Dihydromyricetin improves high glucose induced dopaminergic neuronal damage by activating AMPK-autophagy signaling pathway.

In recent years, a growing number of clinical and biological studies have shown that patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing Parkinson's disease (PD). Prolonged exposure to hyperglycemia results in abnormal glucose metabolism, which in turn cause pathological changes similar to PD, leading to selective loss of dopaminergic neurons in the compact part of substantia nigra. Dihydromyricetin (DHM) is a naturally occurring flavonoid with various biological activities including antioxidant and hepatoprotective properties. The aim of this study was to investigate whether DHM modulates high glucose-induced dopaminergic neuronal damage and its mechanism. We found that DHM ameliorated high glucose-induced dopaminergic neuronal damage and autophagy injury. Inhibition of autophagy by 3-methyladenine (3-MA) abrogated the beneficial effects of DHM on high glucose-induced dopaminergic neuronal damage. In addition, DHM increased levels of p-AMPK and p-ULK1. The AMPK inhibitor Compound C (CC) eliminated DHM-induced autophagy and subsequently inhibited the ameliorative effects of DHM on high glucose-induced dopaminergic neuronal damage. Taken together, DHM ameliorate high glucose-induced dopaminergic neuronal damage by activating AMPK-autophagy pathway.

Regulatory T and CXCR3+ Circulating Tfh Cells Concordantly Shape the Neutralizing Antibody Responses in Individuals Who Have Recovered from Mild COVID-19.

Regulatory T (Treg) cells are involved in the antiviral immune response in patients with coronavirus disease 2019 (COVID-19); however, whether Treg cells are involved in the neutralizing antibody (nAb) response remains unclear. Here, we found that individuals who recovered from mild but not severe COVID-19 had significantly greater frequencies of Treg cells and lower frequencies of CXCR3+ circulating T follicular helper (cTfh) cells than healthy controls. Furthermore, the frequencies of Treg and CXCR3+ cTfh cells were negatively and positively correlated with the nAb responses, respectively, and Treg cells was inversely associated with CXCR3+ cTfh cells in individuals who recovered from mild COVID-19 but not in those with severe disease. Mechanistically, Treg cells inhibited memory B-cell differentiation and antibody production by limiting the activation and proliferation of cTfh cells, especially CXCR3+ cTfh cells, and functional molecule expression. This study provides novel insight showing that mild COVID-19 elicits concerted nAb responses, which are shaped by both Treg and Tfh cells.

Characterization and Dissolution Mechanism of Low-Molecular-Weight Organic Acids or Inorganic Mesoporous Particle-Based Piperine Amorphous Solid Dispersions.

The objective of the current study is to prepare amorphous solid dispersions (ASDs) containing piperine (PIP) by utilizing organic acid glycyrrhizic acid (GA) and inorganic disordered mesoporous silica 244FP (MSN/244FP) as carriers and to investigate their dissolution mechanism. The physicochemical properties of ASDs were characterized with scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). Fourier transform infrared spectroscopy (FTIR) and one-dimensional proton nuclear magnetic resonance (1H NMR) studies collectively proved that strong hydrogen-bonding interactions formed between PIP and the carriers in ASDs. Additionally, molecular dynamic (MD) simulation was conducted to simulate and predict the physical stability and dissolution mechanisms of the ASDs. Interestingly, it revealed a significant increase in the dissolution of amorphous PIP in ASDs in in vitro dissolution studies. Rapid dissolution of GA in pH 6.8 medium resulted in the immediate release of PIP drugs into a supersaturated state, acting as a dissolution-control mechanism. This exhibited a high degree of fitting with the pseudo-second-order dynamic model, with an R2 value of 0.9996. Conversely, the silanol groups on the outer surface of the MSN and its porous nanostructures enabled PIP to display a unique two-step drug release curve, indicating a diffusion-controlled mechanism. This curve conformed to the Ritger-Peppas model, with an R2 > 0.9. The results obtained provide a clear evidence of the proposed transition of dissolution mechanism within the same ASD system, induced by changes in the properties of carriers in a solution medium of varying pH levels.

SARS-CoV-2 spike-specific TFH cells exhibit unique responses in infected and vaccinated individuals.

Long-term humoral immunity to SARS-CoV-2 is essential for preventing reinfection. The production of neutralizing antibody (nAb) and B cell differentiation are tightly regulated by T follicular help (TFH) cells. However, the longevity and functional role of TFH cell subsets in COVID-19 convalescents and vaccine recipients remain poorly defined. Here, we show that SARS-CoV-2 infection and inactivated vaccine elicited both spike-specific CXCR3+ TFH cell and CXCR3- TFH cell responses, which showed distinct response patterns. Spike-specific CXCR3+ TFH cells exhibit a dominant and more durable response than CXCR3- TFH cells that positively correlated with antibody responses. A third booster dose preferentially expands the spike-specific CXCR3+ TFH cell subset induced by two doses of inactivated vaccine, contributing to antibody maturation and potency. Functionally, spike-specific CXCR3+ TFH cells have a greater ability to induce spike-specific antibody secreting cells (ASCs) differentiation compared to spike-specific CXCR3- TFH cells. In conclusion, the persistent and functional role of spike-specific CXCR3+ TFH cells following SARS-CoV-2 infection and vaccination may play an important role in antibody maintenance and recall response, thereby conferring long-term protection. The findings from this study will inform the development of SARS-CoV-2 vaccines aiming to induce long-term protective immune memory.

Synthesis and biological evaluation of substituted 3-(2'-benzimidazolyl)coumarin platinum(II) complexes as new telomerase inhibitors.

Eight new platinum(II) complexes Pt1-Pt8 with substituted 3­(2'­benzimidazolyl) coumarins were successfully synthesized and characterized by single crystal X-ray diffraction analysis, nuclear magnetic resonance spectroscopy (NMR), electrospray ionization-mass spectrometry (ESI-MS), infrared spectrophotometry (IR) and elemental analysis. Crystallographic data of these Pt1-Pt8 complexes showed that the Pt(II) has distorted four-coordinated square planar geometry. Pt1-Pt8 were found to display high cytotoxic activity in vitro against the cisplatin-resistant SK-OV-3/DDP cancer cells with a low IC50 from 1.01-10.32 µM, but low cytotoxicity on the normal HL-7702 cells. Further studies revealed that Pt1-Pt3 induced apoptosis in SK-OV-3/DDP cancer cells via mitochondria dysfunction signaling pathways. Our findings also indicated that Pt1 was a telomerase inhibitor targeting c-myc promoter elements.

Lipase-immobilized biocatalytic membranes for biodiesel production.

Microbial lipase from Candida rugosa (Amano AY-30) has good transesterification activity and can be used for biodiesel production. In this study, polyvinylidene fluoride (PVDF) membrane was grafted with 1,4-diaminobutane and activated by glutaraldehyde for C. rugosa lipase immobilization. After immobilization, the biocatalytic membrane was used for producing biodiesel from soybean oil and methanol via transesterification. Response Surface Methodology (RSM) in combination with a 5-level-5-factor central composite rotatable design (CCRD) was employed to evaluate the effects of reaction time, reaction temperature, enzyme amount, substrate molar ratio and water content on the yield of soybean oil methyl ester. By ridge max analysis, the predicted and experimental yields under the optimum synthesis conditions were 97% and 95%, respectively. The lipase-immobilized PVDF membrane showed good reuse ability for biodiesel production, enabling operation for at least 165 h during five reuses of the batch, without significant loss of activity.