent enzyme inhibitory activity and binding affinity with mutant IDH1. It inhibits the proliferation of HT1080 cells by selectively inhibiting the activity of mutant IDH1. Since Ixocarpalactone A, another major type-B withanolide in this plant, could act on another energy metabolism target PHGDH, the presence of different types of withanolides in tomatillo and their synergistic effect could make it a potential antitumor functional food or drug.

Diterpenoids from the seeds of Euphorbia lathyris and their anti-inflammatory activity.

Twelve previously undescribed diterpenoids, euplarisans A-L (1-12), including one premyrsinane and eleven lathyranes, along with ten known analogues 13-22 were isolated from the seeds of Euphorbia lathyris. Their chemical structures were delineated by spectroscopic analysis and single-crystal X-ray diffraction. Interestingly, both 5 and 6 possessed an unusual trans-gem-dimethylcyclopropane as structural features and compound 8 was elucidated as premyrsinane-type diterpenoid. Meanwhile, a plausible biogenetic pathway for compounds 1-12 was proposed. In the anti-inflammatory bioassay, compounds 1, 2, 4, 13, 16, and 18 markedly inhibited the nitric oxide production in LPS-induced RAW264.7 macrophage cells. Compound 1 showed a more remarkable anti-inflammatory effect than others. It inhibited the generation of inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and also obviously decreased the expression of iNOS, COX-2, and p-IκBα in a dose-dependent manner. The structure-activity relationships (SARs) of these diterpenoids were also discussed.

Withanolides isolated from Tubocapsicum anomalum and their antiproliferative activity.

Seven undescribed withanolides (1-7) and six artificial withanolides (8-13), along with 20 known compounds (14-33) were isolated from the aerial parts of Tubocapsicum anomalum. Their structures were confirmed by comprehensive spectroscopic analyses. The absolute configuration of compound 1 was defined by single-crystal X-ray crystallography. All isolates were evaluated for their antiproliferative effects against five human tumor cell lines (Hep3B, MDA-MB-231, SW480, HCT116 and A549), among which compound 24 (tubocapsanolide A) exhibited the highest activities against the MDA-MB-231 cells with an IC50 value of 1.89 ± 1.03 µM. Further studies showed that 24 exhibited significant damage to mitochondria in MDA-MB-231 cells, including excess reactive oxygen species, decreased mitochondrial membrane potential, and apoptosis initiation. In addition, compound 24 also inhibited cell migration. These findings show that tubocapsanolide A may be a promising molecule for triple-negative breast cancer treatment and merit further evaluation.

[Micro-dissection testicular sperm extraction for non-obstructive azoospermia patients with the history of secondary testicular injury].

Objective: To investigate the value of micro- dissection testicular sperm extraction (micro-TESE) in the treatment of non-obstructive azoospermia (NOA) in patients with the history of secondary testicular injury. METHODS: Totally, 121 NOA patients with the history of secondary testicular injury underwent micro-TESE in our hospital from September 2014 to December 2017. We analyzed the correlation of the sperm retrieval rate with the causes of testicular injury and compared the outcomes of the ICSI cycles with the sperm retrieved from the NOA males by micro-TESE (the micro-TESE group) and those with the sperm ejaculated from severe oligospermia patients (sperm concentration <1×106/ml, the ejaculate group). Comparisons were also made between the two groups in the female age, two-pronucleus (2PN) fertilization rate, transferrable embryos on day 3 (D3), D3 high- quality embryos, D14 blood HCG positive rate, embryo implantation rate, and clinical pregnancy rate. RESULTS: Testicular sperm were successfully retrieved by micro-TESE in 86.0% of the patients (104/121), of whom 98.4% had the history of orchitis, 75.5% had been treated surgically for cryptorchidism, and 63.6% had received chemo- or radiotherapy. No statistically significant differences were observed between the micro-TESE and ejaculate groups in the 2PN fertilization rate (59.4% vs 69.3%, P > 0.05), D14 blood HCG positive rate (44.6% vs 57.9%, P > 0.05), embryo implantation rate (31.8 %% vs 32.6%, P > 0.05) and clinical pregnancy rate (41.5% vs 48.7%, P > 0.05). However, the rate D3 transferrable embryos was significantly lower in the micro-TESE than in the ejaculate group (40.5% vs 52.2%,P < 0.05), and so was that of D3 high-quality embryos (32.5% vs 42.1%, P < 0.05). CONCLUSIONS: Micro-TESE can be applied as the first choice for NOA patients with the history of secondary testicular injury, but more effective strategies are to be explored for the improvement of ICSI outcomes with the sperm retrieved by micro- TESE.