Construction of an Angular Tricyclic Benzofuran Skeleton Using the C-H Activation Strategy.

A protocol for the construction of an angular tricyclic benzofuran skeleton based on the C-H activation strategy has been established. Different phthalide lactones on this skeleton can be easily assembled with various side chains by using C-H activation with aldehydes and subsequent reduction. This skeleton provides a versatile and crucial motif for the total synthesis of naturally occurring angular tricyclic benzofurans and their derivatives. Based on this protocol, the improved total syntheses of daldinin A and annullatin D were achieved in yields of 17.3 and 7.6%, respectively.

Ursolic acid alleviates chronic prostatitis via regulating NLRP3 inflammasome-mediated Caspase-1/GSDMD pyroptosis pathway.

Ursolic acid (UA) is a naturally occurring pentacyclic triterpenoid widely found in fruits and vegetables. It has been reported that UA has anti-inflammatory effects. However, its efficacy and mechanism of action in the treatment of chronic prostatitis (CP) remain unclear. This study aimed to investigate the efficacy of UA treatment in CP and further explore the underlying mechanism. CP rat and pyroptosis cell models were established in vivo and in vitro, respectively. The efficacy of UA in inhibiting CP was evaluated via haematoxylin-eosin (HE) staining and measurement of inflammatory cytokines. RNA sequencing and molecular docking were used to predict the therapeutic targets of UA in CP. The expression of pyroptosis-related proteins was examined using various techniques, including immunohistochemistry, immunofluorescence, and flow cytometry. UA significantly ameliorated pathological damage and reduced the levels of proinflammatory cytokines in the CP model rats. RNA sequencing analysis and molecular docking suggested that NLRP3, Caspase-1, and GSDMD may be key targets. We also found that UA decreased ROS levels, alleviated oxidative stress, and inhibited p-NF-κB protein expression both in vivo and in vitro. UA improved pyroptosis morphology as indicated by electron microscope and inhibited the expression of the pyroptosis-related proteins NLRP3, Caspase-1, ASC, and GSDMD, reversed the levels of IL-1ß, IL-18, and lactate dehydrogenase in vivo and in vitro. UA can mitigate CP by regulating the NLRP3 inflammasome-mediated Caspase-1/GSDMD pathway. Therefore, UA may be a potential for the treatment of CP.

Unraveling the Binding Mode of Cyclic Adenosine-Inosine Monophosphate (cAIMP) to STING through Molecular Dynamics Simulations.

The stimulator of interferon genes (STING) plays a significant role in immune defense and protection against tumor proliferation. Many cyclic dinucleotide (CDN) analogues have been reported to regulate its activity, but the dynamic process involved when the ligands activate STING remains unclear. In this work, all-atom molecular dynamics simulations were performed to explore the binding mode between human STING (hSTING) and four cyclic adenosine-inosine monophosphate analogs (cAIMPs), as well as 2',3'-cGMP-AMP (2',3'-cGAMP). The results indicate that these cAIMPs adopt a U-shaped configuration within the binding pocket, forming extensive non-covalent interaction networks with hSTING. These interactions play a significant role in augmenting the binding, particularly in interactions with Tyr167, Arg238, Thr263, and Thr267. Additionally, the presence of hydrophobic interactions between the ligand and the receptor further contributes to the overall stability of the binding. In this work, the conformational changes in hSTING upon binding these cAIMPs were also studied and a significant tendency for hSTING to shift from open to closed state was observed after binding some of the cAIMP ligands.

Lysine-Specific Demethylase 1 Inhibitors: A Comprehensive Review Utilizing Computer-Aided Drug Design Technologies.

Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising therapeutic target for treating various cancers (such as breast cancer, liver cancer, etc.) and other diseases (blood diseases, cardiovascular diseases, etc.), owing to its observed overexpression, thereby presenting significant opportunities in drug development. Since its discovery in 2004, extensive research has been conducted on LSD1 inhibitors, with notable contributions from computational approaches. This review systematically summarizes LSD1 inhibitors investigated through computer-aided drug design (CADD) technologies since 2010, showcasing a diverse range of chemical scaffolds, including phenelzine derivatives, tranylcypromine (abbreviated as TCP or 2-PCPA) derivatives, nitrogen-containing heterocyclic (pyridine, pyrimidine, azole, thieno[3,2-b]pyrrole, indole, quinoline and benzoxazole) derivatives, natural products (including sanguinarine, phenolic compounds and resveratrol derivatives, flavonoids and other natural products) and others (including thiourea compounds, Fenoldopam and Raloxifene, (4-cyanophenyl)glycine derivatives, propargylamine and benzohydrazide derivatives and inhibitors discovered through AI techniques). Computational techniques, such as virtual screening, molecular docking and 3D-QSAR models, have played a pivotal role in elucidating the interactions between these inhibitors and LSD1. Moreover, the integration of cutting-edge technologies such as artificial intelligence holds promise in facilitating the discovery of novel LSD1 inhibitors. The comprehensive insights presented in this review aim to provide valuable information for advancing further research on LSD1 inhibitors.

Design, synthesis, and biological evaluation of novel napabucasin-melatonin hybrids as potent STAT3 inhibitors.

The current work developed diverse novel napabucasin-melatonin hybrids as potent STAT3 inhibitors. Several biological studies have suggested many compounds demonstrating potent inhibition against different tumor cells. Among these, compound 7e depicted enhanced inhibition against HepG2, MDA-MB-231, and A549 cells than napabucasin, with IC50 values of 1.06, 1.38, and 1.3 µM, respectively. Based on fluorescence polarization analysis, compound 7e was bound to the SH2 domain in STAT3, with an IC50 value of 12.95 µM. Molecular docking further confirmed the 7e binding mode inside the SH2 domain of STAT3. Further mechanistic studies indicated that 7e inhibited the activation of STAT3 (Y705), and thus reduced the expression of STAT3 downstream genes (CyclinD1, Bcl-2 and c-Myc) instead of affecting p-STAT1 expression. Meanwhile, the phosphorylation levels of its upstream kinases JAK2 and bypass kinase Erk1/2 remain unaffected. Simultaneously, 7e induced cancer cell apoptosis in a concentration-dependent manner. Significantly, 20 mg/kg (i.p.) compound 7e suppressed the mouse HepG2 xenograft development in vivo without body weight loss, suggesting that it could be an effective antitumor agent.

Danggui Buxue decoction alleviates cyclophosphamide-induced myelosuppression by regulating ß-hydroxybutyric acid metabolism and suppressing oxidative stress.

CONTEXT: Danggui Buxue Decoction (DBD) is an effective complementary medicine in alleviating myelosuppression after chemotherapy (MAC). However, its mechanism of action is elusive. OBJECTIVE: To illustrate that regulating ß-hydroxybutyric acid (ß-OHB) metabolism and suppressing oxidative stress could be a potential mechanism of action for DBD in alleviating MAC. MATERIALS AND METHODS: After HPLC quantification and dose testing (3, 6 and 10 g/kg, gavage) of DBD, Sprague-Dawley rats were divided into control, cyclophosphamide (CTX) (30 mg/kg CTX for 5 days, intraperitoneal administration) and CTX + DBD groups (6 g/kg DBD for 14 days, gavage). Blood cell counts, thigh bone histological examination, ß-OHB levels, oxidative stress indices and HDAC1 activity were tested. The biological function of ß-OHB was verified in vitro (hBMSC cells were incubated in culture mediums that contained 40 µM CTX and ß-OHB in 0, 1, 2.5, 5, 10 mM) and in vivo (MAC rat model, 3 g/kg ß-OHB for 14 days, gavage). RESULTS: Rats in the CTX + DBD group showed upregulated blood cell counts (118-243%), ß-OHB levels (495 nmol/mL in blood, 122 nmol/mg in marrow supernatant) and downregulated HDAC1 activity (59%), and oxidative stress indices (60-85%). In vitro, 5 mM ß-OHB improved hBMSC cell migration (123%) and proliferation (131%). In vivo, rats treated with 3 g/kg ß-OHB showed upregulated blood cell counts (121-182%) and downregulated HDAC1 activity (64%) and oxidative stress indices (65-83%). DISCUSSION AND CONCLUSIONS: DBD, a traditional Chinese medicine, alleviates MAC by intervening in ß-OHB metabolism and oxidative stress.

[Discussion on the biological basis of chronic prostatitis based on the "brain-centre-kidney-vessel" axis].

Chronic prostatitis is a common disease in male clinics. The theory of "brain-centre-kidney-vessel" axisis based on the basic theories of traditional Chinese medicine, the pathogenesis of modern men's diseases, and the theory of traditional Chinese medicine in men's medicine proposed by clinical practice. It takes the "brain-heart-kidney-vessel" axis as the entry point, the use of the vessel as the core pathogenesis, the meridians as the link, and the dysfunction of the brain, heart, and kidneys as the important conditions, and proposes that the biological basis between chronic prostatitis and the "brain-heart-kidney-vessel" axis is related to neurological, endocrine, and immunological disorders, as well as the biological basis of the "brain-heart-kidney-vessel" axis. It is also suggested that the biological basis between chronic prostatitis and the "brain-heart-kidney-sperm chamber" axis is related to the nerves, endocrine, immune and microenvironment. Through in-depth study of the biological basis of the "brain-cardiac-kidney-peritoneum" axis, we can better understand the pathogenesis of chronic prostatitis and provide reference for future clinical treatment.

Recent advances in 3-aminoindazoles as versatile synthons for the synthesis of nitrogen heterocycles.

Nitrogen-based heterocycles are an important class of structural scaffolds distributed in biologically active natural products, medicinal chemistry, and agrochemicals. Hence, there is increasing interest in the development of novel synthetic strategies for the construction of these privileged structural motifs. Recently, 3-aminoindazoles have emerged as versatile synthons participating in a variety of condensation annulation, denitrogenative transannulation and rearrangement ring expansion reactions, which provide efficient synthetic routes for the formation of nitrogen heterocycles. This review systematically highlights for the first time the most recent advances in 3-aminoindazoles to provide a deep understanding of using 3-aminoindazoles as versatile synthons in organic transformations for synthetic and medicinal chemists.

Quality assessment and relevant clinical impact of randomized controlled trials on chronic prostatitis/chronic pelvic pain syndrome.

OBJECTIVE: This study evaluated the quality of randomized controlled trials (RCTs) on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: We searched PubMed, Web of Science, and Embase for RCTs (original articles) on CP/CPPS published from database establishment to 2021. The RCT quality assessment was performed using the Consolidated Standards of Reporting of Trials (CONSORT) statement and the improved Jadad scale. RESULTS: In total, 77 RCTs were included. According to the evaluation, 26 (33.77%) papers presented the description of the specific random methods, only 6 (7.79%) papers described the allocation concealment methods, and 26 (33.77%) articles referred to the "blind method". Of the RCTs, 34 (44.16%) papers recorded the number of patients who withdrew from the study, and 67 (87.01%) papers reported adverse reactions. However, few reports mentioned the sample size calculation, clinical trial registration, or information about the relevant research programs and funding. In addition, 19 (24.68%) reports had Jadad scale scores of ≥ 4 points, and 58 (75.32%) reports had Jadad scale scores of ≤ 3 points. CONCLUSION: To date, the quality of RCT reports on CP/CPPS needs to be further improved, and the results of the RCTs should be accepted and utilized cautiously. It is suggested that researchers should follow the CONSORT statement and the improved Jadad scale to standardize the design and implementation of RCTs to improve the quality of RCTs and provide reliable evidence for the treatment of CP/CPPS.

Reasons and treatment strategy for discontinuation of dapoxetine treatment in premature ejaculation patients in China: A retrospective observational study.

To assess dapoxetine discontinuation rates and the reasons for discontinuation in Chinese men with premature ejaculation (PE). Information on 906 PE outpatients was obtained from the hospital information system (HIS) in 2019. Of these, 150 patients were chosen. We analysed the dapoxetine discontinuation rate and the reasons for discontinuation over a 12-week follow-up period. The mean age of all patients was 33.6 years (range = 18-55), the mean PE duration was 12.36 ± 9.45 months. The 5-item International Index of Erectile Function (IIEF-5) score was 21.51 ± 3.80. A total of 37.3% of all the patients remained on the treatment until the 12th week. The cumulative discontinuation rates at the 4th, 8th and 12th weeks were 12%, 41.3% and 62.7%, respectively. The discontinuation rates for all the patients in weeks 0-4, weeks 4-8 and weeks 8-12 were 19.1%, 46.8% and 34.0%, respectively. After 4 weeks, the discontinuation rates dropped sharply. The reasons for patients' discontinuation were as follows: overexpectation of efficacy (30.9%), relapsing after drug withdrawal (26.6%), high cost (25.5%), side effects (9.6%), fear of drug addiction (4.3%), failure of follow-up (2.1%) and choosing other treatments (1.1%). The dapoxetine treatment discontinuation rate was very high. The main reasons for discontinuation were overexpectation of efficacy and high cost.

Design Two Novel Tetrahydroquinoline Derivatives against Anticancer Target LSD1 with 3D-QSAR Model and Molecular Simulation.

Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which is a significant target for anticancer drug research. In this work, 40 reported tetrahydroquinoline-derivative inhibitors targeting LSD1 were studied to establish the three-dimensional quantitative structure-activity relationship (3D-QSAR). The established models CoMFA (Comparative Molecular Field Analysis (q2 = 0.778, Rpred2 = 0.709)) and CoMSIA (Comparative Molecular Similarity Index Analysis (q2 = 0.764, Rpred2 = 0.713)) yielded good statistical and predictive properties. Based on the corresponding contour maps, seven novel tetrahydroquinoline derivatives were designed. For more information, three of the compounds (D1, D4, and Z17) and the template molecule 18x were explored with molecular dynamics simulations, binding free energy calculations by MM/PBSA method as well as the ADME (absorption, distribution, metabolism, and excretion) prediction. The results suggested that D1, D4, and Z17 performed better than template molecule 18x due to the introduction of the amino and hydrophobic groups, especially for the D1 and D4, which will provide guidance for the design of LSD1 inhibitors.

[Biological basis of oligoasthenospermia based on the theory of "kidney governing reproduction"].

Guided by the theory of "kidney governing reproduction", ancient and present-day physicians treat male infertility mainly by tonifying the kidneys, with some innovation and development based on inheritance. Relating oligoasthenospermia (OAS), the author emphasizes "the kidney as the base and the essence chamber for use", and proposes "the deficiency of kidney essence and disability of the essence chamber" as the core pathogenesis of the disease. Kidney essence deficiency is the primary cause and essence chamber disability is the main factor for the development and progression of OAS. Disorders in the reproductive microenvironment are also important causes of OAS. Studies on the biological basis of the treatment of OAS from the kidney suggest that kidney tonification has a regulatory effect on the reproductive microenvironment. A systematic investigation into the molecular mechanism of "the deficiency of kidney essence and disability of the essence chamber" in the development and pathogenesis of OAS from the perspective of the reproductive microenvironment may provide some evidence for clinical intervention in the biological basis of OAS based on the theory of "kidney governing reproduction".

[Research progress of Angelicae Sinensis Radix and predictive analysis on its quality markers].

Angelicae Sinensis Radix, as a medicinal and edible Chinese medicinal herb, is widely used in clinical practice. It is mainly cultivated in Minxian, Tanchang, Zhangxian and Weiyuan counties of Gansu province. In recent years, with the comprehensive and in-depth study of Angelicae Sinensis Radix in China and abroad, its chemical composition, pharmacological effects and application and development have attracted much attention. In this study, the chemical composition, traditional efficacy, and modern pharmacological effects of Angelicae Sinensis Radix were summarized. On this basis, combined with the core concept of quality markers(Q-markers), the Q-markers of Angelicae Sinensis Radix were discussed from the aspects of mass transfer and traceability and chemical composition specificity, availability, and measurability, which provided scientific basis for the quality evaluation of Angelicae Sinensis Radix.

Open-Air Dual-Diamination of Aromatic Aldehydes: Direct Synthesis of Azolo-Fused 1,3,5-Triazines Facilitated by Ammonium Iodide.

A new and practical protocol for the synthesis of medicinally privileged azolo[1,3,5]triazines by simply heating under air has been presented. The in situ generated N-azolo amidines from commercially available aromatic aldehydes and 3-aminoazoles with ammonium iodide undergo the second diamination to accomplish the [3 + 1 + 1 + 1] heteroannulation reaction. This convenient process is appreciated by high efficiency, broad substrate scope, gram-scale synthesis, and operational simplicity under reagent-free conditions.

Safety and efficacy of traditional Chinese medicine, Qiaoshao formula, combined with dapoxetine in the treatment of premature ejaculation: An open-label, real-life, retrospective multicentre study in Chinese men.

To evaluate the safety and efficacy of Chinese medicine, Qiaoshao formula combined with dapoxetine was used for the treatment of premature ejaculation in a real-life setting. Nine hundred and five males diagnosed with premature ejaculation were reviewed in this retrospective cohort study. We divided the patients into two groups: dapoxetine alone and Qiaoshao formula combined with dapoxetine according to actual interventions provided to patients in clinics. The perceived intravaginal ejaculation latency time and the premature ejaculation profile measures markedly improved in both groups. However, in men with severe premature ejaculation (baseline perceived intravaginal ejaculation latency time <1 min) and those with baseline age ≤30 years, the perceived intravaginal ejaculation latency time was slightly but significantly longer with combined therapy than with dapoxetine alone (p < .05). Therefore, combined therapy involving the Qiaoshao formula and dapoxetine proved to safe as well as effective for treating premature ejaculation while prolonging the perceived intravaginal ejaculation latency time, which significantly improved the overall satisfaction of the patient and likely that of the couple.

Total Synthesis, Discovery and Biological Evaluation of Daldinin A Derivatives for Improving Hyperglycemia-Induced Endothelial Cell Death.

Daldinins are a novel type of naturally occurring tricyclic heterocycles isolated from Daldinia concentrica. In this study, four daldinin A derivatives with different alkyl side chains were synthesized using the same synthetic protocol. Bioactivity tests first indicated that the daldinin A derivatives showed significant protection for endothelial cells against damage caused by high glucose. The derivative compound with three carbon atoms on the alkyl side exhibited the best effect.

[Mechanisms of Huanshao Capsules protecting the reproductive function in rats with ornidazole-induced asthenozoospermia].

OBJECTIVE: To explore the possible mechanism of Huanshao Capsules (HSC) protecting the reproductive function in rats with ornidazole-induced asthenozoospermia (AZS). METHODS: Forty SD male rats were randomly divided into four groups of equal number, blank control, AZS model control, HSC and L-carnitine (LC) intervention. The AZS model was established in the latter three groups of rats by intragastrical administration of ornidazole at 400 mg/kg/d for 28 days, and meanwhile the animals in the HSC and LC groups were treated by gavage of HSC at 0.31 g/kg/d and LC at 100 mg/kg/d, respectively. Then, all the rats were killed for examination of the LC content, sperm concentration, sperm motility and expression of OCTN2 mRNA in the epididymis and observation of the histopathological changes in the testis tissue. RESULTS: Compared with the AZS model controls, the rats in the HSC and LC groups showed significantly increased LC content (2 880.3 vs 6 366.5 and 6 934.7 mg/L, P < 0.01), sperm concentration (ï¼»34.58 ± 10.25ï¼½ vs ï¼»46.19 ± 14.23ï¼½ and ï¼»42.25 ± 6.11ï¼½ ×106/ml, P < 0.01), sperm motility (ï¼»42.59 ± 7.54ï¼½% vs ï¼»61.34 ± 7.98ï¼½% and ï¼»61.34 ± 7.98ï¼½%, P < 0.01) and expression of OCTN2 mRNA in the epididymis (26.07% vs 27.26% and 27.15%, P < 0.01). The animals of the HSC group exhibited a higher comparability than those of the LC group to the blank controls in the morphology, arrangement and activity of spermatogenic cells. CONCLUSIONS: HSC can protect the reproductive function and improve sperm concentration and motility in the model rats with ornidazole-induced AZS, which may be associated with its abilities of up-regulating the expression of OCTN2 mRNA and increasing the LC content in the epididymis.

Investigating the Binding Mode of Reversible LSD1 Inhibitors Derived from Stilbene Derivatives by 3D-QSAR, Molecular Docking, and Molecular Dynamics Simulation.

Overexpression of lysine specific demethylase 1 (LSD1) has been found in many cancers. New anticancer drugs targeting LSD1 have been designed. The research on irreversible LSD1 inhibitors has entered the clinical stage, while the research on reversible LSD1 inhibitors has progressed slowly so far. In this study, 41 stilbene derivatives were studied as reversible inhibitors by three-dimensional quantitative structure-activity relationship (3D-QSAR). Comparative molecular field analysis (CoMFA q 2 = 0.623, r 2 = 0.987, r pred 2 = 0.857) and comparative molecular similarity indices analysis (CoMSIA q 2 = 0.728, r 2 = 0.960, r pred 2 = 0.899) were used to establish the model, and the structure-activity relationship of the compounds was explained by the contour maps. The binding site was predicted by two different kinds of software, and the binding modes of the compounds were further explored. A series of key amino acids Val288, Ser289, Gly314, Thr624, Lys661 were found to play a key role in the activity of the compounds. Molecular dynamics (MD) simulations were carried out for compounds 04, 17, 21, and 35, which had different activities. The reasons for the activity differences were explained by the interaction between compounds and LSD1. The binding free energy was calculated by molecular mechanics generalized Born surface area (MM/GBSA). We hope that this research will provide valuable information for the design of new reversible LSD1 inhibitors in the future.

[Effect and safety of the Chinese medicine Qianlieshutong Capsules in the treatment of benign prostatic hyperplasia: A meta-analysis].

OBJECTIVE: To evaluate the effect and safety of Qianlieshutong Capsules (QC) in the treatment of BPH. METHODS: We searched 10 Chinese and English databases up to July 2019 for randomized controlled trials (RCT) on treatment of BPH with QC followed by a meta-analysis on the included articles using Cochrane Handbook 5.1.0 and Revman5.3 software. RESULTS: A total of 18 RCTs involving 1 802 cases of BPH were included out of the 175 articles identified. The baseline data from the RCTs were all comparable. Compared with the controls, the patients treated with QC showed a significantly higher rate of clinical effectiveness and better improvement in IPSS as well as in the maximum urinary flow rate (Qmax), postvoid residual urine (PVR) and prostate volume after 3 months of medication. No serious adverse drug events or reactions were reported. CONCLUSIONS: The existing data and methodology indicate the efficacy and safety of Qianlieshutong Capsules in the treatment of BPH, which, however, has to be further verified by more well-designed large-sample multi-center high-quality randomized controlled trials.

[Linggui Fang protects the reproductive system of asthenospermia rats: An experimental study based on the L-carnitine pathway].

OBJECTIVE: To explore the protective effect of the Chinese medicinal prescription Linggui Fang (LGF) on the reproductive system of the ornidazole-induced asthenospermia (AS) rat and its possible action mechanisms. METHODS: Forty male SD rats weighing 200－230 g were equally randomized into four groups, blank control, AS model control, LGF treatment and L-carnitine (LC) intervention. The AS models were made in the latter three groups by intragastrical administration of ornidazole at 400 mg/kg. Meanwhile, the rats in the LGF group were treated intragastrically with LGF at 17.5 g/kg, those in the LC group with LC at 100 mg/kg, and the control animals with 0.5% sodium carboxymethylcellulose (CMC-Na), all once a day for 4 successive weeks. Then, all the rats were sacrificed for examination of the semen parameters, determination of the LC content and OCTN2 mRNA expression in the epididymis and observation of the histopathological changes in the testis. RESULTS: Compared with the AS model controls, the rats in the other groups showed significantly higher percentages of progressively motile sperm and total motile sperm (P < 0.01) as well as a higher LC content in the epididymis (P < 0.01), but no statistically significant difference in sperm concentration (P > 0.05). The expression of OCTN2 mRNA was remarkably upregulated in the LGF and LC groups in comparison with that in the AS model control (P < 0.05). Compared with the rats in the blank control group, the AS model controls exhibited markedly increased morphologically abnormal seminiferous tubules, irregularly arranged, with narrowed lumens and reduced numbers of sperm and sperm cells, as well as significantly increased hollow seminiferous tubules with deficient and disorderly arranged spermatogenic cells and partial epithelial degeneration and vacuolization. Those in the LGF and LC groups, however, manifested almost normal testicular histomorphology, with basically regular arrangement of different layers of seminiferous tubules. CONCLUSIONS: ①Ornidazole induces AS in rats by reducing the LC content in the epididymis, while LGF can improve the sperm motility and testicular morphology of the rats and upregulate the expression of OCTN2 mRNA in the epididymis by increasing the LC concentration.