A randomized, double-blind, positive-controlled, Phase-II clinical trial to evaluate efficacy and safety of Fuke Qianjin capsule in Pakistani patients with pelvic inflammatory disease.

Ethnopharmacological relevance: Pelvic inflammatory disease (PID) is a frequently occurring gynecological disorder mainly caused by the inflammation of a woman's upper genital tract. Generally, antibiotics are used for treating PID, but prolonged use poses potential risks of gut bacterial imbalance, bacterial resistance, super bacteria production, and associated adverse reactions. Traditional Chinese medicine (TCM) has shown unique advantages in various ailments and has received widespread clinical research attention. Fuke Qianjin (FUKE) capsule is an approved National Medical Products Administration (NMPA License No. Z20020024) Chinese herbal prescription that has been widely used individually or in combination with other Western medicines for the treatment of various gynecological inflammatory diseases, including chronic cervicitis, endometritis, and chronic PID. Aim: This clinical trial was designed to assess the safety and efficacy of FUKE capsule in mild-to-moderate symptomatic PID patients. Materials and methods: This phase 2, randomized, double-blind, positive controlled clinical trial was conducted in mild-to-moderate symptomatic PID patients at a single center in Pakistan from 21 September 2021 to 11 March 2022. Eligible female participants were randomly assigned to a test and a control group with a ratio of 1:1. The test group subjects received two metronidazole (METRO) tablets and one doxycycline hyclate (DOXY) simulant at a time, twice daily for 14 days, and two Fuke Qianjin (FUKE) capsules, three times a day after a meal for 28 days. Subjects in the control group received two METRO tablets and one DOXY tablet at a time, twice daily for 14 days, and two FUKE simulant capsules, three times a day after meal for 28 days. The primary efficacy outcome was an improvement in pelvic pain symptoms assessed through a visual analog scale (VAS). The secondary outcomes were the improvement in secondary efficacy symptoms like local physical signs, clinical assessment of leucorrhea and cervical secretions through laboratory examination, and improvement in the maximum area of pelvic effusion assessed through gynecological ultrasound after the treatment. The safety outcomes were assessed through vital signs, laboratory tests, electrocardiogram findings, and adverse events/serious adverse events. Results: A total of 198 subjects with active PID were randomly assigned to a test group (n = 99) and a control group (n = 99). The baseline characteristics of the subjects in the two groups were similar. In the intention-to-treat analysis, the primary efficacy was 84.9% for the test group and 71.6% for the control group, with a statistically significant difference (p = 0.0370; 95% CI -0.2568 to -0.0088). The secondary clinical efficacy was 88.4% for the test group and 82.7% for the control group, with no significant difference (p = 0.2977; 95% CI -0.1632 to 0.0501). The improvement in local physical signs was 95.8% for the test group and 76.9% for the control group, with no significant difference (p = 0.0542; 95% CI -0.3697 to -0.0085). The inter-group non-inferiority comparison showed that the upper limit of the 95% CI was less than 0.15 and thus met the non-inferiority requirements of the test group to the control group. The results of clinical signs of leucorrhea and cervical secretions showed that there was no difference in the rate of improvement between the test and control groups, indicating that FUKE was non-inferior to DOXY. A total of 14 adverse events in eight subjects were observed in the trial, with an incidence rate of 4.7%. Four subjects in each group experienced seven adverse events with 4.5% and 4.8% incidence rates of adverse reactions in the test and control groups, with no statistically significant differences (p = 0.2001). No serious adverse events occurred in the trial. Conclusion: The results of this trial indicate that the test drug (Fuke Qianjin capsule) is non-inferior to the control drug (doxycycline hyclate tablet) in treating mild-to-moderate PID patients with comparable efficacy, safety, and tolerability to the control drug. Clinical Trial Registration: www.clinicaltrials.gov, identifier NCT04723069.

A novel Apigenin derivative suppresses renal cell carcinoma via directly inhibiting wild-type and mutant MET.

MET, the receptor of hepatocyte growth factor (HGF), is a driving factor in renal cell carcinoma (RCC) and also a proven drug target for cancer treatment. To improve the activity and to investigate the mechanisms of action of Apigenin (APG), novel derivatives of APG with improved properties were synthesized and their activities against Caki-1 human renal cancer cell line were evaluated. It was found that compound 15e exhibited excellent potency against the growth of multiple RCC cell lines including Caki-1, Caki-2 and ACHN and is superior to APG and Crizotinib. Subsequent investigations demonstrated that compound 15e can inhibit Caki-1 cell proliferation, migration and invasion. Mechanistically, 15e directly targeted the MET kinase domain, decreased its auto-phosphorylation at Y1234/Y1235 and inhibited its kinase activity and downstream signaling. Importantly, 15e had inhibitory activity against mutant MET V1238I and Y1248H which were resistant to approved MET inhibitors Cabozantinib, Crizotinib or Capmatinib. In vivo tumor graft study confirmed that 15e repressed RCC growth through inhibition of MET activation. These results indicate that compound 15e has the potential to be developed as a treatment for RCC, and especially against drug-resistant MET mutations.

Eucalyptal D Enhances the Antifungal Effect of Fluconazole on Fluconazole-Resistant Candida albicans by Competitively Inhibiting Efflux Pump.

The frequent emergence of azole-resistant strains has increasingly led azoles to fail in treating candidiasis. Combination with other drugs is a good option to effectively reduce or retard its incidence of resistance. Natural products are a promising synergist source to assist azoles in treating resistant candidiasis. Eucalyptal D (ED), a formyl-phloroglucinol meroterpenoid, is one of the natural synergists, which could significantly enhance the anticandidal activity of fluconazole (FLC) in treating FLC resistant C. albicans. The checkerboard microdilution assay showed their synergistic effect. The agar disk diffusion test illustrated the key role of ED in synergy. The rhodamine 6G (R6G) efflux assay reflected ED could reduce drug efflux, but quantitative reverse transcription PCR analysis revealed the upregulation of CDR1 and CDR2 genes in ED treating group. Efflux pump-deficient strains were hyper-susceptible to ED, thus ED was speculated to be the substrate of efflux pump Cdr1p and Cdr2p to competitively inhibit the excretion of FLC or R6G, which mainly contributed to its synergistic effect.

Twelve formyl phloroglucinol meroterpenoids from the leaves of Eucalyptus robusta.

Twelve formyl phloroglucinol meroterpenoids (FPMs) were isolated from the leaves of Eucalyptus robusta Smith. Their structures were elucidated via spectroscopic data analysis, the circular dichroism (CD) exciton chirality method, Rh2(OCOCF3)4-induced CD experiments, and application of the Snatzke chirality rules. Eucalrobusones Q, S, and X are the first FPMs that have been identified in which the C-7' of phloroglucinol is linked to the C-15 of cadinane, the C-4 of cubebane, and the C-8 of menthane, respectively. (+)-Eucalrobusone X exhibited the most potent antifungal ability against Candida albicans with a MIC50 value of 10.78 µg/mL, and eucalrobusone U exhibited the greatest anti-C. glabrata activity with MIC50 value of 1.53 µg/mL.

Sublimable cationic iridium(iii) complexes with large steric hindrance for high-performance organic light-emitting diodes.

A series of novel sublimable cationic iridium(iii) complexes with 2-phenylquinoline as the major cyclometalated ligand and imidazole-type ancillary ligands were designed and synthesized. It is found that complexes containing active hydrogen atoms in the ancillary ligands exhibited poor electroluminescence performance. By introducing a phenyl group into the ancillary ligands to protect the active hydrogen atoms and simultaneously increase the steric hindrance of complexes, the device performance was drastically improved, due to the reduced negative effects of the active hydrogen atoms and the decreased intermolecular interaction and aggregation. We obtained high efficiency devices with a superior external quantum efficiency of 14.7%, high brightness, a low turn-on voltage of only 2.4 V and low efficiency roll-off at high luminance, the best results for yellow OLEDs based on sublimable cationic iridium(iii) complexes.

Controlling Ion Distribution for High-Performance Organic Light-Emitting Diodes Based on Sublimable Cationic Iridium(III) Complexes.

Sublimable charged iridium(III) complexes are becoming an attractive family of new phosphors and making their way into vacuum-evaporated-deposited organic light-emitting diodes, while it remains challenging to achieve high device performance. Here, we demonstrate a substantial mitigation of exciton quenching not only by reducing the dopant concentration, but also by controlling the ion distribution in the emissive material layers. We, therefore, achieved green luminescence with high brightness, superior efficiencies, and low driving voltages. Following this strategy, we further developed another six sublimable charged iridium(III) complexes and attained blue-green, yellow, and red-emitting devices with record-high performance. This study represents an important advance in the construction of bright electroluminescence from ionic transition metal complexes and shows their great promise in various optoelectronic applications.

Hypoxia-Protective Azaphilone Adducts from Peyronellaea glomerata.

Peyronellones A and B (1 and 2), a pair of rare tetracyclic caged adducts of azaphilone with pyruvic acid, along with four new analogues (3-6), were isolated from solid cultures of the endophytic fungus Peyronellaea glomerata. Their structures were elucidated through spectroscopic analysis, and their absolute configurations were unambiguously determined by a combination of single-crystal X-ray crystallography, Rh2(OCOCF3)4-induced ECD experiments, ECD calculations, and modified Mosher methods. Compound 2 (5 µM) was found to have a significant hypoxia-protective effect that improved the survival rate of hypoxia/reoxygenation-treated human umbilical vein endothelial cells from 35% to 70%, which was equal to the potency of the positive control, verapamil. Flow cytometry analysis suggested 2 could inhibit H/R-induced late-stage apoptosis of this cell line.

Toward High-Performance Vacuum-Deposited OLEDs: Sublimable Cationic Iridium(III) Complexes with Yellow and Orange Electroluminescence.

Great advances in the development of efficient luminescent materials are the driving force behind organic light-emitting diodes (OLEDs). Sublimable ionic transition-metal complexes (iTMCs) have emerged as a large family of new emissive dopants applied for vacuum-deposited OLEDs, while the achievement of excellent performance remains arduous. A series of novel sublimable cationic iridium(III) complexes have been designed and synthesized, containing an imidazole-type ancillary ligand and tetraphenylborate-type negative counter-ions with large steric hindrance and well-dispersed charges. The photophysical properties, electrochemical behaviors, and thermal stability are fully investigated and discussed, then demonstrated by theoretical calculations. Yellow- and orange-emitting OLEDs thereof are fabricated by vacuum evaporation deposition, realizing a high external quantum efficiency of up to 11 %, maximum brightness over 27.3×103  cd m-2 and low turn-on voltages below 2.4 V, among the best results of analogous phosphorescent OLEDs based on iTMCs. This work indicates the promising applications of sublimable iTMCs in state-of-the-art vacuum-deposited optoelectronic devices.

Physakengoses K-Q, seven new sucrose esters from Physalis alkekengi var. franchetii.

Seven sucrose esters, physakengoses K-Q (1-7) were isolated from the aerial parts of Physalis alkekengi var. franchetii. Their structures were elucidated on the basis of extensive spectroscopic analyses and chemical methods. These new compounds were tested for their antimicrobial abilities against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Escherichia coli. Among the isolated sucrose esters, compounds 1-5 showed potent antibacterial activity with MIC values ranging from 2.16 to 12.76 µg/mL.

Isocoumarin derivatives from the endophytic fungus, Pestalotiopsis sp.

Five new isocoumarin derivatives, pestalactone A-C (1-3) and pestapyrone D-E (4-5), together with two known compounds (6-7) were isolated from the solid cultures of the endophytic fungus Pestalotiopsis sp. obtained from Photinia frasery. Their structures were mainly determined by extensive spectroscopic analysis, Mo2(OCOCH3)4-induced electronic circular dichroism (ECD), and ECD calculation. Compounds 1 and 2 were rare isocoumarin derivatives and derived from distinctive polyketide pathways. Compound 3 exhibited potent antifungal activity against Candida glabrata (ATCC 90030) with an MIC50 value of 3.49±0.21µg/mL.

In Vitro Antibiofilm Activity of Eucarobustol E against Candida albicans.

Formyl-phloroglucinol meroterpenoids (FPMs) are important types of natural products with various bioactivities. Our antifungal susceptibility assay showed that one of the Eucalyptus robusta-derived FPMs, eucarobustol E (EE), exerted a strong inhibitory effect against Candida albicans biofilms at a concentration of 16 µg/ml. EE was found to block the yeast-to-hypha transition and reduce the cellular surface hydrophobicity of the biofilm cells. RNA sequencing and real-time reverse transcription-PCR analysis showed that exposure to 16 µg/ml of EE resulted in marked reductions in the levels of expressions of genes involved in hyphal growth (EFG1, CPH1, TEC1, EED1, UME6, and HGC1) and cell surface protein genes (ALS3, HWP1, and SAP5). Interestingly, in response to EE, genes involved in ergosterol biosynthesis were downregulated, while the farnesol-encoding gene (DPP3) was upregulated, and these findings were in agreement with those from the quantification of ergosterol and farnesol. Combined with the obvious elevation of negative regulator genes (TUP1, NRG1), we speculated that EE's inhibition of carbon flow to ergosterol triggered the mechanisms of the negative regulation of hyphal growth and eventually led to biofilm inhibition.

New phenalenone derivatives from Pinellia ternata tubers derived Aspergillus sp.

Nine new phenalenone derivatives (1-9), along with two known analogues (10-11) have been isolated from the solid cultures of an endophytic fungus Aspergillus sp. which was obtained from Pinellia ternate. Their structures were established through interpretations of spectroscopic evidence, and some of their absolute configurations were determined by electronic circular dichroism (ECD) and Mo2(OCOCH3)4 induced ECD. All of the phenalenones are unusual acyclic diterpenoid adducts, which are diversely oxidized and partly epoxidized to form different heterocycles. In addition, compound 10 exhibited significant antimicrobial activity against Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis with MIC50 values of 1.87, 2.77, and 4.80µg/mL, respectively.

Two new compounds from the green peel of Juglans mandshurica.

A new cyclic diarylheptanoid (1) and a new flavone glucoside (2), along with seven known compounds, were isolated from the green peel of Juglans mandshurica. Their structures were elucidated based on extensive spectroscopic analyses. Moreover, the cytotoxicity against NCI-H460, A549, and K562 cancer cells of compounds 1-6 was evaluated. The results showed that compound 3 exhibited moderate inhibitory potency against the growth of three cell lines.

Antimicrobial metabolites from the plant endophytic fungus Penicillium sp.

Five rare dichloro aromatic polyketides (1-5) were obtained from an endophytic fungus Penicillium sp., along with five known metabolites (6-10). Their structures were elucidated by extensive spectroscopic analysis, Mosher methods, as well as [Rh2(OCOCF3)4]-induced electronic circular dichroism (ECD) experiments. Compounds 2-4 and 6 structurally involved acyclic 1.3-diols, the uneasy configuration determinations of which were well carried out by double-derivation NMR methods. Compounds 1-10 were evaluated for their antibacterial and antifungal activities against five strains of human pathogenic microorganisms. Helvolic acid (7) showed potent inhibitory effects against Staphylococcus aureus and Pseudomonas aeruginosa with MIC (minimum inhibitory concentration) values of 5.8 and 4.6µg/mL, respectively.

New Formyl Phloroglucinol Meroterpenoids from the Leaves of Eucalyptus robusta.

Seven new formyl phloroglucinol meroterpenoids (FPMs), namely eucalrobusones J-P (1-7), as well as three known ones (8-10) were isolated from the leaves of Eucalyptus robusta. Their structures were elucidated by spectroscopic data analysis, and their absolute configurations were determined by applications of the Snatzke's helicity rule and the electron circular dichroism (ECD) calculation. These FPMs are diverse in coupling patterns between phloroglucinol and sesquiterpenoid units, forming novel polycyclic ring systems. Compound 1 possesses a new carbon skeleton that a 1-oxaspiro[5.6]dodecane core is formed through C-14 rather than C-4 of the aromadendrane moiety. Compound 2 features a novel 6/7/5 ring-fused 6-oxabicyclo[3.2.2]nonane skeleton. Compounds 3-5 are rare aristolane-based FPMs. By forming different oxo bridges, compound 3 is the first sample of FPM with benzo-dihydrofuran structure, and compound 4 possesses a novel 6/6/6/6/3-fused pentacyclic skeleton. Compounds 1, 6, and 8 exhibited significant antifungal activities against Candida glabrata with MIC50 values of 2.57, 1.95, and 2.49 µg/mL, respectively.

1H NMR spectroscopy-guided isolation of new sucrose esters from Physalis alkekengi var. franchetii and their antibacterial activity.

Ten new sucrose esters, physakengoses A-J (1-10), were isolated from the aerial parts of Physalis alkekengi var. franchetii under the guidance of 1H NMR spectroscopy. Their structures were determined by spectroscopic analyses (HRESIMS, 1D and 2D NMR, and ESIMS) and chemical methods. These new compounds were tested for antibacterial activities against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Escherichia coli. Among them, compounds 2 and 5-8 showed potent inhibitory effects against test strains with MIC values ranging from 3.5 to 14.9µg/mL. These findings may indicate that the P. alkekengi var. franchetii has potential application as an ingredient in pharmaceuticals.

New alkaloids from the leaves of Evodia rutaecarpa.

One new indole alkaloid (1) and one new indole alkaloidal glycoside (2), together with nine known alkaloids (3-11), were isolated from the leaves of Evodia rutaecarpa. Their structures were determined on the basis of spectroscopic and chemical methods. Compound 4 exhibited potent activity against Pseudomonas aeruginosa with an MIC value of 7.13 µg/ml.

Sarglaperoxides A and B, Sesquiterpene-Normonoterpene Conjugates with a Peroxide Bridge from the Seeds of Sarcandra glabra.

Sarglaperoxides A (1) and B (2), a pair of unusual sesquiterpene-normonoterpene conjugates with a peroxide bridge, were isolated from the seeds of Sarcandra glabra. The structures and absolute configurations of 1 and 2 were determined on the basis of spectroscopic data analysis, including MS, NMR, CD, and XRD. The two compounds were screened in antimicrobial, anti-inflammatory, and cytotoxic bioassays and showed moderate bioactivities.

Unciflavones A-F, six novel flavonoids from Selaginella uncinata (Desv.) Spring.

Six new flavonoids, unciflavones A-F (1-6), have been isolated from medicinal plant Selaginella uncinata (Desv.) Spring. Their structures were established on the basis of extensive NMR analysis including 1D NMR ((1)H, (13)C and DEPT) and 2D NMR (COSY, HSQC, HMBC) experiments as well as HRESIMS analysis. All compounds possess exceptional structural features with an aryl substituent at the C-8 position, which are uncommonly encountered in natural resources and firstly reported in genus Selaginella.

[Research progresses of the PARP inhibitors for the treatment of cancer].

The poly(ADP-ribose) polymerases (PARPs) is an important group of enzymes in DNA repair pathways, especially the base excision repair (BER) for DNA single-strand breaks (SSBs) repair. Inhibition of PARP in DNA repair-defective tumors (like those with BRAC1/2 mutations) can lead to cell death and genomic instability, what is so called "synthetic lethality". Currently, PARP inhibitors combined with cytotoxic chemotherapeutic agents in the treatment of BRCA-1/2 deficient cancers are in the clinical development. In this review, we will be focused on the development of combination application of PARP inhibitors with other anticancer agents in clinical trials.