Positive association between serum bilirubin within the physiological range and serum testosterone levels.

BACKGROUNDS: Research has demonstrated that elevated serum total bilirubin (STB) levels have a beneficial impact on various diseases, particularly metabolic syndrome. This study aims to investigate the association between STB levels and serum testosterone (STT) in order to determine if bilirubin plays a protective role in relation to testosterone deficiency (TD) risk. METHODS: In this study, a total of 6,526 eligible male participants aged 20 years or older were analyzed, all of whom took part in the National Health and Nutrition Examination Survey (NHANES) conducted between 2011 and 2016. To investigate the relationship between STB and STT levels, we employed weighted multivariate regression models along with restricted cubic splines (RCS). Additionally, a subgroup analysis was conducted to explore the heterogeneity of this relationship across different subpopulations. RESULTS: Among the participants, 1,832 individuals (28.07%) were identified as having testosterone deficiency (TD), defined as an STT level below 300 ng/dL. A significant positive correlation between STB and STT levels was observed in both crude and adjusted models (all P < 0.0001). The association between STB and STT levels was found to be statistically significant up to a threshold of 17.1 µmol/L, after which it became statistically insignificant(P for non-linearity = 0.0035). Weighted logistic regression analysis indicated that a 1 µmol/L increase in STB was associated with a 4% decrease in the likelihood of TD (odds ratio = 0.96, P < 0.0001). Subgroup analysis showed that the inverse relationship was limited to individuals aged 60 and over, non-smokers/drinkers, and obese individuals. CONCLUSION: STB within the physiological range(17.1 µmol/L) was positively associated with STT in adult males. The potential protective role of bilirubin regarding testosterone levels merits further exploration.

Afterglow Electrochemiluminescence from Nitrogen-Deficient Graphitic Carbon Nitride.

Almost all current electrochemiluminescent reagents require real-time electrochemical stimulation to emit light. Here, we report a novel electrochemiluminescent reagent, nitrogen-deficient graphitic carbon nitride (CNx), that can emit afterglow electrochemiluminescence (ECL) after cessation of electric excitation. CNx obtained by post-thermal treatment of graphitic carbon nitride (CN) with KSCN has a cyanamide group and a nitrogen vacancy, which created defects to trap electrically injected electrons. The trapped electrons can slowly release and react with coreactants to emit light with longevity. The cathodic afterglow ECL lasts for 70 s after pulsing the CNx nanosheet (CNxNS-1.6)-modified glassy carbon electrode at -1.0 V for 20 s in 2.0 M PBS containing 1 mM K2S2O8. The afterglow ECL mechanism is revealed by investigation of its influencing factors and ECL wavelength. The discovery of afterglow ECL may open a new doorway for new significant applications of the ECL technique and provide a deeper understanding of the structure-property relationships of CN.

Calcium sensing receptor mediated the excessive generation of ß-amyloid peptide induced by hypoxia in vivo and in vitro.

Hypoxia played an important role in the pathogenesis of AD. Hypoxia increased Aß formation, then caused Alzheimer's disease. Calcium sensing receptor (CaSR) was involved in the regulation of cell growth, differentiation, hormonal secretion and other physiological function. Increasing evidence supported CaSR might play a more prominent role in susceptibility to AD, but the role of CaSR in Aß overproduction induced by hypoxia and its mechanisms remain unclear. To investigate whether CaSR mediated the overproduction of Aß induced by hypoxia, immunoblot and immunochemistry were employed to determine the expression of CaSR and BACE1 in hippocampal neurons and tissue and Ca(2+) image system was used to measure [Ca(2+)]i in hippocampal neurons. The content of Aß was detected with ELISA kits. Our research found that hypoxia increased the expression of CaSR in hippocampal neurons and tissue and [Ca(2+)]i in hippocampal neurons. Calhex 231, a selective blocher of CaSR, inhibited the increase in [Ca(2+)]i induced by hypoxia. Hypoxia or GdCl3, an agonist of CaSR, increased the expression of BACE1 in hippocampal neurons and tissue, but Calhex 231 or Xesto C (a selective inhibitor of IP3 receptor) partly prevented hypoxia-induced BACE1 overexpression. Hypoxia or GdCl3 increased the content of Aß42 and Aß40 in hippocampal tissue, however Calhex 231 or Xesto C prevented hypoxia-induced the overproduction of Aß42 and Aß40 partly. Based on the above data, we suggested that hypoxia increased [Ca(2+)]i by elevated CaSR expression to promote BACE1 expression, thereby resulting in the overproduction of Aß42 and Aß40.

Enhancing the biocatalytic synthesis of chiral drug intermediate by rational design an aldo-keto reductase from Bacillus megaterium YC4-R4.

In recent years, with the increasing number of patients with depression, the efficient synthesis of the first-line antidepressant drug duloxetine intermediate (S-N,N-dimethyl-3-hydroxy-3-(2-thienyl)-1-propanamine, S-DHTP) has attracted great attention. The wild-type AKR3-2-9 from Bacillus megaterium YC4-R4 exhibits high application potential of catalyzing N,N-dimethyl-3-keto-3-(2-thienyl)-1-propanamine (DKTP) to prepare S-DHTP, but there is still much room for improvement. In this work, rational design was carried out to enhance the catalytic potential of AKR3-2-9. Notably, compared to the wild-type AKR3-2-9, three mutants (Ile189Val, Asn256Asp, and Ile189Val + Asn256Asp) were obtained, and their catalytic efficiencies were increased by 1.3 times, 2.3 times, and 1.31 times, respectively. Besides, the thermal stability and organic solvent resistance were improved. More importantly, when the concentration of the substrate DKTP was 0.5 g/L, the catalytic yields of Ile189Val, Asn256Asp and Ile189Val + Asn256Asp were increased by 1.45 times, 1.86 times, and 2.05 times, respectively. Besides, the corresponding optical purities of the three mutants were 92.7 %, 94.3 % and 93.8 %. The above results indicated that the rational design of the AKR of Bacillus megaterium YC4-R4 enhanced its potential for biocatalytic preparation of S-DHTP.

Tumor Cell-Specific and Lipase-Responsive Delivery of Hydrogen Sulfide for Sensitizing Chemotherapy of Pancreatic Cancer.

The inability of small molecule drugs to diffuse into tumor interstitium is responsible for the relatively low effectiveness of chemotherapy. Herein, a hydrogen sulfide (H2S) gas-involved chemosensitization strategy is proposed for pancreatic cancer treatment by developing a tumor-specific lipase-responsive nanomedicine based on aptamer-conjugated DATS/Dox co-loaded PCL-b-PEO micelle (DA/D@Ms-A). After receptor-mediated endocytosis and subsequent digestion of PCL blocks by intracellular lipase, the nanomedicine releases Dox and DATS, which then react with intracellular glutathione to produce H2S. The cytotoxicity result indicates that H2S can enhance Dox chemotherapy efficiency owing to the synergetic therapeutic effect of Dox and H2S. Moreover, the nanomedicine is featured with well tumor penetration capability benefitting from the targeting ability of aptamers and high in vivo biocompatibility due to the high density of PEO and biodegradable PCL. The nanomedicine capable of synergetic gas-chemotherapy holds great potential for pancreatic cancer treatment.

Enhanced targeting of 3D pancreatic cancer spheroids by aptamer-conjugated polymeric micelles with deep tumor penetration.

Pancreatic cancer is a high degree malignant tumor which makes its diagnosis and treatment highly critical. The effect of conventional chemotherapy for pancreatic cancer is quite poor due to the low accumulation of the chemotherapeutic drugs at the tumor site. Therefore, enhancing the targeting efficiency and accumulation of the drug carrier at tumor site with subsequent release of drug within the effective time period is one of the key factors for successful targeted chemotherapy of pancreatic cancer. Our previous studies have demonstrated that aptamer can be a valid targeting moiety to guide the chemotherapeutic drug doxorubicin (DOX) to accumulate at the tumor tissue. Herein, the present study aims to further investigate the targeting efficiency as well as therapeutic efficacy of the drug delivery system comprised of aptamer-modified polymeric nano drug carrier encapsulated with DOX (DOX@PCL-b-PEO-Aptamer micelles). The in vitro cytotoxicity studies and laser confocal microscopy indicated that DOX@PCL-b-PEO-Aptamer micelles exhibited enhanced targeting and cytotoxic efficacy towards human pancreatic cancer cells (Panc-1 cells) as compared to free DOX and DOX-loaded PCL-b-PEO-NH2 micelles (DOX@PCL-b-PEO-NH2 micelles). Furthermore, the aptamer-decorated drug delivery system exhibited better tumor penetration into the three-dimensional (3D) spheroid of Panc-1 cells with successful release of DOX as compared to the drug delivery system without aptamer modification. Overall, this study suggests that the aptamer-modified polymeric micelles could be effectively employed for the targeted delivery of anticancer drug to treat pancreatic cancer in near future.