A Versatile Thioesterase Involved in Dimerization during Cinnamoyl Lipid Biosynthesis.

The cinnamoyl lipid compound youssoufene A1 (1), featuring a unique dearomatic carbon-bridged dimeric skeleton, exhibits increased inhibition against multidrug resistant Enterococcus faecalis as compared to monomeric youssoufenes. However, the formation process of this intriguing dearomatization/dimerization remains unknown. In this study, an unusual "gene-within-gene" thioesterase (TE) gene ysfF was functionally characterized. The gene was found to naturally encodes two proteins, an entire YsfF with α/ß-hydrolase and 4-hydroxybenzoyl-CoA thioesterase (4-HBT)-like enzyme domains, and a nested YsfFHBT (4-HBT-like enzyme). Using an intracellular tagged carrier-protein tracking (ITCT) strategy, in vitro reconstitution and in vivo experiments, we found that: i) both domains of YsfF displayed thioesterase activities; ii) YsfF/YsfFHBT could accomplish the 6π-electrocyclic ring closure for benzene ring formation; and iii) YsfF and cyclase YsfX together were responsible for the ACP-tethered dearomatization/dimerization process, possibly through an unprecedented Michael-type addition reaction. Moreover, site-directed mutagenesis experiments demonstrated that N301, E483 and H566 of YsfF are critical residues for both the 6π-electrocyclization and dimerization processes. This study enhances our understanding of the multifunctionality of the TE protein family.

Efficient visible light-initiated hydrogenation of nitrobenzene for chemoselective production of aniline, azoxybenzene, azobenzene and hydrazobenzene over CQDs/CdS nanocomposites.

Carbon quantum dot (CQD)-decorated CdS nanocomposites were successfully fabricated via the self-assembly of CdS in the presence of preformed CQDs and were found to be efficient photocatalysts for the hydrogenation of nitrobenzene under visible light. Due to the presence of the frustrated Lewis acid-base pairs (FLPs) in their structure, CQDs act as an efficient catalyst to promote the proton-coupled hydrogenation of nitrobenzene over CQDs/CdS nanocomposites. Controllable and chemoselective hydrogenation of nitrobenzene to produce aniline, azoxybenzene, azobenzene and hydrazobenzene can be realized over CQDs/CdS via simply regulating the reaction medium including the hydrogen source, the solvent and the alkalinity. This study provides a highly efficient and economical photocatalytic system for the controllable and chemoselective hydrogenation of nitrobenzene under visible light. This work also highlights the great potential of semiconductor-based photocatalysis in light-initiated organic syntheses.

Inhibition of Ribosomal RNA Processing 15 Homolog (RRP15) Suppressed Tumor Growth, Invasion and Epithelial to Mesenchymal Transition (EMT) of Colon Cancer.

Although ribosomal RNA processing 15 Homolog (RRP15) has been implicated in the occurrence of various cancers and is considered a potential target for cancer treatment, its significance in colon cancer (CC) is unclear. Thus, this present study aims to determine RRP15 expression and biological function in CC. The results demonstrated a strong expression of RRP15 in CC compared to normal colon specimens, which was correlated with poorer overall survival (OS) and disease-free survival (DFS) of the patients. Among the nine investigated CC cell lines, RRP15 demonstrated the highest and lowest expression in HCT15 and HCT116 cells, respectively. In vitro assays demonstrated that the knockdown of RRP15 inhibited the growth, colony-forming ability and invasive ability of the CC cells whereas its overexpression enhanced the above oncogenic function. Moreover, subcutaneous tumors in nude mice showed that RRP15 knockdown inhibited the CC growth while its overexpression enhanced their growth. Additionally, the knockdown of RRP15 inhibited the epithelial-mesenchymal transition (EMT), whereas overexpression of RRP15 promoted the EMT process in CC. Collectively, inhibition of RRP15 suppressed tumor growth, invasion and EMT of CC, and might be considered a promising therapeutic target for treating CC.

Wumei Pill Ameliorates AOM/DSS-Induced Colitis-Associated Colon Cancer through Inhibition of Inflammation and Oxidative Stress by Regulating S-Adenosylhomocysteine Hydrolase- (AHCY-) Mediated Hedgehog Signaling in Mice.

Wumei Pill (WMP) is a traditional Chinese herbal formulation and widely used to treat digestive system diseases in clinical. S-Adenosylhomocysteine hydrolase (AHCY) can catalyze the hydrolysis of S-adenosylhomocysteine to adenosine and homocysteine in living organisms, and its abnormal expression is linked to the pathogenesis of many diseases including colorectal cancer (CRC). A previous study reported that WMP could prevent CRC in mice; however, the underlying mechanisms especially the roles of AHCY in WMP-induced anti-CRC remain largely unknown. Here, we investigated the regulatory roles and potential mechanisms of AHCY in WMP-induced anti-CRC. WMP notably alleviated the azoxymethane/dextran sulfate sodium- (AOM/DSS-) induced colitis-associated colon cancer (CAC) in mice. Besides, WMP inhibited the inflammation and oxidative stress in AOM/DSS-induced CAC mice. AHCY was high expression in clinical samples of colon cancer compared to the adjacent tissues. WMP inhibited the AHCY expression in AOM/DSS-induced CAC mice. An in vitro study found that AHCY overexpression induced cell proliferation, colony formation, invasion, and tumor angiogenesis, whereas its knockdown impaired its oncogenic function. AHCY overexpression enhanced, while its knockdown weakened the inflammation and oxidative stress in colon cancer cells. Interestingly, WMP potently suppressed the hedgehog (Hh) signaling in AOM/DSS-induced CAC mice. A further study showed that AHCY overexpression activated the Hh signaling while AHCY knockdown inactivated the Hh signaling. Moreover, activation of the Hh signaling reversed the effect of AHCY silencing on inflammation and oxidative stress in vitro. In conclusion, WMP alleviated the AOM/DSS-induced CAC through inhibition of inflammation and oxidative stress by regulating AHCY-mediated hedgehog signaling in mice. These findings uncovered a potential molecular mechanism underlying the anti-CAC effect of WMP and suggested WMP as a promising therapeutic candidate for CRC.

Role of curcumin in the treatment of acute kidney injury: research challenges and opportunities.

BACKGROUND: Acute kidney injury (AKI) is a common complication in clinical inpatients, and it continues a high morbidity and mortality rate despite many clinical treatment measures. AKI is triggered by infections, surgery, heavy metal exposure and drug side effects, but current chemical drugs often fall short of expectations for AKI treatment and have toxic side effects. Therefore, finding new interventions and treatments, especially of natural origin, is of remarkable clinical significance and application. The herbal monomer curcumin is a natural phenolic compound extracted from the plant Curcuma longa and showed various biological activities, including AKI. Furthermore, recent studies have shown that curcumin restores renal function by modulating the immune system and the release of inflammatory mediators, scavenging oxygen free radicals, reducing apoptosis and improving mitochondrial dynamics. However, curcumin has a low bioavailability, which limits its clinical application. For this reason, it is essential to investigate the therapeutic effects and molecular mechanisms of curcumin in AKI, as well as to improve its bioavailability for curcumin formulation development and clinical application. PURPOSE: This review summarizes the sources, pharmacokinetics, and limitations in the clinical application of curcumin and explores methods to optimize its bioavailability using nanotechnology. In particular, the therapeutic effects and molecular mechanisms of curcumin on AKI are highlighted to provide a theoretical basis for AKI treatment in clinical practices. METHODS: This review was specifically searched by means of a search of three databases (Web of Science, PubMed and Science Direct), till December 2021. Search terms were "Curcumin", "Acute kidney injury", "AKI", " Pharmacokinetics", "Mitochondria" and "Nano formulations". The retrieved data followed PRISMA criteria (preferred reporting items for systematic review) RESULTS: Studies have shown that curcumin responded to AKI-induced renal injury and restored renal tubular epithelial cell function by affecting multiple signaling pathways in AKI models induced by factors such as cisplatin, lipopolysaccharide, ischemia/reperfusion, gentamicin and potassium dichromate. Curcumin was able to affect NF-κB signaling pathway and reduce the expression of IL-1ß, IL-6, IL-8 and TNF-α, thus preventing renal inflammatory injury. In the prevention of renal tubular oxidative damage, curcumin reduced ROS production by activating the activity of Nrf2, HO-1 and PGC-1α. In addition, curcumin restored mitochondrial homeostasis by upregulating OPA1 and downregulating DRP1 expression, while reducing apoptosis by inhibiting the caspase-3 apoptotic pathway. In addition, due to the low bioavailability and poor absorption of curcumin in vivo, curcumin nanoformulations including nanoparticles, liposomes, and polymeric micelles are formulated to improve the bioavailability. CONCLUSION: This review provides new ideas for the use of curcumin in the prevention and treatment of AKI by modulating the molecular targets of several different cellular signaling pathways.

Novel 5-fluorouracil sensitizers for colorectal cancer therapy: Design and synthesis of S1P receptor 2 (S1PR2) antagonists.

Sphingosine-1-phosphate receptor 2 (S1PR2) has been identified as a brand-new GPCR target for designing antagonists to reverse 5-FU resistance. We herein report the structural optimization and structure-activity relationship of JTE-013 derivatives as S1PR2 antagonists. Compound 9d was the most potent S1PR2 antagonist (KD = 34.8 nM) among developed compounds. Here, compound 9d could significantly inhibit the expression of dihydropyrimidine dehydrogenase (DPD) to reverse 5-FU-resistance in HCT116DPD and SW620/5-FU cells. Further mechanism studies demonstrated that compound 9d not only inhibited S1PR2 but also affected the transcription of S1PR2. In addition, compound 9d also showed acceptable selectivity to normal cells (NCM460). Importantly, compound 9d with suitable pharmacokinetic properties could significantly reverse 5-FU-resistance in the HCT116DPD and SW620/5-FU xenograft models without obvious toxicity, in which the inhibition rates of 5-FU were increased from 23.97% to 65.29% and 27.23% to 60.81%, respectively. Further immunohistochemistry and western blotting analysis also demonstrated that compound 9d significantly decreases the expression of DPD in tumor and liver tissues. These results indicated that compound 9d is a promising lead compound to reverse 5-FU-resistance for colorectal cancer therapy.

One facile fluorescence strategy for sensitive determination of baicalein using trypsin-templated copper nanoclusters.

Herein, we established a fluorescent detection platform for baicalein (Bai) based on copper nanoclusters, which were prepared by using copper sulfate as the precursor, trypsin (Tryp) as the template and hydrazine hydrate as the reducing agent. The entire preparation and testing process were rapid, facile and green. Many characterization methods, such as UV-vis absorption spectroscopy, fluorescence spectroscopy, fourier transform infrared spectroscopy (FT-IR), fluorescence lifetime, transmission electron microscope (TEM) and X-ray photoelectron spectroscopy (XPS), were applied for the analysis of trypsin-templated copper nanoclusters (Cu NCs@Tryp). The Cu NCs@Tryp released green fluorescence at maximum emission wavelength of 457 nm under maximum excitation wavelength of 377 nm. More importantly, the fluorescence of Cu NCs@Tryp was efficiently quenched by Bai. According to this phenomenon, a facile, rapid and selective turn-off fluorescence probe for Bai sensing was developed. Under the optimized testing conditions, the ln(F0/F) value and concentration of Bai displayed excellent linear relationship changing from 0.5 to 60 µM (R2 = 0.9969), and the detection limit was 0.078 µM. Furthermore, the Cu NCs@Tryp has been successfully employed to measure the amount of Bai in bovine serum samples with satisfactory recoveries.

An Unusual Type II Polyketide Synthase System Involved in Cinnamoyl Lipid Biosynthesis.

As a unique structural moiety in natural products, cinnamoyl lipids (CLs), are proposed to be assembled by unusual type II polyketide synthases (PKSs). Herein, we demonstrate that the assembly of the CL compounds youssoufenes is accomplished by a PKS system that uniquely harbors three phylogenetically different ketosynthase/chain length factor (KS/CLF) complexes (YsfB/C, YsfD/E, and YsfJ/K). Through in vivo gene inactivation and in vitro reconstitution, as well as an intracellular tagged carrier-protein tracking (ITCT) strategy developed in this study, we successfully elucidated the isomerase-dependent ACP-tethered polyunsaturated chain elongation process. The three KS/CLFs were revealed to modularly assemble different parts of the youssoufene skeleton, during which benzene ring closure happens right after the formation of an ACP-tethered C18 polyene. Of note, the ITCT strategy could significantly contribute to the elucidation of other carrier-protein-dependent biosynthetic machineries.

Genetic Manipulation of an Aminotransferase Family Gene dtlA Activates Youssoufenes in Marine-Derived Streptomyces youssoufiensis.

Disruption of an aminotransferase family gene dtlA activated the production of a novel dimeric benzoic polyene acids (BPAs), named youssoufene A1 (1), along with four new (2-5, youssoufenes B1-B4) and a known (6) monomeric BPA in the marine-derived Streptomyces youssoufiensis OUC6819. The structures of 1-5 were elucidated by extensive spectroscopic and computational approaches. Youssoufene A1 (1) exhibited notably increased growth inhibition (MIC = 12.5 µg/mL) against multidrug resistant Enterococcus faecalis compared to monomeric structures (2-6).

Pharmacological Activity of Eriodictyol: The Major Natural Polyphenolic Flavanone.

Eriodictyol is a flavonoid that belongs to a subclass of flavanones and is widespread in citrus fruits, vegetables, and medicinally important plants. Eriodictyol has been anticipated to explain the method of its activity via multiple cellular signaling cascades. Eriodictyol is an effective natural drug source to maintain higher health standards due to its excellent therapeutic roles in neuroprotection, cardioprotective activity, hepatoprotective activity, antidiabetes and obesity, and skin protection and having highly analgesic, antioxidant, and anti-inflammatory effects, antipyretic and antinociceptive actions, antitumor activity, and much more. This review aims to highlight the modes of action of eriodictyol against various diseases via multiple cellular signaling pathways.

Conservation and variation in mitochondrial genomes of gastropods Oncomelania hupensis and Tricula hortensis, intermediate host snails of Schistosoma in China.

The complete mitochondrial genomes of intermediate host snails for Schistosoma in China were sequenced, including the sub-species Oncomelania hupensis hupensis in two types, and O. hupensis robertsoni, intermediate hosts for S. japonicum, and Tricula hortensis, the intermediate host of S. sinensium. Four genomes have completely the same gene order as in other caenogastropods, containing 13 protein-coding genes and 22 transfer RNAs. The gene size, start codon and termination codon are mostly the same for all protein-coding genes. However, pairwise sequence alignments revealed quite different degrees of variation. The ribbed-shelled O. hupensis hupensis and the smooth-shelled but with varix O. hupensis hupensis had a lower level of genetic distance (3.1% for protein-coding genes), but the coden usages differed obviously in the mitochondrial genomes of these two types of snails, implying that their genetic difference may be larger than previously recognized. The mean genetic distance between O. hupensis hupensis and O. hupensis robertsoni was 12% for protein-coding genes, indicating a higher degree of genetic difference. In consideration of the difference in morphology and distribution, we considered that O. hupensis hupensis and O. hupensis robertsoni can be considered as separate species. The ribbed-shelled O. hupensishupensis and smooth-shelled O. hupensis robertsoni were phylogenetically clustered together within a same clade, which was then clustered with T. hortensis, confirming their close relationship. However, species or sub-species in the Oncomelania from southeastern Asian countries should be included in future study in order to resolve the phylogenetic relationship and origination of all snails in the genus.