Lower body bone fractures have high mortality rates and poor prognosis in the patients with hemodialysis.

INTRODUCTION: The objective of the current study was to investigate the association between lower body bone fractures occurring during maintenance hemodialysis and prognosis. METHODS: This study included 151 hemodialysis patients at the dialysis center of our hospital as of December 2017, and data were systematically gathered from medical records over a period of 5 years, concluding in December 2022. RESULTS: Fourteen patients, 3.0 per 100 person-years, in 151 hemodialysis patients suffered from lower body bone fractures. The ratio of males was significantly lower, and age was significantly higher in the lower body bone fracture group than in the no lower body bone fracture group. Duration of hemodialysis prior to entry into this study was significantly shorter in the lower body bone fracture group than in the no lower body bone fracture group. Serum albumin was significantly lower and alkaline phosphatase was significantly higher in the lower body bone fracture group than in the no lower body bone fracture group. Mortality rate was significantly higher in the lower body bone fracture group (85.7%) compared to no lower body bone fracture group (28.5%) (p = 0.01). Kaplan-Meier survival curves for mortality showed that lower body bone fracture group had poor prognosis compared to no lower body bone fracture group. Multivariable-adjusted odds ratio for mortality were significantly higher for cases with lower body bone fractures. CONCLUSION: Lower body bone fractures have high mortality rates and poor prognosis in the patients with hemodialysis.

The Effect of Prior Creatine Intake for 28 Days on Accelerated Recovery from Exercise-Induced Muscle Damage: A Double-Blind, Randomized, Placebo-Controlled Trial.

Despite the known beneficial effects of creatine in treating exercise-induced muscle damage (EIMD), its effectiveness remains unclear. This study investigates the recovery effect of creatine monohydrate (CrM) on EIMD. Twenty healthy men (21-36 years) were subjected to stratified, randomized, double-blind assignments. The creatine (CRE) and placebo (PLA) groups ingested creatine and crystalline cellulose, respectively, for 28 days. They subsequently performed dumbbell exercises while emphasizing eccentric contraction of the elbow flexors. The EIMD was evaluated before and after exercise. The range of motion was significantly higher in the CRE group than in the PLA group 24 h (h) post exercise. A similar difference was detected in maximum voluntary contraction at 0, 48, 96, and 168 h post exercise (p = 0.017-0.047). The upper arm circumference was significantly lower in the CRE group than in the PLA group at 48, 72, 96, and 168 h post exercise (p = 0.002-0.030). Similar variation was observed in the shear modulus of the biceps brachii muscle at 96 and 168 h post exercise (p = 0.003-0.021) and in muscle fatigue at 0 and 168 h post exercise (p = 0.012-0.032). These findings demonstrate CrM-mediated accelerated recovery from EIMD, suggesting that CrM is an effective supplement for EIMD recovery.

Relationships between Changes in Muscle Shear Modulus, Urinary Titin N- Terminal Fragment, and Maximum Voluntary Contraction Torque after Eccentric Exercise of the Elbow Flexors.

The study aimed to investigate the relationships between the shear modulus of the biceps brachii (BB) and brachialis muscle (BA) and the total of the two (BB+BA), and urinary titin N-terminal fragment (UTF), maximum voluntary isometric contraction (MVC), and other indirect markers. Fifteen healthy men performed five sets of 10 eccentric contractions using a dumbbell corresponding to 50% of MVC at 90° measured at baseline. The elbow joint of the left arm was extended from 90° to 180° (180° = full extension) in 5 s in the exercise, and was returned with support from the examiner to prevent concentric contraction. Shear modulus of BB and BA were measured by ultrasound shear wave elastography, and UTF, MVC, and range of motion of the elbow joint (ROM) were recorded before; immediately after; and 1, 24, 48, 72, 96, and 168 h after the exercise. After calculating the shear modulus of BB and BA, two values were added (BB+BA). The shear modulus peaked at 48 h, UTF peaked at 96 h, MVC and ROM changed largest at immediately, and muscle soreness peaked at 48 h post-exercise. Significant (p < 0.05) relationships were found between changes in BB shear modulus and BA shear modulus (r = 0.874), BB+BA shear modulus (r = 0.977), UTF (r = 0.681), and MVC (r = -0.538). Significant (p < 0.05) relationships were also observed between changes in BA shear modulus and BB+BA shear modulus (r = 0.957), UTF (r = 0.682), MVC (r = -0.522), and ROM (r = -0.600). Moreover, significant (p < 0.05) relationships were observed between changes in BB+BA shear modulus and UTF (r = 0.703), MVC (r = -0.549), and ROM (r = -0.547). These results indicate that shear modulus of each muscle (i.e., BB and BA) provide more precise information about muscle damage than UTF, MVC and ROM.

Changes in Muscle Shear Modulus and Urinary Titin N-Terminal Fragment after Eccentric Exercise.

This study aimed to investigate the relationship between the muscle shear modulus of the biceps brachii, urinary titin N-terminal fragment (UTF), and other damage markers after eccentric exercise. Seventeen healthy males performed five sets of ten eccentric exercises with dumbbells weighing 50% of the maximum voluntary contraction (MVC) at the elbow joint. Muscle shear modulus with range of interest set to only biceps brachii muscle measured by ultrasound shear wave elastography, UTF, MVC, range of motion (ROM), and soreness (SOR) were recorded before, immediately after, and 1, 24, 48, 72, 96, and 168 h after eccentric exercise. Each marker changed in a time course pattern, as found in previous studies. The peak shear modulus showed a moderate negative correlation with peak MVC (r = -0.531, P < 0.05) and a strong positive correlation with peak UTF (r = 0.707, P < 0.01). Our study results revealed a significant relationship between muscle strength, shear modulus measured by ultrasound SWE, and titin measured by UTF, as a non-invasive damage marker after eccentric exercise to track changes in EIMD.

Optically active distorted cyclic triptycenes: chiral stationary phases for HPLC.

A pair of optically active triptycene derivatives ((R,R)- and (S,S)-8) with a distorted cyclic structure were synthesized via an intramolecular etherification and evaluated as a novel chiral selector for high-performance liquid chromatography. The (R,R)- and (S,S)-8-based chiral stationary phases (CSPs) were found to be particularly effective in the resolution of axially chiral biaryl compounds. The importance of the distorted cyclic structure present in 8 for chiral recognition was demonstrated by comparisons with the corresponding non-cyclic model compound ((R,R)-9), which did not display enantioselectivity in the separation of the test racemates.

Identification of protein kinase CK2 inhibitors using solvent dipole ordering virtual screening.

Novel protein kinase CK2 inhibitors were identified using the solvent dipole ordering virtual screening method. A total of 26 compounds categorized in 15 distinct scaffold classes inhibited greater than 50% of enzyme activity at 50 µM, and eight exhibited IC50 values less than 10 µM. Most of the identified compounds are lead-like and dissimilar to known inhibitors. The crystal structures of two of the CK2 complexes revealed the high accuracy of the predicted binding modes.

Discovery and SAR study of 2-(4-pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-ones as soluble and highly potent PDE7 inhibitors.

The discovery and SAR study of a new series of soluble and highly potent phosphodiesterase (PDE) 7 inhibitors are described herein. We explored a new lead compound with improved solubility, which led to the discovery of a 2-(4-pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-one series. The introduction of 3-piperidines at the 7-position resulted in the significant enhancement of PDE7 activity. In particular, compound 32 also showed strong PDE7 inhibitory activity; good selectivity against PDE3, 4, and 5; and good aqueous solubility.

Discovery of 2-(cyclopentylamino)thieno[3,2-d]pyrimidin-4(3H)-one derivatives as a new series of potent phosphodiesterase 7 inhibitors.

The discovery of a new series of potent phosphodiesterase 7 (PDE7) inhibitors is described. Novel thieno[3,2-d]pyrimidin-4(3H)-one hit compounds were identified from our chemical library. Preliminary modifications of the hit compounds were performed, resulting in the discovery of a fragment-sized compound (10) with highly improved ligand efficiency. Compound design was guided by structure-activity relationships and computational modeling. The 6-substituted derivatives of the thienopyrimidinone showed diminished activity and enzyme selectivity. However, synthesis of the 7-substituted derivatives resulted in the discovery of 28e, a desirable lead compound that selectively inhibits PDE7 with single-digit nanomolar potency while displaying potent cellular efficacy.

Lead evaluation of tetrahydroquinolines as nonsteroidal selective androgen receptor modulators for the treatment of osteoporosis.

Tetrahydroquinoline (THQ) was deemed to be a suitable scaffold for our nonsteroidal selective androgen receptor modulator (SARM) concept. We adapted the strategy of switching the antagonist function of cyano-group-containing THQ (CN-THQ) to the agonist function and optimized CN-THQ as an orally available drug candidate with suitable pharmacological and ADME profiles. Based on binding mode analyses and synthetic accessibility, we designed and synthesized a compound that possesses a para-substituted aromatic ring attached through an amide linker. The long-tail THQ derivative 6-acetamido-N-(2-(8-cyano-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl)-2-methylpropyl)nicotinamide (1 d), which bears a para-acetamide-substituted aromatic group, showed an appropriate in vitro biological profile, as expected. We considered that the large conformational change at Trp741 of the androgen receptor (AR) and the hydrogen bond between 1 d and helix 12 of the AR could maintain the structure of the AR in its agonist form; indeed, 1 d displays strong AR agonistic activity. Furthermore, 1 d showed an appropriate in vivo profile for use as an orally available SARM, displaying clear tissue selectivity, with a separation between its desirable osteoanabolic effect on femoral bone mineral density and its undesirable virilizing effects on the uterus and clitoral gland in a female osteoporosis model.

De novo design of drug-like molecules by a fragment-based molecular evolutionary approach.

This paper describes a similarity-driven simple evolutionary approach to producing candidate molecules of new drugs. The aim of the method is to explore the candidates that are structurally similar to the reference molecule and yet somewhat different in not only peripheral chains but also their scaffolds. The method employs a known active molecule of our interest as a reference molecule which is used to navigate a huge chemical space. The reference molecule is also used to obtain seed fragments. An initial set of individual structures is prepared with the seed fragments and additional fragments using several connection rules. The fragment library is preferably prepared from a collection of known molecules related to the target of the reference molecule. Every fragment of the library can be used for fragment-based mutation. All the fragments are categorized into three classes; rings, linkers, and side chains. New individuals are produced by the crossover and the fragment-based mutation with the fragment library. Computer experiments with our own fragment library prepared from GPCR SARfari verified the feasibility of our approach to drug discovery.

Subtle structural changes in tetrahydroquinolines, a new class of nonsteroidal selective androgen receptor modulators, induce different functions.

Tetrahydroquinolines (THQs), a new class of nonsteroidal selective androgen receptor (AR) modulators, have two indispensable functional groups, that is, a hydroxyl group for AR binding and a nitro group for agonistic activity. Interestingly, switching the nitro to a cyano group, the compound acts as an antagonist. To understand this phenomenon, molecular dynamics simulations were applied for dihydrotestosterone (DHT) and representative THQs complexes with AR. Upon ligand binding, the hydroxyl group formed a tight hydrogen-bond (H-bond) with Asn705 on Helix 3 (H3). The immobilization of Asn705 on H3 is helpful in the formation of tight H-bonds with Asp890 on loop 11-12, and this immobilization consequently leads to a stabilization of H12. The difference in the DHT carbonyl isosteres affected the presence or absence of the H-bonds between the hydroxyl group of THQ and Thr877 and the distortion of H12, which is caused by the methyl group of THQ. Thus, the binding, agonist, and antagonist functions were controlled by subtle structural changes in THQ.

Metal-ligand interactions: an analysis of zinc binding groups using the Protein Data Bank.

In the present study, we investigated zinc binding groups (ZBGs) using the coordinates of protein-ligand complex structures obtained from the Protein Data Bank. The distance from the zinc to the nearest ligand atom was measured to determine whether the atom was part of the ZBG. The most frequently found ZBG was carboxylate, followed by sulfonamide, hydroxamate, and phosphonate/phosphate. Because it was found that few heteroatoms, such as nitrogen, oxygen, and sulfur atoms, interacted with zinc, ideal distances between the zinc and these heteroatoms were identified. Whereas carboxylates bound to the zinc via both monodentate and bidentate interactions, the hydroxamates bound dominantly in a bidentate manner. These results will aid in the design of new inhibitors with the potential to interact with zinc in the target protein.

Anti-androgenic effects of S-40542, a novel non-steroidal selective androgen receptor modulator (SARM) for the treatment of benign prostatic hyperplasia.

BACKGROUND: Selective androgen receptor modulators (SARMs) would provide alternative therapeutic agent for androgen-related diseases. We identified a tetrahydroquinoline (THQ) derivative, 1-(8-nitro-3a, 4, 5, 9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl) ethane-1, 2-diol (S-40542) as a novel SARM antagonist. METHODS: Affinity for nuclear receptors of S-40542 was evaluated in receptor-binding studies. Androgen receptor (AR) transcriptional activity of S-40542 was investigated by luciferase reporter assay in DU145AR cells. Normal and benign prostatic hyperplasia (BPH) model rats were repeatedly treated with S-40542 and flutamide. The tissue weights of prostate and levator ani muscle as well as blood levels of testosterone and luteinizing hormone were measured. RESULTS: S-40542 bound to the AR with high affinity. S-40542 at relatively high concentrations increased the transcriptional activity. This agent also showed a concentration-dependent AR antagonistic action in the presence of 1 nM 5α-dihydrotestosterone. Repeated treatment with S-40542 and flutamide decreased dose-dependently the weights of the prostate to a similar extent. In contrast, the tissue weight-reducing effect by S-40542 treatment on the levator ani muscle was much weaker than that of flutamide. S-40542 had little effect on the blood level of testosterone and luteinizing hormone, whereas flutamide increased the level of both hormones. Furthermore, S-40542 decreased dose-dependently prostate weight of BPH rats. CONCLUSIONS: The current results indicate that S-40542 possesses the prostate-selective SARM activity, suggestive of clinical benefit against benign prostate hyperplasia. THQ compounds may be useful for the research of mode of action of SARMs and for the development of safe SARM antagonists.

Tetrahydroquinolines as a novel series of nonsteroidal selective androgen receptor modulators: structural requirements for better physicochemical and biological properties.

A rationally designed tetrahydroquinoline (1) for nonsteroidal selective androgen receptor modulators was modified for the exploration of promising compounds by Grieco three-component condensation using various dienophiles. Based on the in vitro effects and physicochemical properties of the synthesized compounds, compound 4c was selected for further study. Compound 4c increased the femoral bone mineral density as much as DHT, but it reduced the uterus effect compared with DHT in ovariectomized rats. Thus, compound 4c has desirable osteoanabolic effects with weak undesirable effects on the uterus in a female osteoporosis model.

Design and synthesis of tricyclic tetrahydroquinolines as a new series of nonsteroidal selective androgen receptor modulators (SARMs).

Some tricyclic tetrahydroquinolines (THQs) were found to have the potential of a new series of nonsteroidal selective androgen receptor modulators (SARMs). Compound 5b was first designed and synthesized under our hypothesis based on a four-point pharmacophoric requirement of the 3-carbonyl, 18-methyl, 17-hydroxyl, and 13-quaternary carbon groups of dihydrotestosterone (DHT). It was revealed that this compound exhibits not only a strong androgen receptor (AR) agonistic activity (EC(50)=9.2 nM) but also the highest selectivity in binding affinity to AR among the steroid hormone receptors. Furthermore, this compound showed a weak virilizing effect with retention of the desired anabolic effect as compared with DHT in vivo.

SDOVS: a solvent dipole ordering-based method for virtual screening.

We previously reported that solvent dipole ordering (SDO) at the ligand binding site of a protein indicates an outline of the preferred shape and binding pose of the ligands. We suggested that SDO-mimetic pseudo-molecules that mimic the 3D shape of the SDO region could be used as molecular queries with a shape similarity matching method in virtual screening. In this work, a virtual screening method based on SDO, named SDOVS, was proposed. This method was applied to virtual screening of ligands for four typical drug target proteins and the performance compared with that of FRED (well-known rigid docking method); the efficiency of SDOVS was demonstrated to be better than FRED.

Ligand shape emerges in solvent dipole ordering region at ligand binding site of protein.

Solvent dipole ordering (SDO), introduced by Higo et al. (Proteins Struct Funct Genet 2000, 40, 193), is an entity that captures an aspect of hydration structure. We have studied SDO in the ligand binding site of two proteins (FK506 binding protein and dihydrofolate reductase) and found that the high SDO regions overlap significantly with the 3D structures of known inhibitors bound to the proteins. Thus, the SDO region might be used to predict the preferred molecular shape of ligands that bind to a protein. Based on this finding, we propose a novel docking procedure using model molecules that mimic the shape of the SDO region. To prove the validity of thisapproach, we performed a redocking experiment for p38 mitogen-activated protein kinase ligands using model molecules for search queries; we succeeded in identifying the binding conformations and binding modes of known inhibitors.