Efficacy of Warm Acupuncture Therapy Combined with Kegel Exercise on Postpartum Pelvic Floor Dysfunction in Women.

INTRODUCTION AND HYPOTHESIS: The objective was to observe the clinical efficacy of warm acupuncture combined with Kegel exercise in treating postpartum pelvic floor dysfunction in women. METHODS: A total of 70 primiparous women with postpartum pelvic floor muscle (PFM) injury were randomly divided into a combination group (n = 35, receiving warm acupuncture at Zhibian (BL54) acupoint and Kegel exercise) and a sham control group (n = 35, receiving sham warm acupuncture and Kegel exercise). Both groups were treated three times a week for 4 consecutive weeks. The recovery of PFM strength and changes in Urethral Rotation Angle (URA), Bladder Neck Descent (BND), and Retrovesical Angle (RVA) in pelvic floor ultrasound reports, the scores of pelvic floor dysfunction-related questionnaires, and the efficacy of urinary incontinence treatment of the two groups were compared before and after treatment. RESULTS: After treatment, the recovery rates of type I and II PFM strength, pelvic floor ultrasound parameters, pelvic floor dysfunction-related scale scores, and urinary incontinence treatment efficacy in the combination group were significantly better than those in the sham control group (p < 0.05). CONCLUSION: Warm acupuncture combined with Kegel exercise can significantly improve PFM strength and promote the recovery of postpartum pelvic floor function in women.

Association between nineteen dietary fatty acids and hearing thresholds: findings from a nationwide survey.

INTRODUCTION: Hearing loss is a prevalent health concern, and dietary factors, such as fatty acid intake, may play a role in its development. The current study aimed to investigate the association between the intake of dietary fatty acids and hearing thresholds among U.S. adults. METHODS: The researchers examined data from the National Health and Nutrition Examination Survey (NHANES), including 7,623 participants with available dietary fatty acid intake and audiometry data. Dietary fatty acid intake was assessed using dietary recalls, and hearing thresholds were measured using pure-tone audiometry. Multivariate linear regression models and smoothing curve fitting were utilized to explore the associations between dietary fatty acid intake and hearing thresholds, adjusting for relevant covariates. RESULTS: This study reveals a direct association between both low and high frequency pure tone average (PTA) hearing thresholds and the dietary intake of total saturated fatty acids (SFAs) and total polyunsaturated fatty acids (PUFAs). Conversely, the intake of total monounsaturated fatty acids (MUFAs) demonstrates an inverted U-shaped correlation with low-frequency and high-frequency PTA hearing thresholds, having inflection points at 11.91 (energy (%)) and 10.88 (energy (%)), respectively. CONCLUSION: Dietary intake of certain fatty acids may influence hearing thresholds in adults.

A comprehensive review on ß-lapachone: Mechanisms, structural modifications, and therapeutic potentials.

ß-Lapachone (ß-lap, 1), an ortho-naphthoquinone natural product isolated from the lapacho tree (Tabebuia avellanedae) in many regions of South America, has received extensive attention due to various pharmacological activities, such as antitumor, anti-Trypanosoma cruzi, anti-Mycobacterium tuberculosis, antibacterial, and antimalarial activities. Related mechanisms of ß-lap have been widely investigated for a full understanding of its therapeutic potentials. Numerous derivatives of ß-lap have been reported with aims to generate new chemical entities, improve the corresponding biological potency, and overcome disadvantages of its physical and chemical properties and safety profiles. This review will give insight into the pharmacological mechanisms of ß-lap and provide a comprehensive understanding of its structural modifications with regard to different therapeutic potentials. The available clinical trials related to ß-lap and its derivatives are also summarized.

Discovery of Clinical Candidate (5-(3-(4-Chlorophenoxy)prop-1-yn-1-yl)-3-hydroxypicolinoyl)glycine, an Orally Bioavailable Prolyl Hydroxylase Inhibitor for the Treatment of Anemia.

The design and discovery of a new series of (5-alkynyl-3-hydroxypicolinoyl)glycine inhibitors of prolyl hydroxylase (PHD) are described. These compounds showed potent in vitro inhibitory activity toward PHD2 in a fluorescence polarization-based assay. Remarkably, oral administration of 17, with an IC50 of 64.2 nM toward PHD2, was found to stabilize HIF-α, elevate erythropoietin (EPO), and alleviate anemia in a cisplatin-induced anemia mouse model with an oral dose of 25 mg/kg. Rat and dog studies showed that 17 has good pharmacokinetic properties, with oral bioavailabilities of 55.7 and 54.0%, respectively, and shows excellent safety profiles even at a high dose of 200 mg/kg in these animals. Based on these results, 17 is currently being evaluated in a phase I clinical trial for anemia.

Discovery of prolyl hydroxylase 2 inhibitors with new chemical scaffolds as in vivo active erythropoietin inducers through a combined virtual screening strategy.

Hypoxia-inducible factor (HIF) is identified to be a promising target to mediate the response to hypoxia. Its stability and activation are negatively controlled by prolyl hydroxylase 2 (PHD2). Thus, PHD2 inhibition has been perceived as a promising anti-anemia therapy. In this study, we carried out a structure-based virtual screening followed by in vitro and in vivo biological validation, with the goal to identify novel PHD2 inhibitors. As a result, a set of hits with new chemical scaffolds were revealed to be active in vitro for PHD2 inhibition. Compounds 2 and 3 were revealed to be capable of stabilizing HIF-α and stimulating erythropoietin (EPO) expression in cell-based assays. Notably, further in vivo assays revealed that 2 was capable of elevating the EPO plasma levels in C57BL/6 mice model. These findings provide new chemical scaffolds for further development of PHD2 inhibitors.

Carbon dots as an "on-off-on" fluorescent probe for detection of Cu(II) ion, ascorbic acid, and acid phosphatase.

Carbon dot (CD)-based fluorescent probes have been widely exploited; however, multi-component detection using CDs without tedious surface modification is always a challenging task. Here, we develop a convenient and simple CD-based "on-off-on" fluorescent probe for detection of copper(II) ion (Cu2+), ascorbic acid (AA), and acid phosphatase (ACP). Cu2+ leads to the fluorescence quenching of CDs. The limit of detection (LOD) for Cu2+ is 2.4 µM. When AA is added into the CDs + Cu2+ solution, Cu2+ is reduced by AA to Cu+, causing the fluorescence recovery of CDs. The fluorescent intensity linearly correlates with the concentration of AA in the range of 100-2800 µM with LOD of 60 µM. Besides, the probe has potential application for detection of AA in real samples such as VC tablets, orange juice, and fresh orange. The probe can also indirectly detect ACP that enzymatically hydrolyzes ascorbic acid-phosphate (AAP) to produce AA. This work expands the application of CDs in the multi-component detection and provides a facile fluorescent probe for detection of AA in real samples. Graphical abstract.

Application of in-vitro screening methods on hypoxia inducible factor prolyl hydroxylase inhibitors.

Anemia resulting from the reduced expression of erythropoietin (EPO) is a common complication of patients with chronic kidney diseases (CKD). Hypoxia inducible transcription factor-α (HIF-α), which adapts cellular hypoxia condition, regulates the expression of many downstream genes including the EPO gene. Hypoxia inducible transcription factor prolyl hydroxylase 2 (HIF-PHD2), as the key regulator of hypoxia response, is function of hydroxylating specify proline residues of HIF-α, which may lead to the degradation of HIF-α and eventually cause disenabling the expression of erythropoietin. Therefore, it is valid to improve anemia by inhibiting HIF-PHD2. In-vitro screening plays a vital role in searching for novel small molecule HIF-PHD2 inhibitors, thus, this review classified in-vitro screening methods which are used to hit novel HIF-PHD2 inhibitors.

Discovery, design and synthesis of 6H-anthra[1,9-cd]isoxazol-6-one scaffold as G9a inhibitor through a combination of shape-based virtual screening and structure-based molecular modification.

Protein lysine methyltransferase G9a is widely considered as an appealing antineoplastic target. Herein we present an integrated workflow combining shape-based virtual screening and structure-based molecular modification for the identification of novel G9a inhibitors. The shape-based similarity screening through ROCS overlay on the basis of the structure of UNC0638 was performed to identify CPUY074001 contained a 6H-anthra[1,9-cd]isoxazol-6-one scaffold as a hit. Analysis of the binding mode of CPUY074001 with G9a and 3D-QSAR results, two series compounds were designed and synthesized. The derivatives were confirmed to be active by in vitro assay and the SAR was explored by docking stimulations. Besides, several analogues showed acceptable anti-proliferative effects against several cancer cell lines. Among them, CPUY074020 displayed potent dual G9a inhibitory activity and anti-proliferative activity. Furthermore, CPUY074020 induced cell apoptosis in a dose-dependent manner and displayed a significant decrease in dimethylation of H3K9. Simultaneously, CPUY074020 showed reasonable in vivo PK properties. Altogether, our workflow supplied a high efficient strategy in the identification of novel G9a inhibitors. Compounds reported here can serve as promising leads for further study.

Novel naphtho[2,1-d]oxazole-4,5-diones as NQO1 substrates with improved aqueous solubility: Design, synthesis, and in vivo antitumor evaluation.

A new series of ortho-naphthoquinone analogs of ß-lapachone were designed, synthesized and evaluated. The biological results indicated that most of our compounds were efficient substrates for NQO1. The new scaffold with water-soluble side chain resulted in greater solubility under acidic condition compared to ß-lapachone. Thus avoiding the use of hydroxylpropyl ß-cyclodextrin which would finally cause the rapid drug clearance from the blood and dose-limiting toxicity in the form of hemolytic anemia. The most soluble and promising compound in this series was 2-((4-benzylpiperazin-1-yl)methyl)naphtho[2,1-d]oxazole-4,5-dione (3k), which inhibited cancer cell (NQO1-rich A549 cell line) growth at IC50 values of 4.6±1.0µmol·L(-1). Furthermore, compound 3k had in vivo antitumor activity in an A549 tumor xenografts mouse model comparable to the activity obtained with ß-lapachone. The results indicated that these ortho-naphthoquinones could serve as promising leads for further optimization as novel substrates for NQO1.

Discovery and Modification of in Vivo Active Nrf2 Activators with 1,2,4-Oxadiazole Core: Hits Identification and Structure-Activity Relationship Study.

Induction of phase II antioxidant enzymes by activation of Nrf2/ARE pathway has been recognized as a promising strategy for the regulation of oxidative stress-related diseases. Herein we report our effort on the discovery and optimization of Nrf2 activators with 1,2,4-oxadiazole core. Screening of an in-house collection containing 7500 compounds by ARE-luciferase reporter assay revealed a moderate Nrf2 activator, 1. Aimed at obtaining more derivatives efficiently, molecular similarity search by the combination of 2D fingerprint-based and 3D shape-based search was applied to virtually screening the Chemdiv collection. Three derivatives with the same core were identified to have better inductivity of Nrf2 than 1. The best hit 4 was selected as starting point for structurally optimization, leading to a much more potent derivative 32. It in vitro upregulated gene and protein level of Nrf2 as well as its downstream markers such as NQO1, GCLM, and HO-1. It remarkably suppressed inflammation in the in vivo LPS-challenged mouse model. Our results provide a new chemotype as Nrf2-ARE activators which deserve further optimization with the aim to obtain active anti-inflammatory agents through Nrf2-ARE pathway.

Discovery and design of tricyclic scaffolds as protein kinase CK2 (CK2) inhibitors through a combination of shape-based virtual screening and structure-based molecular modification.

Protein kinase CK2 (CK2), a ubiquitous serine/threonine protein kinase for hundreds of endogenous substrates, serves as an attractive anticancer target. One of its most potent inhibitors, CX-4945, has entered a phase I clinical trial. Herein we present an integrated workflow combining shape-based virtual screening for the identification of novel CK2 inhibitors. A shape-based model derived from CX-4945 was built, and the subsequent virtual screening led to the identification of several novel scaffolds with high shape similarity to that of CX-4945. Among them two tricyclic scaffolds named [1,2,4]triazolo[4,3-c]quinazolin and [1,2,4]triazolo[4,3-a]quinoxalin attracted us the most. Combining strictly chemical similarity analysis, a second-round shape-based screening was performed based on the two tricyclic scaffolds, leading to 28 derivatives. These compounds not only targeted CK2 with potent and dose-dependent activities but also showed acceptable antiproliferative effects against a series of cancer cell lines. Our workflow supplies a high efficient strategy in the identification of novel CK2 inhibitors. Compounds reported here can serve as ideal leads for further modifications.

Synthesis and antibacterial evaluation of a novel series of 10-hydroxyl ketolide derivatives.

A novel series of 10-hydroxyl ketolide derivatives were synthesized, during which a distinctive intermediate, 3-O-descladinosyl-3-oxo-11-deoxy-10,11-epoxy-6-O-methylerythromycin A, was obtained from 6-O-methylerythromycin A. The structure and stereochemistry of this novel structure were confirmed via NMR and X-ray crystallography. Moreover, antibacterial evaluations were established in order to assess our modifications and acquire a deep understanding of the ketolides' structure-activity relationship (SAR).

Novel IKKß inhibitors discovery based on the co-crystal structure by using binding-conformation-based and ligand-based method.

IκB kinase ß (IKKß), an attractive anti-inflammation and anti-cancer target, plays a crucial role in the activation of NF-κB signalling pathway. To identify novel IKKß inhibitors, we combined structure-based and ligand-based methods based on the co-crystal structure of IKKß. According to the chemical similarity, 162 reported IKKß inhibitors were divided into five classes. For each class, a 3D pharmacophore model was established based on the binding conformations of the compounds. The validated models were further used in virtual screening. Twelve drugable compounds were retained for biological test, resulting in two novel inhibitors with IC50 values lower than 10 µM. Compared to other models, our method considers the crystal structure of IKKß for the first time.

[Prelimary exploration on Chinese medicine syndrome type distribution in patients with polycystic ovary syndrome].

OBJECTIVE: To explore the Chinese medicine syndrome type distribution in patients with polycystic ovary syndrome (PCOS) and its relationship with sexual hormones. METHODS: Chinese medicine syndrome types of 212 PCOS patients were differentiated and sorted by adopting fuzzy mean C clustering method, and their relationship with the indices of sexual hormones detected on the 3rd to 5th day of menstrual cycle was analyzed, with the values got from 20 healthy women for controls. RESULTS: Intermingling syndromes were commonly seen in PCOS patients. Shen-deficiency syndrome (presented in 64 patients) and Gan-qi stagnancy syndrome (61 patients) were the dominance, accounting for 30.2% and 28.8% respectively, significantly higher than that of other syndromes (P < 0.05), which were Pi-deficiency syndrome (41 patients, 19.3%), phlegm-dampness syndrome (33 patients, 15.6%) and blood stasis syndrome (13 patients, 6.1%). Levels of estradiol (E2), testosterone (T), luteinzing hormone (LH), dehydroiso-androsterone (DHEA-S) and prolactin (PRL) were higher, while the level of sexual hormone binding protein (SHBG) was lower in PCOS patients than those in control, follicular stimulating hormone (FSH) level in patients of Shen-deficiency syndrome and phlegm-dampness syndrome was high than that in control (P < 0.05 and P < 0.01). However, no significant differences were found in comparing the various sexual endocrinal indices between patients with different syndrome types (P > 0.05). Besides, the level of PRL was positively correlated with LH and E2 levels in patients. CONCLUSION: Chinese medicine syndromes presented in patients with PCOS are mostly intermingling, Shen-deficiency and Gan-stagnancy are the basic syndromes, and there is some correlation between syndrome type and sexual hormone levels.

Treatment of non-alcoholic fatty liver disease by Qianggan Capsule.

OBJECTIVE: To observe the therapeutic effect and safety of Qianggan Capsule (QGC) in treating non-alcoholic fatty liver disease (NAFLD), using polyene phosphatidylcholine capsule (PPC) as a reference. METHODS: Eighty-eight patients with NAFLD were randomly assigned to two groups, 45 in the treatment group treated with QGC and 43 in the control group treated with PPC. The course of treatment lasted for 6 months. Changes in liver function, blood lipids, and iconographic indexes before and after treatment were observed, and clinical efficacy was evaluated. RESULTS: In the treatment group, alanine aminotransferase (ALT) was lowered significantly from 56.02 + or - 32.59 IU/L before treatment to 38.27 + or - 22.68 IU/L after treatment, and CT liver/spleen ratio significantly increased from 0.69 + or - 0.18 to 0.91 + or - 0.25, showing statistical significance (P<0.05); in contrast, the corresponding changes of the two indexes in the control group were 56.56 + or - 26.33 IU/L to 49.67 + or - 26.22 IU/L, and 0.66 + or - 0.20 to 0.75 + or - 0.24, respectively, the pre-post treatment difference showing insignificant difference (P>0.05). No severe adverse reactions occurred during the whole treatment course. CONCLUSION: QGC is an effective and safe remedy for the treatment of NAFLD.