The small-molecule drug homoharringtonine targets HSF1 to suppress pancreatic cancer progression.

Heat shock factor 1 (HSF1), an essential transcription factor for stress response, is exploited by various tumors to facilitate their initiation, progression, invasion, and migration. Amplification of HSF1 is widely regarded as an indicator in predicting cancer severity, the likelihood of treatment failure and reduced patient survival. Notably, HSF1 is markedly amplified in 40% of pancreatic cancer (PC), which typically have limited treatment options. HSF1 has been proven to be a promising therapeutic target for multiple cancers. However, a direct small molecule HSF1 inhibitor with sufficient bioactivity and reliable safety has not been developed clinically. In this study, we successfully established a high-throughput screening system utilizing luciferase reporter assay specifically designed for HSF1, which leads to the discovery of a potent small molecule inhibitor targeting HSF1. Homoharringtonine (HHT) selectively inhibited PC cell viability with high HSF1 expression and induced a markedly stronger tumor regression effect in the subcutaneous xenograft model than the comparator drug KRIBB11, known for its direct action on HSF1. Moreover, HHT shows promise in countering the resistance encountered with HSP90 inhibitors, which have been observed to increase heat shock response intensity in clinical trials. Mechanistically, HHT directly bound to HSF1, suppressing its expression and thereby inhibiting transcription of HSF1 target genes. In conclusion, our work presents a preclinical discovery and validation for HHT as a HSF1 inhibitor for PC treatment.

ZY-444 inhibits the growth and metastasis of prostate cancer by targeting TNFAIP3 through TNF signaling pathway.

Prostate cancer is one of the most lethal malignancies, and androgen deprivation therapy remains the mainstay of treatment for prostate cancer patients. Although androgen deprivation can initially come to remission, the disease often develops into castration-resistant prostate cancer (CRPC), which is still dependent on androgen receptor (AR) signaling and is related to a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance uninterrupted emerges, and new therapies are urgently needed. In this study, we identified a potent small molecule compound, ZY-444, that suppressed PCa cells proliferation and metastasis, and inhibited tumor growth both in subcutaneous. Transcriptome sequencing analysis showed that TNFAIP3 was significantly elevated in prostate cancer cells after ZY-444 treatment. Further studies through overexpression of TNFAIP3 confirmed that TNFAIP3, as a direct target gene of ZY-444, contributes to the functions of ZY-444. In addition, we demonstrated the effects of TNFAIP3 on prostate cancer cell apoptosis, migration and proliferation to elucidate the mechanism of ZY-444. We found that TNFAIP3 inhibited the TNF signaling pathway, which could inhibit cell migration and proliferation and contribute to apoptosis. Overall, these findings highlighted TNFAIP3 as a tumor suppressor gene in the regulation of the progression and metastatic potential of prostate cancer and that targeting TNFAIP3 by ZY-444 might be a promising strategy for prostate cancer treatment.

Synthesis and pharmacological validation of fluorescent diarylsulfonylurea analogues as NLRP3 inhibitors and imaging probes.

The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) is a key cytosolic pattern recognition receptor that senses diverse pathogen- and host-originated threat signals. Aberrant activation of NLRP3 inflammasomes is closely associated with the pathogenesis of various complex inflammatory diseases. Nevertheless, the detailed regulation mechanism of NLRP3 inflammasome and its pathogenic roles in the inflammation progression remain to be fully elucidated. Fluorescent imaging with small molecule probe can provide valuable visualization information on the expression, occupancy and bio-distribution of target protein. Herein, we reported a series of diarylsulfonylurea NLRP3 fluorescent inhibitors bearing an amino benzodiazole fluorophore. Compared to the previously reported NLRP3 fluorescent probes, these inhibitors are more structurally concise and membrane permeable due to no additionally appended fluorophore via a linker. Among this series, compound 13a exhibited the most potent cellular NLRP3 inhibitory effect with an IC50 value of 49 nM, and significantly suppressed LPS/Nigericin-induced secretion of active caspase-1 and mature IL-1ß in a dose-dependent manner to block the activation of NLRP3 inflammasome. Meanwhile, this new probe exhibited promising fluorescent properties for specifically detecting and imaging the LPS-induced or constitutively expressed NLRP3 proteins in RAW264.7 cells. Collectively, probe 13a is a potent NLRP3 fluorescent inhibitor with cellular NLRP3 imaging ability, which is useful for NLRP3 inhibitor screening and related mechanism study.

Two new sesquiterpenoid lactone derivatives from Lindera aggregata.

Two new sesquiterpenoid lactone derivatives, linderin A (1) and linderin B (2) comprising a sesquiterpenoid lactone and a methyl geranylhomogentisate moiety together with six known compounds were isolated from the roots of Lindera aggregata. Their chemical structures were elucidated using extensive spectroscopic analysis including 1 D, 2 D NMR, and HR-ESI-MS data and compared with previously reported data. The absolute configurations of 1 and 2 were assigned based on the electronic circular dichroism calculation. Compound 2 showed moderate anticoagulant activity.

Analysis of fecal microbiota in patients with functional constipation undergoing treatment with synbiotics.

This study was performed to identify changes to microbial composition after treatment with synbiotics in patients with functional constipation and to define the key microbiota in the pathogenesis of functional constipation. Fecal samples from 53 patients diagnosed with chronic functional constipation according to the Rome III criteria were analyzed using 16S rRNA sequencing. After treatment with synbiotics for 1 month, fecal samples were collected from 36 patients; after a total of 3 months, fecal samples were collected from 15 patients. The outcomes were compared with the intestinal microbiota profiles of 53 healthy community volunteers. The microbiota in the constipation group differed from that in the treatment group and healthy group. After synbiotic treatment for 1 and 3 months, the abundance of Escherichia/Shigella decreased, whereas that of Prevotella_9 and Lactococcus increased. Comparison of the microbiota among the three groups showed that Prevotella_9 was the characteristic bacteria that decreased in the constipation group and increased in the treatment group. Synbiotic treatment can improve the microbiota in patients with constipation. Identification of the key bacterial genus is important to reveal the mechanism and provide a reliable theoretical basis of synbiotic treatment. It will also promote relevant research of microbiota treatment and individualized treatments.

Extraction, preliminary characterization and evaluation of in vitro antitumor and antioxidant activities of polysaccharides from Mentha piperita.

This study describes the extraction, preliminary characterization and evaluation of the in vitro antitumor and antioxidant activities of polysaccharides extracted from Mentha piperita (MPP). The optimal parameters for the extraction of MPP were obtained by Box-Behnken experimental design and response surface methodology (RSM) at the ratio of water to raw material of 20, extraction time of 1.5 h and extraction temperature at 80 °C. Chemical composition analysis showed that MPP was mainly composed of glucuronic acid, galacturonic acid, glucose, galactose and arabinose, and the molecular weight of its two major fractions were estimated to be about 2.843 and 1.139 kDa, respectively. In vitro bioactivity experiments showed that MPP not only inhibited the growth of A549 cells but possessed potent inhibitory action against DNA topoisomerase I (topo I), and an appreciative antioxidant action as well. These results indicate that MPP may be useful for developing safe natural health products.

Bioactive saponins from the fruits of Aesculus pavia L.

Continued chemical investigation on the fruits of Aesculus pavia L. resulted in theisolation and identification of two new oleanolic acid saponins, namely vaccaroside A (1) andvaccaroside B (2). The isolated furostanol saponins were evaluated for cytotoxic activity againsthuman normal amniotic and human lung carcinoma cell lines using neutral red and MTT assays.In vitro experiments showed significant cytotoxicity in a dose dependent manner with IC50 valuesin the range of 27.80-79.02 µM.

Antifungal and cytotoxic activities of the secondary metabolites from endophytic fungus Massrison sp.

Three novel compounds with spiro-5, 6-lactone ring skeleton has been isolated from the fermentation broth of Massrison sp. which could be isolated repeatedly from wild Rehmannia glutinosa. Psetariae oryza P-2b was applied to guide fractionation of bioactive compounds produced by Massrison sp. The molecular structures were established by a variety of one- and two-dimensional NMR experiments and the compounds with similar skeleton were reported for the first time from endophytic fungi of terraneous plant. Antifungal and cytotoxic activities of the compounds were tested, compounds 2 and 3 displayed stronger antifungal and cytotoxic activities. The compounds have the potential to be antibiotic against fungal pathogens and tumor cells.

A new hepoprotective saponin from Semen Celosia cristatae.

A new triterpenoid saponin, named semenoside A (1), was isolated from Semen Celosia cristatae. Its structure was elucidated on the basis of 1D, 2D NMR, HR-FAB-MS and ESI-MS techniques, and physicochemical properties. The hepatoprotective activity of semenoside A with an oral dose of 1.0, 2.0 and 4.0mg/kg, respectively, were investigated by carbon tetrachloride (CCl(4))-induced hepatotoxicity in mice. The results indicated that it had significant hepatoprotective effects (p < 0.01).

A new active compound against kidney deficiency from the fruits of Rubus corchorifolius.

Constituents of the fruits of Rubus corchorifolius were investigated. A new compound, namely rubusin A (1), along with three known compounds, was isolated and characterized. Among them, the new compound exhibited significant activity against kidney deficiency, and quercetin and kaempferol were isolated from the fruits of R. corchorifolius for the first time.

Two new compounds from Semen celosiae and their protective effects against CCl4-induced hepatotoxicity.

Two new oleanolic acid saponins, namely celosin A (1) and celosin B (2), together with six known compounds, stigmasterol, ß-sitosterol, ß-daucosterol, hexacosoic acid, palmitic acid and stearic acid, were isolated from the ethanolic extract of Semen celosiae. The structures of celosin A (1) and celosin B (2) were determined by spectral analysis (including 1D- and 2D-NMR). The hepatoprotective activity of 1 and 2 with oral doses 1.0, 2.0 and 4.0 mg kg⁻¹ were investigated by carbon tetrachloride CCl4-induced hepatotoxicity in mice. The results indicate that they have significant hepatoprotective effects, and that these hepatoprotective effects may be due to the antioxidant capability.

A new neuroprotective bakkenolide from the rhizome of Peatasites tatewakianus.

Constituents of the fruits of Peatasites tatewakianus were investigated. A new compound, namely bakkenolide-VI (1), was isolated. The structures was elucidated on the basis of 1D, 2D NMR, TOF-MS and ESI-MS techniques, and physicochemical properties. The neuroprotective activity of the new compound was assayed with primary cultured neurons exposed to oxygen-glucose deprivation and oxidative insults.

Two new hepaprotective saponins from Semen celosiae.

Two new oleanolic acid saponins, namely celosin C (1) and celosin D (2), were isolated from the ethanol extract of Semen celosiae. Their structures were identified as celosin C (1) and celosin D (2) by spectroscopic and chemical analyses. The hepatoprotective activity of 1 and 2 with oral dose 1.0, 2.0 and 4.0 mg/kg, respectively, were investigated by carbon tetrachloride (CCl(4))-induced hepatotoxicity in mice. The results indicate that they have significant hepatoprotective effects (p<0.01).