Human Carboxylesterase 1A Plays a Predominant Role in Hydrolysis of the Anti-Dyslipidemia Agent Fenofibrate in Humans.

Fenofibrate, a marketed peroxisome proliferator-activated receptor- (PPAR) agonist, has been widely used for treating severe hypertriglyceridemia and mixed dyslipidemia. As a canonical prodrug, fenofibrate can be rapidly hydrolyzed to release the active metabolite (fenofibric acid) in vivo, but the crucial enzyme(s) responsible for fenofibrate hydrolysis and the related hydrolytic kinetics have not been well-investigated. This study aimed to assign the key organs and crucial enzymes involved in fenofibrate hydrolysis in humans, as well as reveal the impact of fenofibrate hydrolysis on its non-PPAR-mediated biologic activities.

New bysspectin A derivatives as potent inhibitors of human carboxylesterase 2A.

Human carboxylesterase 2A (hCES2A), the most abundant carboxylesterase in the human gut, plays a crucial role in the metabolic clearance and activation of various ester-bearing drugs, environmental toxins and carcinogens. Inhibition of intestinal hCES2A can alleviate irinotecan-induced gut toxicity and modulate the oral bioavailability of hCES2A-substrate drugs. Bysspectin A, a natural product isolated from the endophytic fungus Byssochlamys spectabilis, has been identified as a highly selective hCES2A inhibitor.

Copper(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of 1,3-enynes and azomethine ylides.

Herein, we report a copper(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides and 1,3-enynes, which provides a series of chiral poly-substituted pyrrolidines in high regio-, diastereo-, and enantioselectivities. Both 4-aryl-1,3-enynes and 4-silyl-1,3-enynes serve as suitable dipolarophiles while 4-alkyl-1,3-enynes are inert. Moreover, the method is successfully applied in the construction of both tetrasubstituted stereogenic carbon centers and chiral spiro pyrrolidines.

Cobalt-Catalyzed Chemo- and Stereoselective Arylative Carbocyclization of 1,6-Allenynes.

Different from the well-investigated enynes, transition-metal-catalyzed carbocyclization reactions of allenynes are more attractive as a result of the unique structure and versatile reactivity of allenes. Herein, we report the first cobalt-catalyzed highly chemo- and stereoselective arylative carbocyclization of 1,6-allenynes with arylboronic acids, affording five-membered carbocycles and heterocycles with moderate to high yields, broad substrate scope, and wide functional group compatibility. Moreover, several mechanistic experiments were conducted to gain insight into the reaction process.

Protective effects and regulatory mechanisms of Shen-shuai-yi recipe on renal fibrosis in unilateral ureteral obstruction-induced mice.

Renal fibrosis (RF) is a common pathological feature of chronic kidney disease (CKD), which remains a major public health problem. As now, there is still lack of chemical or biological drugs to reverse RF. Shen-shuai-yi Recipe (SSYR) is a classical Chinese herbal formula for the treatment of CKD.

Huzhangqingmaiyin protected vascular endothelial cells against cerebral small vessel disease through inhibiting inflammation.

Ethnopharmacological Relevance: Huzhangqingmaiyin (HZQMY) is a Chinese medicine formula used to treat small vessel disease, but the mechanism is unclear.

Aim Of The Study: This study aimed to reveal the protective effects of HZQMY on human brain microvascular endothelial cells (HBMECs) and explore the potential targets and mechanistic pathways using network pharmacology on treating cerebral small vessel disease (CSVD).

Materials And Methods: HBMECs were cultured in vitro and an endothelial cell injury model was constructed by hypoxia for 12 h followed by reoxygenation for 8 h (H/R).

Corylifol A ameliorates muscle atrophy by inhibiting TAOK1/p38-MAPK/FoxO3 pathway in cancer cachexia.

Background: Corylifol A (CYA) is one of the main active components of Psoralea corylifolia L. CYA had been reported to have ameliorating effects on dexamethasone-induced atrophy of C2C12 mouse skeletal myotubes, but its effects on cancer cachexia were unclear. Here, we checked the influence of CYA on muscle atrophy in cancer cachexia mice and tried to clarify its mechanisms.

Molecular mechanisms of ferroptosis and its antitumor applications in natural products.

Ferroptosis, an iron-dependent form of regulated cell death, results in lipid peroxidation of polyunsaturated fatty acids in the cell membrane, which is catalyzed by iron ions and accumulated to lethal levels. It is mechanistically distinct from other forms of cell death, such as apoptosis, pyroptosis, and necroptosis, so it may address the problem of cancer resistance to apoptosis and provide new therapeutic strategies for cancer treatment, which has been intensively studied over the past few years. Notably, considerable advances have been made in the antitumor research of natural products due to their multitargets and few side effects.

Cinobufagin: a promising therapeutic agent for cancer.

Objectives: Cinobufagin is a natural active ingredient isolated from the traditional Chinese medicine Venenum Bufonis (Chinese: Chansu), which is the dried secretion of the postauricular gland or skin gland of the Bufo gargarizans Cantor or Bufo melanostictus Schneider. There is increasing evidence indicating that cinobufagin plays an important role in the treatment of cancer. This article is to review and discuss the antitumor pharmacological effects and mechanisms of cinobufagin, along with a description of its toxicity and pharmacokinetics.

Multifunctional polysaccharide nanoprobes for biological imaging.

Imaging and tracking biological targets or processes play an important role in revealing molecular mechanisms and disease states. Bioimaging via optical, nuclear, or magnetic resonance techniques enables high resolution, high sensitivity, and high depth imaging from the whole animal down to single cells via advanced functional nanoprobes. To overcome the limitations of single-modality imaging, multimodality nanoprobes have been engineered with a variety of imaging modalities and functionalities.

Licochalcone A Derivatives as Selective Dipeptidyl Peptidase 4 Inhibitors with Anti-Inflammatory Effects.

A set of 22 analogs of licochalcone A was designed and synthesized to explore their potentials as dipeptidyl peptidase 4 (DPP4) inhibitors with anti-inflammatory effects. The anti-DPP4 effects of these analogs were evaluated using the fluorescent substrate Gly-Pro--butyl-4-amino-1,8-naphthalimide (GP-BAN). The nitro-substituted analogue exhibited the most potent activity ( = 0.

Discovery of 4'-trifluoromethylchalcones as novel, potent and selective hCYP1B1 inhibitors without concomitant AhR activation.

Human cytochrome P450 1B1 (hCYP1B1), an extrahepatic cytochrome P450 enzyme over-expressed in various tumors, has been validated as a promising target for preventing and treating cancers. Herein, two series of chalcone derivatives were synthesized to discover potent hCYP1B1 inhibitors without AhR agonist effect. Structure-activity relationship (SAR) studies demonstrated that 4'-trifluoromethyl on the B-ring strongly enhanced the anti-hCYP1B1 effects, identifying A9 as a promising lead compound.

Fluoroindole chalcone analogues targeting the colchicine binding site of tubulin for colorectal oncotherapy.

Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract with high morbidity and mortality. Our previous studies have demonstrated that indole-chalcone-based compounds targeting tubulin displayed potential cytotoxicity to CRC cells. Herein, three new series of derivatives were systematically designed and synthesized to explore their structure-activity relationship (SAR) against CRC based on prior research.

Liver-targeting MRI contrast agent based on galactose functionalized o-carboxymethyl chitosan.

Commercial gadolinium (Gd)-based contrast agents (GBCAs) play important role in clinical diagnostic of hepatocellular carcinoma, but their diagnostic efficacy remained improved. As small molecules, the imaging contrast and window of GBCAs is limited by low liver targeting and retention. Herein, we developed a liver-targeting gadolinium (Ⅲ) chelated macromolecular MRI contrast agent based on galactose functionalized o-carboxymethyl chitosan, namely, CS-Ga-(Gd-DTPA), to improve hepatocyte uptake and liver retention.

FXR agonist GW4064 enhances anti-PD-L1 immunotherapy in colorectal cancer.

Colorectal cancer (CRC) is one of the top three malignant tumors in terms of morbidity, and the limited efficacy of existing therapies urges the discovery of potential treatment strategies. Immunotherapy gradually becomes a promising cancer treatment method in recent decades; however, less than 10% of CRC patients could really benefit from immunotherapy. It is pressing to explore the potential combination therapy to improve the immunotherapy efficacy in CRC patients.

Supramolecular Cyclic Dinucleotide Nanoparticles for STING-Mediated Cancer Immunotherapy.

Activation of stimulator of interferon genes (STING) can reprogram the immunosuppressive tumor microenvironment (TME) by initiating innate and adaptive immunity. As natural STING agonists, clinical translation of cyclic dinucleotides (CDNs) has been challenged by their short half-life in circulation, poor stability, and low membrane permeability. Herein, we use the natural endogenous small molecules oleic acid and deoxycytidine to construct a ligand for the STING agonist c-di-GMP (CDG), a hydrophobic nucleotide lipid (3',5'-diOA-dC), which can assemble with CDG into stable cyclic dinucleotide nanoparticles (CDG-NPs) through various supramolecular forces driven by molecular recognition.

Uncovering the active constituents and mechanisms of Rujin Jiedu powder for ameliorating LPS-induced acute lung injury using network pharmacology and experimental investigations.

Acute lung injury (ALI) is a common clinical disease with high mortality. Rujin Jiedu powder (RJJD) has been clinically utilized for the treatment of ALI in China, but the active constituents in RJJD and its protective mechanisms against ALI are still unclear. ALI mice were established by intraperitoneal injection of LPS to test the effectiveness of RJJD in treating ALI.

Discovery of anthraquinones as DPP-IV inhibitors: Structure-activity relationships and inhibitory mechanism.

Dipeptidyl peptidase IV (DPP-IV) is an integrated type II transmembrane protein that reduces endogenous insulin contents and increases plasma glucose levels by hydrolyzing glucagon-like peptide-1 (GLP-1). Inhibition of DPP-IV regulates and maintains glucose homeostasis, making it an attractive drug target for the treatment of diabetes II. Natural compounds have tremendous potential to regulate glucose metabolism.

Nanotechnology-based photo-immunotherapy: a new hope for inhibition of melanoma growth and metastasis.

Melanoma is the most aggressive form of skin cancer and there is a need for the development of effective anti-melanoma therapies as it shows high metastatic ability and low response rate. In addition, it has been identified that traditional phototherapy could trigger immunogenic cell death (ICD) to activate antitumor immune response, which could not only effectively arrest primary tumour growth, but also exhibit superior effects in terms of anti-metastasis, anti-recurrence for metastatic melanoma treatment. However, the limited tumour accumulation of photosensitizers/photothermal agents and immunosuppressive tumour microenvironment severely weaken the immune effects.

Enzyme-Based Biosensors and Their Applications.

Enzymes constitute an extremely important class of biomacromolecules with diverse catalytic functions, which have been validated as key mediators for regulating cellular metabolism and maintaining homeostasis in living organisms [...

Nature-inspired catalytic asymmetric rearrangement of cyclopropylcarbinyl cation.

In nature, cyclopropylcarbinyl cation is often involved in cationic cascade reactions catalyzed by natural enzymes to produce a great number of structurally diverse natural substances. However, mimicking this natural process with artificial organic catalysts remains a daunting challenge in synthetic chemistry. We report a small molecule-catalyzed asymmetric rearrangement of cyclopropylcarbinyl cations, leading to a series of chiral homoallylic sulfide products with good to excellent yields and enantioselectivities (up to 99% enantiomeric excess).

Xanthotoxin, a novel inducer of platelet formation, promotes thrombocytopoiesis via IL-1R1 and MEK/ERK signaling.

Background: Thrombocytopenia is a common hematological disease caused by many factors. It usually complicates critical diseases and increases morbidity and mortality. The treatment of thrombocytopenia remains a great challenge in clinical practice, however, its treatment options are limited.