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Existing studies have revealed that microRNAs (miRNAs) have a role in cognitive deficits in Alzheimer's disease (AD). However, the function and pathophysiological mechanism of deregulated miRNAs underlying AD pathology remain to be investigated. The present study aimed to clarify the role and mechanism of miR-148a-3p in AD. RNA sequencing, qRT-PCR, and western blot analysis were used to identify the aberrant expression and signaling of miR-148a-3p within cells, mice, and patients with AD. Molecular biology techniques involving luciferase reporter assays, gene overexpression and silencing, chromatin immunoprecipitation, and adeno-associated virus-based miRNA overexpression were used to explore the biological function and mechanisms of miR-148a-3p. Downregulation of miR-148a-3p was identified in AD. Upregulation of miR-148a-3p was found to protect neuronal cells against Aβ-associated tau hyperphosphorylation by directly targeting p35/CDK5 and PTEN/p38 mitogen-activated protein kinase (MAPK) pathways. A mutual regulatory link between miR-148a-3p and PTEN using a feedforward arrangement was confirmed via promotion of transcription and expression of miR-148a-3p by way of the PTEN/Akt/CREB pathway. Significantly, in vivo targeting of miR-148a-3p signaling ameliorated cognitive deficits by decreasing p35/PTEN-elicited tau hyperphosphorylation, accompanied by feedforward transduction of the PTEN/Akt/CREB pathway. In conclusion, the present study implicated the miR-148a-3p/p35/PTEN pathway as an essential contributor to tau hyperphosphorylation and feedforward regulation in AD., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Vascular dementia (VaD) is a common cause of cognitive decline and dementia of vascular origin, but the precise pathological mechanisms are unknown, and so effective clinical treatments have not been established. Tilianin, the principal active compound of total flavonoid extract from Dracocephalum moldavica L., is a candidate therapy for cardio-cerebrovascular diseases in China. However, its potential in the treatment of VaD is unclear. The present study is aimed at investigating the protective effects of tilianin on VaD and exploring the underlying mechanism of the action. A model of VaD was established by permanent 2-vessel occlusion (2VO) in rats. Human neurons (hNCs) differentiated from human-induced pluripotent stem cells were used to establish an oxygen-glucose deprivation (OGD) model. The therapeutic effects and potential mechanisms of tilianin were identified using behavioral tests, histochemistry, and multiple molecular biology techniques such as Western blot analysis and gene silencing. The results demonstrated that tilianin modified spatial cognitive impairment, neurodegeneration, oxidation, and apoptosis in rats with VaD and protected hNCs against OGD by increasing cell viability and decreasing apoptosis rates. A study of the mechanism indicated that tilianin restored p-CaMKII/ERK1/2/CREB signaling in the hippocampus, maintaining hippocampus-independent memory. In addition, tilianin inhibited an ox-CaMKII/p38 MAPK/JNK/NF- κ B associated inflammatory response caused by cerebral oxidative stress imbalance in rats with VaD. Furthermore, specific CaMKII α siRNA action revealed that tilianin-exerted neuroprotection involved increase of neuronal viability, inhibition of apoptosis, and suppression of inflammation, which was dependent on CaMKII α . In conclusion, the results suggested the neuroprotective effect of tilianin in VaD and the potential mechanism associated with dysfunction in the regulation of p-CaMKII-mediated long-term memory and oxidation and inflammation involved with ox-CaMKII, which may lay the foundation for clinical trials of tilianin for the treatment of VaD in the future., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Hailun Jiang et al.)

Tilianin is a naturally occurring phenolic compound with a cardioprotective effect against myocardial ischemia/reperfusion injury (MIRI). The aim of our study was to determine the potential targets and mechanism of action of tilianin against cardiac injury induced by MIRI. An in silico docking model was used in this study for binding mode analysis between tilianin and Ca 2+ /calmodulin-dependent protein kinase II (CaMKII). Oxygen-glucose deprivation/reperfusion- (OGD/R-) injured H9c2 cardiomyocytes and ischemia/reperfusion- (I/R-) injured isolated rat hearts were developed as in vitro and ex vivo models, respectively, which were both treated with tilianin in the absence or presence of a specific CaMKII inhibitor KN93 for target verification and mechanistic exploration. Results demonstrated the ability of tilianin to facilitater the recovery of OGD/R-induced cardiomyocyte injury and the maintenance of cardiac function in I/R-injured hearts. Tilianin interacted with CaMKII δ with an efficient binding performance, a favorable binding score, and restraining p-CaMKII and ox-CaMKII expression in cardiomyocytes injured by MIRI. Importantly, inhibition of CaMKII abolished tilianin-mediated recovery of OGD/R-induced cardiomyocyte injury and maintenance of cardiac function in I/R-injured hearts, accompanied by the disability to protect mitochondrial function. Furthermore, the protective effects of tilianin towards mitochondrion-associated proapoptotic and antiapoptotic protein counterbalance and c-Jun N-terminal kinase (JNK)/nuclear factor- (NF-) κ B-related inflammation suppression were both abolished after pharmacological inhibition of CaMKII. Our investigation indicated that the inhibition of CaMKII-mediated mitochondrial apoptosis and JNK/NF- κ B inflammation might be considered as a pivotal mechanism used by tilianin to exert its protective effects on MIRI cardiac damage., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2020 Hailun Jiang et al.)

Aims: Tilianin, a naturally occurring flavonoid glycoside, possesses versatile biological activities including antioxidant, anti-inflammatory, energy collecting and anti-hypoxic effects. Little is known about the mechanisms underlying the effect of tilianin against ischemic injury in neuronal cells. We aimed to determine the potential targets and mechanisms of tilianin treatment behind the crosstalk pathways induced by oxygen-glucose deprivation (OGD)., Main Methods: We used an in silico docking model for interaction mode analysis and in vitro models for mechanistic exploration and target verification. Protein changes were measured using cellular immunofluorescence and ELISA techniques., Key Findings: The ability of tilianin to promote recovery of OGD-induced neurocytotoxic injury was demonstrated by maintenance of cell viability, membrane integrity and nuclear homogeneity. Tilianin treatment was also found to balance the concentrations of proapoptotic and antiapoptotic proteins that had been modified by OGD-induced mitochondrial dysfunction. Of these intersectional cascades, Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) was found to bind efficiently with tilianin. This presented a certain binding score along with down-regulation of ox-CaMKII and p-CaMKII in SH-SY5Y cells affected by OGD. Importantly, after utilizing KN93, one specific CaMKII inhibitor, tilianin-mediated neuroprotection against OGD was abolished. This effect was accompanied by upregulation of mitochondrial function. Thus, the beneficial effects of tilianin toward mitochondrion-mediated apoptosis and p38/JNK/NF-κB-associated inflammatory pathways were reversed following CaMKII inhibition., Significance: Our study indicated that attenuation of CaMKII-linked signaling mediated through mitochondria and p38/JNK/NF-κB inflammatory pathways is a key mechanism by which tilianin exerts its neuroprotective effects against cerebral ischemia., (Copyright © 2018. Published by Elsevier Inc.)

Objective: To observe the clinical efficacy of methycobal iontophoresis combined with balance acupuncture in the treatment of peripheral facial paralysis., Methods: A total of 108 patients with peripheral facial paralysis were randomly divided into a methycobal iontophoresis combined with balance acupuncture group (a combined group), a methycobal iontophoresis group and a simple balance acupuncture group, 36 cases in each one. Basic medical treatment were given in the three groups. The simple balance acupuncture was applied at contralateral lumbago acupoint, rhinitis acupoint, stomachache acupoint in the simple balance acupuncture group. Methycobal through iontophoresis anodic introduction therapy was given in the methycobal iontophoresis group. On the basic treatment of methycobal iontophoresis, in the combined group, acupuncture was supplied at contralateral lumbago acupoint, rhinitis acupoint and stomachache acupoint. The treatment in all groups was given once a day, for 2 weeks. The House-Brackmann grading scale and the modified portmann score (RPA) method were used to observe the degree of nerve function and facial paralysis before and after treatment, and the clinical efficacy of each group was evaluated., Results: The total effective rate of the combined group was 97.2% (35/36), which was higher than 83.3% (30/36) in the methycobal iontophoresis group and 88.9% (32/36) in the simple balance acupuncture group (all P <0.05). After treatment, the H-B classification of the combined group was significantly different from those of the methycobal iontophoresis group and simple balance acupuncture group (both P <0.05). There was no significant difference between the methycobal iontophoresis group and simple balance acupuncture group ( P >0.05). The RPA score of the combined group was higher than those in the methycobal iontophoresis group and simple balance acupuncture group (both P <0.05), and there was no significant difference in the RPA score between the methycobal iontophoresis group and simple balance acupuncture group ( P >0.05)., Conclusion: Compared with methycobal iontophoresis and simple balance acupuncture therapy, methycobal iontophoresis combined with balance acupuncture therapy can effectively improve the clinical symptoms and signs of peripheral facial paralysis.

A series of chalcone derivatives bearing benzamide or benzenesulfonamide moieties were synthesized and evaluated for their anti-tumor effect on HCT116, MCF7 and 143B cell lines in vitro. SAR analysis showed that compounds bearing a benzenesulfonamide group had greater potency than those bearing a benzamide group. It was also shown that compounds with a mono-methyl or mono-halogen group at the 3-position on the terminal phenyl ring were more effective than those with trifluoromethyl or methoxy groups. Compound 8e exhibited the most potent anti-tumor activities against HCT116, MCF7 and 143B cell lines, with IC 50 values of 0.597, 0.886 and 0.791μM, respectively. Molecular docking studies and enzymatic assays demonstrated that the anti-tumor activity of compound 8e might be regulated by Cat L and Cat K., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In the title compound, C20H19N3O4S, a novel tubulin ligand active against human cancer, the dihedral angle between the pyridine ring and the carbazole ring system is 42.87 (10)°. In the crystal, the mol-ecules are held together by N-H⋯O and C-H⋯O hydrogen bonds into layers, which are assembled into a three-dimensional network via π-π stacking inter-actions between inversion-related pyridine rings, with centroid-centroid distances of 3.5101 (12) Å.

The title compound, C21H22O4, also known as cajanine, features an intra-molecular O-H⋯O hydrogen bond between the adjacent carb-oxy and hy-droxy groups. The benzene rings make an inter-planar angle of 175.4 (2)°. In the crystal, mol-ecules are linked by pairs of O-H⋯O hydrogen bonds, forming inversion dimers.

The title compound, C(17)H(17)ClN(2)O(3)·0.5C(6)H(12), was prepared by the condensation reaction of 4-meth-oxy-3-(propanamido)-benzoic acid with 4-chloro-aniline. The Cl atom, the propionyl CH(3) group and the cyclo-hexyl CH(2) group are disordered over two sets of sites of equal occupancy in both mol-ecules. The cyclo-hexane solvent mol-ecule is disordered over two orientations which were modelled with relative occupancies of 0.484 (4) and 0.516 (4). In the crystal, there are a number of N-H⋯O hydrogen bonds, forming layers perpendicular to (001).

In our previous study, two synthetic thiophenes such as IMB-05 and IMB-15 were found as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and exhibited beneficial effects on glucose tolerance of diabetic mice in vivo. In the present study, their effect on the transactivity of other nuclear receptors was further investigated. IMB-05 and IMB-15 could not only activated PPARγ but also efficiently activate PPARα in GAL4-hPPARα/γ (ligand binding domain (LBD)) chimeric receptor assay and PPAR response element (PPRE)-luc reporter gene assay with EC(50) values of 1.8-5.2 µM, whereas no activity was observed in other nuclear receptor assays. In addition, the maximal efficacy of IMB-05 and IMB-15 in activating PPARα/γ was approximately 30% of that observed with Wy14643 and rosiglitazone. These data indicate that the two thiophene derivatives are novel class of partial PPARα/γ dual agonists, which may be the mechanism underlying their regulatory effects on glucose homeostasis.