Anti-neuroinflammatory effect of hydroxytyrosol: a potential strategy for anti-depressant development.

Introduction: Depression is a complex psychiatric disorder with substantial societal impact. While current antidepressants offer moderate efficacy, their adverse effects and limited understanding of depression's pathophysiology hinder the development of more effective treatments. Amidst this complexity, the role of neuroinflammation, a recognized but poorly understood associate of depression, has gained increasing attention. This study investigates hydroxytyrosol (HT), an olive-derived phenolic antioxidant, for its antidepressant and anti-neuroinflammatory properties based on mitochondrial protection. Methods: In vitro studies on neuronal injury models, the protective effect of HT on mitochondrial ultrastructure from inflammatory damage was investigated in combination with high-resolution imaging of mitochondrial substructures. In animal models, depressive-like behaviors of chronic restraint stress (CRS) mice and chronic unpredictable mild stress (CUMS) rats were examined to investigate the alleviating effects of HT. Targeted metabolomics and RNA-Seq in CUMS rats were used to analyze the potential antidepressant pathways of HT. Results: HT protected mitochondrial ultrastructure from inflammatory damage, thus exerting neuroprotective effects in neuronal injury models. Moreover, HT reduced depressive-like behaviors in mice and rats exposed to CRS and CUMS, respectively. HT's influence in the CRS model included alleviating hippocampal neuronal damage and modulating cytokine production, mitochondrial dysfunction, and brain-derived neurotrophic factor (BDNF) signaling. Targeted metabolomics in CUMS rats revealed HT's effect on neurotransmitter levels and tryptophan-kynurenine metabolism. RNA-Seq data underscored HT's antidepressant mechanism through the BDNF/TrkB signaling pathways, key in nerve fiber functions, myelin formation, microglial differentiation, and neural regeneration. Discussion: The findings underscore HT's potential as an anti-neuroinflammatory treatment for depression, shedding light on its antidepressant effects and its relevance in nutritional psychiatry. Further investigations are warranted to comprehensively delineate its mechanisms and optimize its clinical application in depression treatment.

Efficient Methylamine-Containing Antisolvent Strategy to Fabricate High-Efficiency and Stable FA0.85Cs0.15Pb(Br0.15I2.85) Perovskite Solar Cells.

Antisolvent and additive strategies are significantly positive to improve the crystal quality, device performance, and long-term stability of perovskite solar cells (PSCs). In addition, the high-quality perovskite thin films could be prepared by the methylamine (MA) gas-induced defect-healing process. However, until now, the research on adding MA into the antisolvent, which may take the advantages of two efficiently modified strategies, is still not systematically studied. Here, we add the MA additive into the chlorobenzene antisolvent to fabricate the FA0.85Cs0.15Pb(Br0.15I2.85) films and achieve the high-quality light-absorbing layers with the preferred orientation of (101). The use of an antisolvent, with an appropriate amount of MA in chlorobenzene, leads to extremely uniform and dense perovskite layers with a better hydrophobic performance and enables the fabrication of remarkably improved solar cells with a power conversion efficiency (PCE) of 19.6% for a champion cell. This strategy shows an encouraging improvement of more than 13.95% compared with the traditional antisolvent strategy. The high-efficiency devices could maintain more than 95 or 88% of their initial PCEs after 500 h under continuous light soaking or thermal aging in the dark at 85 °C in a N2-filled glove box, respectively. These results provide an important progress in the realization of highly efficient and stable PSCs.

A chemically inert bismuth interlayer enhances long-term stability of inverted perovskite solar cells.

Long-term stability remains a key issue impeding the commercialization of halide perovskite solar cells (HPVKSCs). The diffusion of molecules and ions causes irreversible degradation to photovoltaic device performance. Here, we demonstrate a facile strategy for producing highly stable HPVKSCs by using a thin but compact semimetal Bismuth interlayer. The Bismuth film acts as a robust permeation barrier that both insulates the perovskite from intrusion by undesirable external moisture and protects the metal electrode from iodine corrosion. The Bismuth-interlayer-based devices exhibit greatly improved stability when subjected to humidity, thermal and light stresses. The unencapsulated device retains 88% of its initial efficiency in ambient air in the dark for over 6000 h; the devices maintain 95% and 97% of their initial efficiencies after 85 °C thermal aging and light soaking in nitrogen atmosphere for 500 h, respectively. These sound stability parameters are among the best for planar structured HPVKSCs reported to date.

Evaluation of pharmacokinetics and pharmaco-dynamics of sinomenine-hyaluronic acid conjugate after intra-articular administration for osteoarthritis treatment.

OBJECTIVES: Intra-articular injection of sinomenine (SN) is an effective treatment method for knee osteoarthritis (OA), however, SN could be eliminated quickly in vivo. To extend the residence time of SN in the joint cavity, the SN-hyaluronic acid (HA) conjugate was prepared previously. This study was performed to evaluate the pharmacokinetics and pharmacodynamics of SN-HA conjugate after intra-articular administration for the treatment of OA. METHODS: A high performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method was established to determine the SN content in rat synovial fluid. One hundred and twenty rats were randomly divided into two groups, the SN-HA group and SN group. The concentration of SN in articular cavity washings was determined by HPLC-MS/MS. The protective effect on the cartilage was evaluated by histological evaluation in a model of papain induced rabbit knee osteoarthritis. RESULTS: The method was validated with respect to sensitivity, specificity, linearity, precision, accuracy and especially the stability of analytes under various conditions, and was successfully applied in evaluating the pharmacokinetic profiles of SN in the joint cavity. Compared to the SN injection, the drug exposure in joint cavity was significantly increased following SN-HA injection administration, and AUC(0-12h) was 2.9 times of SN injection, mean residence time (MRT) was 1.88 times of SN injection. In the pharmacodynamic study, there was no significant difference between the SN-HA twice-treated group and SH/HA five-times mixture-treated group. CONCLUSION: The local bioavailability of SN in joint cavity was improved significantly after conjugated with HA. The SN-HA conjugate showed good synergism effect of OA inhibition. The results indicated that the SN-HA conjugate seemed to be an effective therapeutic means for the treatment of OA.

Determination of gemcitabine and its metabolite in extracellular fluid of rat brain tumor by ultra performance liquid chromatography-tandem mass spectrometry using microdialysis sampling after intralesional chemotherapy.

The cytotoxic agent Gemcitabine (2',2'-difluoro-2'-deoxycytidine) has been proved to be effective in the treatment of malignant gliomas. A rapid, sensitive and specific ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) assay using microdialysis sampling was developed and validated to quantify gemcitabine and its major metabolite 2',2'-difluoro-2'-deoxyuridine (dFdU) in Sprague-Dawley rat bearing 9L glioma. Microdialysis probes were surgically implanted into the area of rat brain tumor in the striatal hemisphere, and artificial cerebrospinal fluid was used as a perfusion medium. The samples were analyzed directly by UPLC-MS/MS after the addition of 5-bromouracil as an internal standard (IS). Separation was achieved on Agilent SB-C(18) (50 mm × 2.1mm I.D., 1.8 µm) column at 40 °C using an isocratic elution method with acetonitrile and 0.1% formic acid (4:96, v/v) at a flow rate of 0.2 mL/min. Detection was performed using electrospray ionization in positive ion selected reaction monitoring mode by monitoring the following ion transitions m/z 264.0→112.0 (gemcitabine), m/z 265.1→113.0 (dFdU) and m/z 190.9→173.8 (IS). The calibration curves of gemcitabine and dFdU were linear in the concentration range of 0.66-677.08 ng/mL and 0.31-312.00 ng/mL, respectively. The lower limit of quantification of gemcitabine and dFdU were 0.66 ng/mL and 0.31 ng/mL, respectively. The lower limit of detection of gemcitabine and dFdU were calculated to be 0.2 ng/mL and 0.1 ng/mL, respectively. All the validation data, such as intra- and inter-day precision, accuracy, selectivity and stability, were within the required limits. The validated method was simple, precise and accurate, which was successfully employed to determinate the concentrations of gemcitabine and dFdU in the extracellular fluid of rat brain tumor.