Amphiphilic Janus Graphene Oxide Acts as a Corrosion Inhibitor to Mitigate the Corrosion Caused by a 1 M HCl Solution on Mild Steel.

Great aqueous dispersibility, a large specific surface area, and high impermeability make graphene oxide (GO) the ideal candidate for a high-performance corrosion inhibitor. Numerous symmetrical modification methods have been reported to enhance the adsorption of GO on metal surfaces in various corrosive media. This work aims to investigate the enhancement and mechanism of unilateral hydrophobic modification on the corrosion inhibition performance of GO. In this study, amphiphilic Janus GO (JGO) was prepared by grafting hydrophobic alkyl chains on one side of GO, and its anticorrosion performance was evaluated via weight loss experiments and electrochemical tests. The results revealed that the corrosion inhibition efficiency for Q235 mild steel (MS) in a 1 M HCl aqueous solution of 25 ppm JGO (81.08%) was much higher than that of GO at the same concentration (22.12%). Furthermore, the Langmuir adsorption isotherm and computational study demonstrated that the synergistic effect of physical adsorption and chemical adsorption promoted the hydrophilic side of JGO close to the surface of the metal, and the dense protective layer was formed by the hydrophobic chains toward the corrosive medium, which effectively hindered the corrosion of MS by the acidic liquid. This study emphasizes the significant role of asymmetrically modified hydrophobic alkyl chains in improving the corrosion prevention performance of GO and provides a perspective for the structural design of GO-based corrosion inhibitors.

Causal effect of blood osteocalcin on the risk of Alzheimer's disease and the mediating role of energy metabolism.

Growing evidence suggests an association between osteocalcin (OCN), a peptide derived from bone and involved in regulating glucose and lipid metabolism, and the risk of Alzheimer's disease (AD). However, the causality of these associations and the underlying mechanisms remain uncertain. We utilized a Mendelian randomization (MR) approach to investigate the causal effects of blood OCN levels on AD and to assess the potential involvement of glucose and lipid metabolism. Independent instrumental variables strongly associated (P < 5E-08) with blood OCN levels were obtained from three independent genome-wide association studies (GWAS) on the human blood proteome (N = 3301 to 35,892). Two distinct summary statistics datasets on AD from the International Genomics of Alzheimer's Project (IGAP, N = 63,926) and a recent study including familial-proxy AD patients (FPAD, N = 472,868) were used. Summary-level data for fasting glucose (FG), 2h-glucose post-challenge, fasting insulin, HbA1c, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol (TC), and triglycerides were incorporated to evaluate the potential role of glucose and lipid metabolism in mediating the impact of OCN on AD risk. Our findings consistently demonstrate a significantly negative correlation between genetically determined blood OCN levels and the risk of AD (IGAP: odds ratio [OR, 95%CI] = 0.83[0.72-0.96], P = 0.013; FPAD: OR = 0.81 [0.70-0.93], P = 0.002). Similar estimates with the same trend direction were obtained using other statistical approaches. Furthermore, employing multivariable MR analysis, we found that the causal relationship between OCN levels and AD was disappeared after adjustment of FG and TC (IGAP: OR = 0.97[0.80-1.17], P = 0.753; FPAD: OR = 0.98 [0.84-1.15], P = 0.831). There were no apparent instances of horizontal pleiotropy, and leave-one-out analysis showed good stability of the estimates. Our study provides evidence supporting a protective effect of blood OCN levels on AD, which is primarily mediated through regulating FG and TC levels. Further studies are warranted to elucidate the underlying physio-pathological mechanisms.

Discovery of a nitroaromatic nannocystin with potent in vivo anticancer activity against colorectal cancer by targeting AKT1.

The development of targeted chemotherapeutic agents against colorectal cancer (CRC), one of the most common cancers with a high mortality rate, is in a constant need. Nannocystins are a family of myxobacterial secondary metabolites featuring a 21-membered depsipeptide ring. The in vitro anti-CRC activity of natural and synthetic nannocystins was well documented, but little is known about their in vivo efficacy and if positive, the underlying mechanism of action. In this study we synthesized a nitroaromatic nannocystin through improved preparation of a key fragment, and characterized its in vitro activity and in vivo efficacy against CRC. We first described the total synthesis of compounds 2-4 featuring Heck macrocyclization to forge their 21-membered macrocycle. In a panel of 7 cancer cell lines from different tissues, compound 4 inhibited the cell viability with IC values of 1-6 nM. In particular, compound 4 (1, 2, 4 nM) inhibited the proliferation of CRC cell lines (HCT8, HCT116 and LoVo) in both concentration and time dependent manners. Furthermore, compound 4 concentration-dependently inhibited the colony formation and migration of CRC cell lines. Moreover, compound 4 induced cell cycle arrest at sub-G1 phase, apoptosis and cellular senescence in CRC cell lines. In three patient-derived CRC organoids, compound 4 inhibited the PDO with IC values of 3.68, 28.93 and 11.81 nM, respectively. In a patient-derived xenograft mouse model, injection of compound 4 (4, 8 mg/kg, i.p.) every other day for 12 times dose-dependently inhibited the tumor growth without significant change in body weight. We conducted RNA-sequencing, molecular docking and cellular thermal shift assay to elucidate the anti-CRC mechanisms of compound 4, and revealed that it exerted its anti-CRC effect at least in part by targeting AKT1.

Association of Fat Mass and Skeletal Muscle Mass with Cardiometabolic Risk Varied in Distinct PCOS Subtypes: A Propensity Score-Matched Case-Control Study.

(1) Background: polycystic ovarian syndrome (PCOS) is a heterogeneous syndrome with a constellation of cardiometabolic risk factors. We aimed to investigate if the association of body fat mass (BFM) and skeletal muscle mass (SMM) with cardiometabolic risk differed in PCOS subtypes. (2) Methods: 401 participants (245 PCOS and 156 controls) were assessed for anthropometric measurements, glucose-lipid profiles, reproductive hormones and body composition with propensity score-matched (PSM) analysis. The association of the cardiometabolic risk score (z score, calculated based on levels of obesity and gluco-lipid measurements) with BFM (estimated by trunk BFM/Height2) and SMM (estimated by SMM/Height2) was calculated. (3) Results: Trunk BFM/Height2 and SMM/Height2 were both positively associated with cardiometabolic risk in PCOS (trunk BFM/Height2, OR 2.33, 95% CI 1.49-3.65; SMM/Height2, OR 2.05, 95% CI 1.12-3.76). SMM/Height2 associated with increased cardiometabolic risk in obese PCOS (BMI ≥ 28 kg/m2, OR 2.27, 95% CI 1.15-4.47). For those with lower BMI (<28 kg/m2), trunk BFM/Height2 showed a higher OR in both groups (PCOS, OR 2.12, 95% CI 1.06-4.24; control 2.04, 95% CI 1.04-4.02). Moreover, distinct associations among BMI-stratified groups were validated in hierarchical clustering identifying metabolic and reproductive clusters. (4) Conclusions: BFM and SMM are synergistically associated with higher cardiometabolic risk in PCOS women. Although BFM contributes to increased cardiometabolic risk, SMM also plays a primary role in obese PCOS. Our results highlight the importance of body composition in the management of PCOS.

Genome-wide DNA methylation analysis identifies potent CpG signature for temzolomide response in non-G-CIMP glioblastomas with unmethylated MGMT promoter: MGMT-dependent roles of GPR81.

PURPOSES: To identify potent DNA methylation candidates that could predict response to temozolomide (TMZ) in glioblastomas (GBMs) that do not have glioma-CpGs island methylator phenotype (G-CIMP) but have an unmethylated promoter of O-6-methylguanine-DNA methyltransferase (unMGMT). METHODS: The discovery-validation approach was planned incorporating a series of G-CIMP-/unMGMT GBM cohorts with DNA methylation microarray data and clinical information, to construct multi-CpG prediction models. Different bioinformatic and experimental analyses were performed for biological exploration. RESULTS: By analyzing discovery sets with radiotherapy (RT) plus TMZ versus RT alone, we identified a panel of 64 TMZ efficacy-related CpGs, from which a 10-CpG risk signature was further constructed. Both the 64-CpG panel and the 10-CpG risk signature were validated showing significant correlations with overall survival of G-CIMP-/unMGMT GBMs when treated with RT/TMZ, rather than RT alone. The 10-CpG risk signature was further observed for aiding TMZ choice by distinguishing differential outcomes to RT/TMZ versus RT within each risk subgroup. Functional studies on GPR81, the gene harboring one of the 10 CpGs, indicated its distinct impacts on TMZ resistance in GBM cells, which may be dependent on the status of MGMT expression. CONCLUSIONS: The 64 TMZ efficacy-related CpGs and in particular the 10-CpG risk signature may serve as promising predictive biomarker candidates for guiding optimal usage of TMZ in G-CIMP-/unMGMT GBMs.

Tyrosine metabolic reprogramming coordinated with the tricarboxylic acid cycle to drive glioma immune evasion by regulating PD-L1 expression.

Due to the existence of the blood-brain barrier in glioma, traditional drug therapy has a poor therapeutic outcome. Emerging immunotherapy has been shown to have satisfactory therapeutic effects in solid tumors, and it is clinically instructive to explore the possibility of immunotherapy in glioma. We performed a retrospective analysis of RNA-seq data and clinical information in 1027 glioma patients, utilizing machine learning to explore the relationship between tyrosine metabolizing enzymes and clinical characteristics. In addition, we also assessed the role of tyrosine metabolizing enzymes in the immune microenvironment including immune infiltration and immune evasion. Highly expressed tyrosine metabolizing enzymes 4-hydroxyphenylpyruvate dioxygenase, homogentisate 1,2-dioxygenase, and fumarylacetoacetate hydrolase not only promote the malignant phenotype of glioma but are also closely related to poor prognosis. The expression of tyrosine metabolizing enzymes could distinguish the malignancy degree of glioma. More importantly, tyrosine metabolizing enzymes regulate the adaptive immune process in glioma. Mechanistically, multiple metabolic enzymes remodel fumarate metabolism, promote α-ketoglutarate production, induce programmed death-ligand 1 expression, and help glioma evade immune surveillance. Our data suggest that the metabolic subclass driven by tyrosine metabolism provides promising targets for the immunotherapy of glioma.

The serum levels of activin A and bone morphogenetic protein-4 and -6 in patients with fibrodysplasia ossificans progressiva.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultrarare and disabling genetic disorder of connective tissue characterized by congenital malformation of the great toes, and progressive heterotopic ossification (HO) in soft connective tissues. A gain-of-function mutation of activin A receptor type I (ACVR1) enables ACVR1 to recognize activin A as an agonist with bone morphogenetic protein (BMP) signalling that leads to HO. Previous studies confirmed that activin A stimulates BMP signalling in vitro and drives HO in mouse models of FOP. However, the roles for BMP4 and BMP6 in FOP are supported only by correlative evidence in vitro. Thus, it remains unclear whether the circulating levels of activin A, BMP4 and BMP6 correlate with flare-ups in FOP patients. Hence, we investigated the protein levels of activin A, BMP4 and BMP6 in the serum of FOP patients. RESULTS: We recruited 16 untreated FOP patients and 16 age- and sex- matched healthy control subjects in this study. The 16 FOP patients were retrospectively divided into the flare-up group (n = 8) and remission group (n = 8) depending on whether they had flare-ups or worsening of any joint movement in the last 6 months. The serum activin A, BMP4 and BMP6 levels were detected by enzyme-linked immunosorbent assay. The serum activin A, BMP4 and BMP6 levels were slightly higher in FOP patients (median: 434.05 pg/mL, 459.48 pg/mL and 67.84 pg/mL) versus healthy control subjects (median: 364.14 pg/mL, 450.39 pg/mL and 55.36 pg/mL). However, there were no statistically significant differences between the two groups (p > 0.05 for all items), nor were there significant differences between the flare-up and remission groups of FOP (p > 0.05 for all items). Univariate and multivariate logistic regression analyses showed that age, sex, and serum activin A, BMP4 and BMP6 levels were not related to flare-up in FOP patients. CONCLUSIONS: There were no significant differences in the serum levels of activin A, BMP4 and BMP6 in FOP patients compared with healthy control subjects. Serum activin A, BMP4 and BMP6 proteins might not be the stimulators for FOP flare-up, and may not be biomarkers for FOP diagnosis.

Osteocalcin ameliorates cognitive dysfunctions in a mouse model of Alzheimer's Disease by reducing amyloid ß burden and upregulating glycolysis in neuroglia.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by the accumulation of amyloid ß peptides (Aß) and impaired glucose metabolism in the brain. Osteocalcin (OCN), an osteoblast-derived protein, has been shown to modulate brain functions but whether it has any effect on AD is undetermined. In this study, daily intraperitoneal injection of OCN for 4 weeks ameliorated the anxiety-like behaviors and cognitive dysfunctions in the APP/PS1 transgenic AD mice model, as shown in the increased entries into the central area in open field test, the increased time and entries into open arms in elevated plus maze test, the increased time spent in the light chamber in light-dark transition test, as well as the reduced escape latency and the increased preference for target quadrant in Morris water maze test. Aß burden in the hippocampus and cortex of AD mice was ameliorated by OCN. Besides, OCN improved the neural network function of the brain, mainly in the enhanced power of high gamma band in the medial prefrontal cortex of AD mice. The proliferation of astrocytes in the hippocampus in AD mice was also inhibited by OCN as demonstrated by immunofluorescence. Furthermore, OCN enhanced glycolysis in astrocytes and microglia, as evidenced by elevated glucose consumption, lactate production, and increased extracellular acidification rate. Such an effect was abolished when the receptor of OCN - Gpr158 was knockdown in astrocytes. Our study revealed OCN as a novel therapeutic factor for AD potentially through reducing Aß burden and upregulation of glycolysis in neuroglia.

RANKL Is Independently Associated with Increased Risks of Non-Alcoholic Fatty Liver Disease in Chinese Women with PCOS: A Cross-Sectional Study.

Women with polycystic ovarian syndrome (PCOS) are more likely to have non-alcoholic fatty liver disease (NAFLD) than non-PCOS women; however, the exact mechanism underlying this trend is unknown. The receptor activator of NF-κB ligand (RANKL) is strongly involved in bone metabolism and has multiple functions. Recent studies suggest that RANKL is implicated in hepatic insulin resistance (IR), which is the highest risk factor for NAFLD. This study aimed to assess the role of RANKL in NAFLD in Chinese women with PCOS. A cross-sectional observational study was conducted on women newly diagnosed with PCOS, which included 146 patients with NAFLD and 142 patients without NAFLD. Sex hormones, glucose, insulin, and lipids were measured, and anthropometric data were collected. The concentration of serum total RANKL was measured using commercial ELISA kits. PCOS patients with NAFLD had a significantly higher mean age, body mass index (BMI), waist circumference (WC), and worsened metabolic profile than non-NAFLD subjects. The concentrations of high-sensitivity C-reactive protein, total cholesterol, and low-density lipoprotein cholesterol increased with the RANKL tertile (p for trend = 0.023, 0.026, and 0.035, respectively). A significantly positive association was found between RANKL (per SD change) and the risks of NAFLD (OR = 1.545, 95% CI = 1.086−2.199) after adjusting for confounders, including demographic factors, metabolic markers, and sex hormones. Subgroup multivariate logistic analyses stratified by age, BMI, and WC showed the same tendency. In addition, the positive association between RANKL and NAFLD seemed more prominent in lean patients with a BMI < 24 kg/m2 (OR = 1.70, 95% CI = 1.06−2.75) when compared to overweight/obesity subjects. Therefore, this study suggests that RANKL is positively associated with the increased risk of NAFLD in Chinese women with PCOS, independent of metabolic and reproductive factors.

New Insights into TRP Ion Channels in Stem Cells.

Transient receptor potential (TRP) ion channels are cationic permeable proteins located on the plasma membrane. TRPs are cellular sensors for perceiving diverse physical and/or chemical stimuli; thus, serving various critical physiological functions, including chemo-sensation, hearing, homeostasis, mechano-sensation, pain, taste, thermoregulation, vision, and even carcinogenesis. Dysregulated TRPs are found to be linked to many human hereditary diseases. Recent studies indicate that TRP ion channels are not only involved in sensory functions but are also implicated in regulating the biological characteristics of stem cells. In the present review, we summarize the expressions and functions of TRP ion channels in stem cells, including cancer stem cells. It offers an overview of the current understanding of TRP ion channels in stem cells.

Low Serum 25-Hydroxyvitamin D Levels Are Associated With Hyperandrogenemia in Polycystic Ovary Syndrome: A Cross-Sectional Study.

Background: Increasing evidence suggests a link between vitamin D and polycystic ovary syndrome (PCOS). However, whether vitamin D is related to hyperandrogenemia in PCOS is still inconclusive. The aim of our study is to elucidate the relationship between vitamin D and hyperandrogenemia in women with PCOS in China. Methods: This is a cross-sectional study including 625 Chinese women with PCOS and 217 controls from January 2016 to June 2020. The anthropometric and biochemical parameters related to 25(OH)D, sex steroids, glucose and lipid profiles were measured. Results: Serum 25(OH)D levels were lower in women with PCOS than controls (33.99 ± 15.05 vs 36.58 ± 16.49 nmol/L, P = 0.034), especially lower in hyperandrogenic women with PCOS (32.79 ± 14.24 vs 36.21 ± 16.27 nmol/L, P = 0.007). Higher 25(OH)D levels were independently associated with lower risks of hyperandrogenemia after adjusting demographic, metabolic and hormonal confounders (OR = 0.982, 95% CI: 0.969 - 0.995, P = 0.006). Consistent results were observed in subgroup analyses. Among PCOS women with vitamin D deficiency, females with age ≥ 26 years had lower risks of hyperandrogenemia (OR = 0.611, 95% CI = 0.389 - 0.958, P = 0.032), while overweight patients had higher risks of hyperandrogenemia (OR = 2.202, 95% CI = 1.130 - 4.293, P = 0.020) after adjusting multiple confounders. Conclusions: Our study reported lower vitamin D levels in Chinese women with PCOS, especially in those with hyperandrogenemia. An independent negative correlation between 25(OH)D and hyperandrogenemia was noted in PCOS. For PCOS women with vitamin D deficiency, females that have higher BMI with age < 26 years may be prioritized for hyperandrogenemia assessment.

Effects of different modified starches and gums on the physicochemical, functional, and microstructural properties of tapioca pearls.

The effects of different modified starch and gums on the physicochemical, functional, and microstructural properties of tapioca pearls were investigated. The addition of starch acetate (SA) and carboxymethylcellulose (CMC) improved the springiness, hardness, cooking properties, and overall acceptability of pearls. Samples added with CMC presented higher peak viscosities, breakdown viscosities, onset gelatinization temperature, and lower enthalpy of gelatinization values compared to control pearls. Furthermore, Rheology and LF-NMR results indicated that all five kinds of modifiers promoted the formation of tighter network structures in products. SEM showed that the addition of SA and hydroxypropyl distarch phosphate (HDP) could fill the voids in the internal gel network of the pearls, thus promoting the formation of a continuous phase network. This study proved SA, HDP, and CMC as modifiers could have tremendous potential to improve the quality of pearls before and after cooking.

Ordered structural changes of retrograded starch gel over long-term storage in wet starch noodles.

Temperature-induced structural variations of retrograded starch gel during long-term storage were investigated in a real food system (wet starch noodles). Fresh starch noodles presented a B-type XRD pattern containing 8.82% crystallinity and 16.04% double helices. In the first 2 weeks, double helices of starch chain formed long-range ordered structure leading to increased crystallinity, and such structural transformation was positively correlated with increasing storage temperature (from 4 °C to 35 °C) and storage time. However, with the extension of storage time to 12 weeks, the disorganization of supra-molecular structure was likely to be observed by decreased crystallinity, double helix and water mobility. Besides, we propose that the area and intensity of Raman band at 2910 cm-1 can be a good indicator for evaluating perfection of crystallinity in starch noodles. These results contributed to a better understanding of mechanisms underlying molecular order changes of retrograded starch gel product during long-term storage.

A non-small cell lung cancer (NSCLC) patient with leptomeningeal metastasis harboring rare epidermal growth factor receptor (EGFR) mutations G719S and L861Q benefited from doubling dosage of osimertinib: a case report.

Leptomeningeal metastasis (LM) is a rare but lethal complication of advanced non-small cell lung cancer (NSCLC) that has a devastating impact on patient survival and quality of life. Osimertinib, an irreversible tyrosine kinase inhibitor, is approved as a therapy for advanced NSCLC with epidermal growth factor receptor (EGFR) mutation. However, the efficacy and optimal dosage of osimertinib in the treatment of NSCLC patients with LM who harbor uncommon EGFR mutations have yet to be fully investigated. Herein, we report a case of an advanced NSCLC patient with LM carrying EGFR G719S and L861Q, who was successfully treated by osimertinib at 160 mg. The patient initially presented with clear cell renal carcinoma and renal metastatic adenocarcinoma, and underwent right nephrectomy. At 2 months after nephrectomy, he developed a disturbance of consciousness and was subsequently diagnosed with NSCLC with LM by meningeal biopsy pathology and cerebrospinal fluid (CSF) cytology. Next-generation sequencing detected the rare EGFR mutations G719S and L861R in the meningeal biopsy tissues. The patient was then administered osimertinib at 80 mg quaque die (QD); after 1 month of treatment, his symptoms were alleviated. However, two months later, he experienced epileptic episode. Subsequently, the osimertinib dosage was doubled to 160 mg QD. After 1 month of treatment, the patient achieved central nervous system (CNS) response, and at the time of this manuscript's submission, he had maintained stable disease (SD) for more than 1 year. To our knowledge, this study provides the first clinical evidence that the administration of osimertinib at 160 mg once daily can achieve an encouraging, durable response in an NSCLC patient with LM carrying EGFR G719S and L861Q.

Evaluation of cooking performance, structural properties, storage stability and shelf life prediction of high-moisture wet starch noodles.

Cooking performance, micro- and molecular structure, storage stability and shelf-life prediction of high-moisture wet starch noodles (SN) were investigated. SEM images revealed that compared to dried SN, cooked wet SN had more evenly honeycomb-like network with smaller size of pores, indicating stronger interaction among molecules and causing favorable cooking performance. XRD and ATR-FTIR results evidenced that wet SN contained more complete crystallites and higher proportion of crystalline region. During storage, the quality decay of wet SN was mainly associated to the increment of total aerobic viable count (TAVC), titrable acidity and amylase, as well as the decreased textural hardness, overall acceptability and lightness. Based on TAVC, titrable acidity and overall acceptability, predicted shelf-life of vacuum-packed wet SN at 25 °C was 15.31, 21.54 and 16.65 weeks respectively, with relative error all within 20%, proving that the validated model could be an effective tool for monitoring the shelf-life of wet SN.

Dissimilarity in sensory attributes, shelf life and spoilage bacterial and fungal microbiota of industrial-scale wet starch noodles induced by different preservatives and temperature.

Shelf life, storage stability and microbial growth of wet starch noodles during storage were investigated, and spoilage microbiota was also analyzed to further reveal the decisive factor shaping the microbial community. Sensory analysis and microbiological results indicated that starch noodles treated with sodium dehydroacetate and stored at 4 °C could effectively delay the moldy decay and extend the shelf-life to 50 days, as compared to control and other treatments. In wet starch noodles, molds were found to have a higher spoilage potential than bacteria and yeasts. 16S rDNA sequencing revealed that preservatives, rather than temperature, could cause the significant difference (PERMANOVA p = 0.001) of spoilage bacterial community among samples and sodium dehydroacetate could markedly reduce the bacterial diversity. ITS rDNA sequencing results demonstrated that temperature was the decisive factor in shaping fungal spoilage microbiota (Mantel test r = 0.413, p = 0.002). Besides, Spearman correlation analysis illustrated that the abundance of some microorganisms such as Pseudomonas, Aspergillus and Penicillium were found to be significantly correlated with pH or temperature. These findings provide guiding information in the selection of preservatives and environmental condition for this high-moisture starch noodles.

Broadening the role of osteocalcin in the hypothalamic-pituitary-gonadal axis.

Bone is emerging as a versatile endocrine organ and its interactions with apparently unrelated organs are being more widely recognized. Osteocalcin (OCN), a polypeptide hormone secreted by osteoblasts, has been found to exert multiple endocrine functions through its metabolically active form, uncarboxylated OCN (uOCN). Mounting evidence has shown that following its binding to G-protein coupled receptor 6a (Gprc6a) in the peripheral tissues, uOCN acts on pancreatic ß cells to increase insulin secretion, and on muscle and white adipose tissue to promote glucose and lipid metabolism. More strikingly, researchers have found a surprising role of uOCN in testicular function to facilitating testosterone biosynthesis and regulating male fertility via a pancreas-bone-gonadal axis. However, the detailed functional mechanisms of uOCN on the hypothalamic-pituitary-gonadal axis or the pancreas-bone-gonadal axis are not fully understood. Besides highlighting the regulatory mechanisms of uOCN in the hypothalamus and pituitary, we also discuss its role in male as well as female fertility and its potential clinical implications in some reproductive endocrine diseases and pubertal developmental disorders.

Gut microbiota-derived propionate mediates the neuroprotective effect of osteocalcin in a mouse model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to identify certain molecule(s) derived from the gut microbiota, which has the potential to manage PD. Osteocalcin (OCN), an osteoblast-secreted protein, has been shown to modulate brain function. Thus, it is of interest to investigate whether OCN could exert protective effect on PD and, if yes, whether the underlying mechanism lies in the subsequent changes in gut microbiota. RESULTS: The intraperitoneal injection of OCN can effectively ameliorate the motor deficits and dopaminergic neuronal loss in a 6-hydroxydopamine-induced PD mouse model. The further antibiotics treatment and fecal microbiota transplantation experiments confirmed that the gut microbiota was required for OCN-induced protection in PD mice. OCN elevated Bacteroidetes and depleted Firmicutes phyla in the gut microbiota of PD mice with elevated potential of microbial propionate production and was confirmed by fecal propionate levels. Two months of orally administered propionate successfully rescued motor deficits and dopaminergic neuronal loss in PD mice. Furthermore, AR420626, the agonist of FFAR3, which is the receptor of propionate, mimicked the neuroprotective effects of propionate and the ablation of enteric neurons blocked the prevention of dopaminergic neuronal loss by propionate in PD mice. CONCLUSIONS: Together, our results demonstrate that OCN ameliorates motor deficits and dopaminergic neuronal loss in PD mice, modulating gut microbiome and increasing propionate level might be an underlying mechanism responsible for the neuroprotective effects of OCN on PD, and the FFAR3, expressed in enteric nervous system, might be the main action site of propionate. Video abstract.

2,3-Dicyano-5,6-dichlorobenzoquinone-Mediated and Selective C-O and C-C Cross-Couplings of Phenols and Porphyrins.

A selective C-O cross-coupling reaction between porphyrins and phenols has been developed through 2,3-dicyano-5,6-dichlorobenzoquinone (DDQ)/Sc(OTf)3 oxidation, efficiently delivering meso-etherified porphyrins in good yields (≤93%). The radical complex process was proposed and calculated as the rationalized mechanism to block the homocoupling process. In addition, the switchable selective C-C cross-coupling reaction was achieved by using bulky electron-rich phenols and naphthols under DDQ oxidation conditions.

Osteocalcin Levels in Male Idiopathic Hypogonadotropic Hypogonadism: Relationship With the Testosterone Secretion and Metabolic Profiles.

Idiopathic hypogonadotropic hypogonadism (IHH) patients are characterized by the absence of puberty and varying degrees of deteriorated metabolic conditions. Osteocalcin (OC) could regulate testosterone secretion and energy metabolism, but it remains unknown whether such an effect exists in IHH patients. Our study is aimed to examine the relationship between serum OC levels with testosterone and its responsiveness to gonadotropin stimulation and metabolic profiles in male IHH patients. A total of 99 male patients aged 18-37 years and diagnosed with IHH were enrolled in the current study, and the relationships between OC and testicular volume, baseline total testosterone (TT), free testosterone (FT), and peak TT (Tmax) levels after human chorionic gonadotropin (hCG) stimulation, gonadotropin responsiveness index (GRI), which is calculated by dividing Tmax by testicular volume, as well as metabolic profiles, such as 2-h post-challenge glucose (2hPG) and fat percentage (fat%), were analyzed. The results showed that OC had an independent negative relationship with testicular volume (r = -0.253, P = 0.012) and a positive association with Tmax (r = 0.262, P = 0.014) after adjusting for confounders. In addition, OC was a major determinant of GRI (adjusted R 2 for the model = 0.164, P = 0.012), fat% (adjusted R 2 for the model = 0.100, P = 0.004), and 2hPG (adjusted R 2 for the model = 0.054, P = 0.013) in IHH patients. In conclusion, OC is associated with testosterone secretion upon gonadotropin stimulation, glucose metabolism, and fat mass variations in IHH. This study was registered at clinicaltrials.gov (NCT02310074).