Umpolung Strategy for the One-Pot Synthesis of Highly Steric Bispirooxindoles via the l-Amino Acid Ester-Promoted In Situ Reduction/Nucleophilic Addition/Cyclization Cascade Reaction.

On the basis of a novel umpolung strategy, an efficient l-amino acid ester-mediated in situ reduction of 2-(2-oxoindolin-3-ylidene)malononitrile and sequential nucleophilic addition/cyclization cascade reaction is reported. Various densely substituted cyclopentene bispirooxindoles and dihydrofuran bispirooxindoles with two quaternary spirocenters were constructed in high yields (≤93%) with excellent diastereoselectivities (>20:1 dr). The method has advantages of readily available starting materials, mild reaction conditions, a one-pot process, a metal-free biomimetic reducing agent, a wide substrate scope, and operational simplicity (single filtration without column chromatography).

Pharmacological and mechanistic aspects of quercetin in osteoporosis.

Osteoporosis (OP) is a bone disease associated with increasing age. Currently, the most common medications used to treat OP are anabolic agents, anti-resorptive agents, and medications with other mechanisms of action. However, many of these medications have unfavorable adverse effects or are not intended for long-term use, potentially exerting a severe negative impact on a patient's life and career and placing a heavy burden on families and society. There is an urgent need to find new drugs that can replace these and have fewer adverse effects. Quercetin (Que) is a common flavonol in nature. Numerous studies have examined the therapeutic applications of Que. However, a comprehensive review of the anti-osteoporotic effects of Que has not yet been conducted. This review aimed to describe the recent studies on the anti-osteoporotic effects of Que, including its biological, pharmacological, pharmacokinetic, and toxicological properties. The outcomes demonstrated that Que could enhance OP by increasing osteoblast differentiation and activity and reducing osteoclast differentiation and activity via the pathways of Wnt/ß-catenin, BMP/SMAD/RUNX2, OPG/RANKL/RANK, ERK/JNK, oxidative stress, apoptosis, and transcription factors. Thus, Que is a promising novel drug for the treatment of OP.

Effects of capsaicin and dihydrocapsaicin on human and rat liver microsomal CYP450 enzyme activities in vitro and in vivo.

Capsaicin and dihydrocapsaicin, the two most abundant members of capsaicinoids in chili peppers, are widely used as food additives and for other purposes. In this study, we examined the inhibitory potentials of capsaicin and dihydrocapsaicin against CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5 activities in human liver microsomes. The effects of these two capsaicinoids on CYP450 enzymes were also evaluated in vivo in rats. The results demonstrated that capsaicin and dihydrocapsaicin moderately inhibited five isozymes (IC50) values ranging from 4.4 to 61.8 µM), with the exception of CYP2E1 (IC50 > 200 µM). Both capsaicinoids exhibited competitive, mixed, and noncompetitive inhibition on these isozymes (K (i) = 3.1 ± 0.5 - 78.6 ± 8.4 µM). Time-dependent inhibition of CYP3A4/5 by capsaicin was found. After multiple administrations of capsaicin and dihydrocapsaicin (1, 4, and 10 mg/kg) to rats, chlorzoxazone 6-hydroxylase activity and the expression of CYP2E1 were increased in liver microsomes. Our findings indicated that the possibility of food-drug interactions mediated by capsaicin and dihydrocapsaicin could not be excluded, and provided the useful information for evaluating the anticarcinogenic potentials of these two capsaicinoids.

H∞ control for singular fractional-order interval systems: The 0<α<1 case.

This paper investigates the H∞ control problems of singular fractional-order interval systems with commensurate order 0<α<1. Firstly, novel conditions for the bounded real lemma in the sense of H∞ norm for nominal singular fractional-order systems are proposed, based on which the sufficient conditions for checking the admissibility and H∞ performance of singular fractional-order interval systems are derived. Secondly, the state feedback H∞ controller synthesis for singular fractional-order interval systems is addressed and the state feedback controller is designed. Thirdly, the dynamic output feedback H∞ controller synthesis for singular fractional-order interval systems is addressed and the dynamic output feedback controller is designed. Finally, three illustrative examples are given to show the effectiveness of the proposed results.

Retraction of lumbar disc herniation achieved by noninvasive techniques: A case report.

BACKGROUND: Lumbar disc herniation (LDH) has emerged as one of the most common causes of low back pain. The routine treatment approach involves chemonucleolysis therapy, discectomy by percutaneous endoscopy, and percutaneous laser disc decompression. Unfortunately, all of these methods carry inherent risk of causing harm to the patient and, as such, there is an unmet but urgent need for an effective and safe noninvasive treatment for LDH. The purpose of this report is to describe a non-invasive method for re-absorption of LDH. CASE SUMMARY: A 34-year-old woman was admitted with a complaint of waist pain that she reported as having become acutely aggravated over the past 3 d and accompanied by discomfort in the right lower limb. Her self-reported medical history included persistent postpartum low back pain from 7 years prior. Physical exam showed positivity for neck flexion test (Lindner sign) and supine abdomen test; the straight leg-raising test showed right 60(+) and left 80(-). Findings from standard imaging (magnetic resonance) and collective physical examinations indicated a L5/S1 herniated lumbar disc. Treatment consisted of three-dimensional (balanced regulating) spinal manipulation and acupuncture, upon which the LDH resolved by retraction. CONCLUSION: Following L5/S1 herniated lumbar disc diagnosis, three-dimensional (balanced regulating) spinal manipulation combined with acupuncture therapy is an effective treatment.

[Quantitative prediction of in vivo drug-drug interactions based on in vitro inhibition or/and induction data for CYP3A4].

Inhibition or/and induction of CYP3A4 are the major mechanisms underlying the common clinical drug-drug interactions, which has been gained attention in new drug discovery and development as well as clinical practice. Quantitative prediction of drug-drug interactions at the early stage of drug development is advantageous for reducing the cost and duration of development and providing more information for the later clinical studies. The review summarizes the update progress on quantitative prediction of in vivo drug-drug interactions derived from models based on in vitro inhibition or/and induction for CYP3A4.

MicroRNAs Involved in the Regulation of LC-PUFA Biosynthesis in Teleosts: miR-33 Enhances LC-PUFA Biosynthesis in Siganus canaliculatus by Targeting insig1 which in Turn Upregulates srebp1.

Post-transcriptional regulatory mechanisms play important roles in the regulation of LC-PUFA biosynthesis. Our previous study revealed that miR-33 could increase the expression of fatty acyl desaturases (fads2) in the rabbitfish Siganus canaliculatus, but the specific mechanism is unknown. Here, we confirmed that miR-33 could target the 3'UTR of insulin-induced gene 1 (insig1), resulting in downregulation of its protein level in the rabbitfish hepatocyte line (SCHL). In vitro overexpression of miR-33 inhibited the mRNA level of insig1 and increased the mRNA levels of Δ6Δ5 fads2 and elovl5, as well as srebp1. In SCHL cells, proteolytic activation of sterol-regulatory-element-binding protein-1 (Srebp1) was blocked by Insig1, with overexpression of insig1 decreasing mature Srebp1 level, while inhibition of insig1 led to the opposite effect. Srebp1 could enhance the promoter activity of Δ6Δ5 fads2 and elovl5, whose expression levels decreased with knockdown of srebp1 in SCHL. Overexpression of miR-33 also resulted in a higher conversion of 18:3n-3 to 18:4n-3 and 20:5n-3 to 22:5n-3, linked to desaturation and elongation via Δ6Δ5 Fads2 and Elovl5, respectively. The results suggested that the mechanism by which miR-33 regulates LC-PUFA biosynthesis in rabbitfish is through enhancing the expression of srebp1 by targeting insig1. The findings here provide more insight to the mechanism of miRNAs involvement in the regulation of LC-PUFA biosynthesis in teleosts.