Cognitive impairment in cerebral small vessel disease induced by hypertension.

ABSTRACT: Hypertension is a primary risk factor for the progression of cognitive impairment caused by cerebral small vessel disease, the most common cerebrovascular disease. However, the causal relationship between hypertension and cerebral small vessel disease remains unclear. Hypertension has substantial negative impacts on brain health and is recognized as a risk factor for cerebrovascular disease. Chronic hypertension and lifestyle factors are associated with risks for stroke and dementia, and cerebral small vessel disease can cause dementia and stroke. Hypertension is the main driver of cerebral small vessel disease, which changes the structure and function of cerebral vessels via various mechanisms and leads to lacunar infarction, leukoaraiosis, white matter lesions, and intracerebral hemorrhage, ultimately resulting in cognitive decline and demonstrating that the brain is the target organ of hypertension. This review updates our understanding of the pathogenesis of hypertension-induced cerebral small vessel disease and the resulting changes in brain structure and function and declines in cognitive ability. We also discuss drugs to treat cerebral small vessel disease and cognitive impairment.

Cornel Iridoid Glycoside Ameliorated Alzheimer's Disease-Like Pathologies and Necroptosis through RIPK1/MLKL Pathway in Young and Aged SAMP8 Mice.

BACKGROUND: Aging is an important risk factor for sporadic Alzheimer's disease (AD) and other neurodegenerative diseases. Senescence-accelerated mouse-prone 8 (SAMP8) is used as an animal model for brain aging and sporadic AD research studies. The aim of the current study was to investigate the pharmacological effects of cornel iridoid glycoside (CIG), an active ingredient of Cornus officinalis, on AD-type pathological changes in young and aged SAMP8 mice. METHODS: Locomotor activity test was used to detect the aging process of SAMP8 mice. Nissl staining and immunohistochemical staining were applied to detect neurons and myelin basic protein-labelled myelin sheath. Western blotting was used to detect the expression levels of related proteins of synapse, APP processing, and necroptosis. RESULTS: The results showed that SAMP8 mice at the age of 6 and 14 months exhibited lower locomotor activity, age-related neuronal loss, demyelination, synaptic damage, and APP amyloidogenic processing. In addition, the increased levels of receptor-interacting protein kinase-1 (RIPK1), mixed lineage kinase domain-like protein (MLKL), and p-MLKL indicating necroptosis were found in the brain of SAMP8 mice. Intragastric administration of CIG for 2 months improved locomotor activity; alleviated neuronal loss and demyelination; increased the expression of synaptophysin, postsynaptic density protein 95, and AMPA receptor subunit 1; elevated the levels of soluble APPα fragment and disintegrin and metalloproteinase 10 (ADAM10); and decreased the levels of RIPK1, p-MLKL, and MLKL in the brain of young and aged SAMP8 mice. CONCLUSION: This study denoted that CIG might be a potential drug for aging-related neurodegenerative diseases such as AD.

Experimental anti-tumor effect of emodin in suspension - in situ hydrogels formed with self-assembling peptide.

Lung cancer is a major cause of cancer-related deaths worldwide. Stimulus-sensitive hydrogels, which can be formed by responding to stimuli in the cancer microenvironment, have been widely studied as controlled-release carriers for hydrophobic anticancer drugs. In this study, self-assembling peptide RADA16-I was used to encapsulate the hydrophobic drug emodin (EM) under magnetic stirring to form a colloidal suspension, and the colloidal suspension (RADA16-I-EM) was introduced into environments with physiological pH/ionic strength to form hydrogels in situ. The results showed that RADA16-I had good cell compatibility and the RADA16-I-EM in situ hydrogels can obviously reduce the toxicity of EM to normal cells. In addition, compared with free EM (in water suspensions without peptide) at equivalent concentrations, RADA16-I-EM in situ hydrogels significantly reduced the survival fraction of LLC lung cancer cells, while increased the uptake of EM by the cells, and it also induced apoptosis and cell cycle arrest in the G2/M phase more significantly and reduced the migration, invasion, and clone abilities of the cells in vitro. The RADA16-I-EM in situ hydrogels also showed better cancer growth inhibition effects in cancer models (mice bearing LLC cells xenograft cancer), which induced cell apoptosis in the cancer tissue and reduced the toxic side effects of EM on normal tissues and organs in vivo compared with the free EM. It was revealed that RADA16-I can be exploited as a promising carrier for hydrophobic anticancer drugs and has the potential to improve the administration of anticancer drugs to treat cancer effectively with enhanced chemotherapy.

Progress in the Application of Drugs for the Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune and chronic inflammatory demyelinating disease of the central nervous system (CNS), which gives rise to focal lesion in CNS and cause physical disorders. Although environmental factors and susceptibility genes are reported to play a role in the pathogenesis of MS, its etiology still remains unclear. At present, there is no complete cure, but there are drugs that decelerate the progression of MS. Traditional therapies are disease-modifying drugs that control disease severity. MS drugs that are currently marketed mainly aim at the immune system; however, increasing attention is being paid to the development of new treatment strategies targeting the CNS. Further, the number of neuroprotective drugs is presently undergoing clinical trials and may prove useful for the improvement of neuronal function and survival. In this review, we have summarized the recent application of drugs used in MS treatment, mainly introducing new drugs with immunomodulatory, neuroprotective, or regenerative properties and their possible treatment strategies for MS. Additionally, we have presented Food and Drug Administration-approved MS treatment drugs and their administration methods, mechanisms of action, safety, and effectiveness, thereby evaluating their treatment efficacy.

Cornel Iridoid Glycoside Protects Against STAT1-Dependent Synapse and Memory Deficits by Increasing N-Methyl-D-aspartate Receptor Expression in a Tau Transgenic Mice.

P301S transgenic mice are an animal model of tauopathy and Alzheimer's disease (AD), exhibiting tau pathology and synaptic dysfunction. Cornel iridoid glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. In the present study, the purpose was to investigate the effects and mechanisms of CIG on tau pathology and synaptic dysfunction using P301S transgenic mice. The results showed that intragastric administration of CIG for 3.5 months improved cognitive impairments and the survival rate of P301S mice. Electrophysiological recordings and transmission electron microscopy study showed that CIG improved synaptic plasticity and increased the ultrastructure and number of synapse. Moreover, CIG increased the expression levels of N-methyl-D-aspartate receptors (NMDAR) subunits GluN1, GluN2A, and GluN2B, and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit GluA1. We inferred that the major mechanism of CIG involving in the regulation of synaptic dysfunctions was inhibiting the activation of Janus kinase-2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) signaling pathway and alleviating STAT1-induced suppression of NMDAR expressions. Based on our findings, we thought CIG might be a promising candidate for the therapy of tauopathy such as AD.

Effects of Xiaochaihu decoction on the expression of cytochrome P450s in rats.

Xiaochaihu decoction is one of the most important traditional Chinese medicines that is widely used with other drugs in clinical practice, and may cause drug-drug interactions. However, there is not sufficient experimental evidence for the effects of Xiaochaihu decoction on cytochrome P450s (CYPs). The aim of the present study was to investigate the effects of Xiaochaihu decoction on the mRNA and protein levels of hepatic CYPs. Eighty normal male Sprague-Dawley (SD) rats were randomly divided into two groups based on body weight and duration of drug administration (3 and 6 days). Each group was further divided into subgroups: Control group (2 ml 5‰ CMC-Na); hepatic enzyme inducer group (50 mg/kg/day rifampicin); and experimental groups (Xiaochaihu decoction: Low dose, 1.7 g/kg/day; medium dose, 3.4 g/kg/day; high dose, 6.8 g/kg/day). The effects of Xiaochaihu decoction on Cyp1a2, Cyp3a1, Cyp2d6, and Cyp1b1 mRNA and protein expression in rats were evaluated using reverse transcription quantitative reverse transcription polymerase chain reaction and western blot analysis. After 3 days, medium dose of Xiaochaihu decoction inhibited the mRNA and protein expression of Cyp1a2, Cyp3a1 and Cyp1b1. In addition, after 6 days, Xiaochaihu decoction induced Cyp3a1 mRNA expression at low and medium doses; Cyp2d6 mRNA expression at low and high doses; and Cyp2d6 protein expression at high doses. Nonetheless, the gene and protein expression of Cyp1b1 was not affected at any dose. The findings of the present study may provide insights into potential drug-drug interactions associated with Xiaochaihu decoction.

Antitumor Effects of Self-Assembling Peptide-Emodin in situ Hydrogels in vitro and in vivo.

PURPOSE: To study the in vitro and in vivo antitumor effects of the colloidal suspension-in situ hydrogel of emodin (EM) constructed with the self-assembling peptide RADA16-I and systematically evaluate the feasibility of the delivery system. METHODS: The MTT and colony-formation assays were used to determine the viability of normal cells NCTC 1469 and tumor cells Hepa1-6. The uptake of EM in the RADA16-I-EM in situ hydrogel by tumor cells was analyzed by laser confocal microscope and flow cytometry. Flow cytometry was used to detect the cell apoptosis and cell cycle distribution. Transwell assay was used to detect the migration and invasion of tumor cells. The antitumor efficacy of the RADA16-I-EM in situ hydrogel and its toxic effects was further assessed in vivo on Hepa1-6 tumor-bearing C57 mice. RESULTS: The results showed that the RADA16-I-EM in situ hydrogels could obviously reduce the toxicity of EM to normal cells and the survival of tumor cells. The uptake of EM by the cells from the hydrogels was obviously increased and could significantly induce apoptosis and arrest cell cycle in the G2/M phase, and reduce the migration, invasion and clone-formation ability of the cells. The RADA16-I-EM in situ hydrogel could also effectively inhibit the tumor growth and obviously decrease the toxic effects of EM on normal tissues in vivo. CONCLUSION: Our results demonstrated that RADA16-I has the potential to be a carrier for the hydrophobic drug EM and can effectively improve the delivery of hydrophobic antitumor drugs with enhanced antitumor effects and reduced toxic effects of the drugs on normal cells and tissues.

Effects of saikosaponin-d on CYP3A4 in HepaRG cell and protein-ligand docking study.

Saikosaponin-d (SSd) is a major bioactive triterpenoid saponin extracted from Bupleurum, which has anti-inflammatory, anticancer, antioxidative and anti-hepatic fibrosis effects. Due to the effects of Bupleurum-related formulations on cytochrome P450 (CYPs) expression still remain unclear, the combination therapies involved formulations containing Bupleurum may sometimes lead to unexpected drug-drug interactions in clinical practice. These interactions can limit the clinical applications of related formulations. In this study, we tried to explore the effects of SSd on CYP3A4 mRNA, protein expression and the enzyme activity in HepaRG cells by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR), Western blot (WB) and HPLC method, respectively. The interaction between SSd and CYP3A4 was analysed by molecular docking. HepaRG cells were cultured with different concentrations of SSd (0.5, 1, 5 and 10 µmol/L) for 72 hours. It is revealed that SSd can inhibit CYP3A4 mRNA and its protein expression, and also the enzyme activity. Molecular docking study demonstrated that SSd can bind to several key active sites of amino acid residues of CYP3A4 protein with hydrogen bonds and hydrophobic interactions. Thus, drug-drug interactions resulted by SSd inhibiting CYP3A4 need attention when formulations containing SSd or Bupleurum are co-administrated with drugs metabolized by CYP3A4.

Effects of Saikosaponin D on CYP1A2 and CYP2D6 in HepaRG Cells.

BACKGROUND: Bupleurum is one of the most important traditional Chinese medicines and an ingredient in many compound preparations. It is widely used together with other drugs in clinical practice, and thus there is great potential for drug-drug interactions. Saikosaponin D (SsD) is a major bioactive triterpenoid saponin extracted from Bupleurum with anti-inflammatory, anticancer, antioxidative, and antihepatic fibrosis effects. Effects of the main components of Bupleurum on cytochromes P450 (CYPs) need to be clarified in the clinical application of combination therapies of formulations containing SsD or Bupleurum. PURPOSE: This study aimed to investigate the effects of SsD on the CYP1A2 and CYP2D6 mRNAs, protein expression, and relative enzyme activities in HepaRG cells. METHODS: HepaRG cells were cultured with SsD at concentrations of 0.5, 1, 5 and 10 µM for 72 hours. mRNA and protein expression of CYP1A2 and CYP2D6 were analyzed with real-time PCR and Western blot analysis. Relative enzyme activities were analyzed with HPLC based on consumption of the specific probe substrate. RESULTS: SsD significantly induced expression of mRNA and increased relative activity of CYP1A2 in HepaRG cells after the cells had been treated with SsD at concentrations of 1, 5 and 10 µM. SsD also induced protein expression of CYP1A2 at concentrations of 5 and 10 µM. SsD exhibited an inductive effect on CYP2D6 mRNA and protein expression, while increasing the relative activity of CYP2D6 at concentrations of 5 and 10 µM. CONCLUSION: This study is the first to investigate the effect of SsD on CYP1A2 and CYP2D6 in HepaRG cells, and the results may provide some useful information on potential drug-drug interactions related to clinical preparations containing SsD or Bupleurum.

Correlation Between Patients' Medication Adherence and Their Psychological Contract with Hospital Pharmacists.

OBJECTIVE: To investigate the correlation between patients' medication adherence and their psychological contract with hospital pharmacists under the background of the pharmacist-patient relationship, providing a reference for improving the pharmacist-patient relationship and the patients' medication adherence based on the patients' psychological contract with the hospital pharmacists. MATERIALS AND METHODS: Some of the patients who received medication dispensing service at the outpatient pharmacies at the First Affiliated Hospital of Zunyi Medical University and the Second Affiliated Hospital of Zunyi Medical University were included and investigated as follows: 320 patients were included through the convenient sampling method for psychological contract and medication adherence questionnaire survey with the self-designed scales for patients' psychological contract with the hospital pharmacists and their medication adherence. SPSS 17.0 was used for reliability and validity testing, correlation analysis, and multiple linear regression analysis. RESULTS: The average score of the psychological contract was 3.80±0.59. The average score of the patients' medication adherence was 2.93±0.70. The patients' psychological contract with the pharmacists and its dimensions (the responsibility of competence, the responsibility of service, and the responsibility of humanistic care) were positively correlated with medication adherence (P<0.05). The results of the multiple linear regression analysis showed that the effect of patients' psychological contract with the pharmacists on medication adherence was statistically significant (P<0.05). CONCLUSION: Outpatients' psychological contract with the pharmacists is positively correlated with their medication adherence. Maintaining the patients' psychological contract with the pharmacists may be an effective way to improve medication adherence.

Application of Once-Monthly Self-Reported ACT Questionnaire in Management of Adherence to Inhalers in Outpatients with Asthma.

PURPOSE: Poor medication adherence can negatively affect health outcomes of patients with asthma from medication and significantly increase the healthcare costs. Management of adherence to inhalers remains a challenging topic in the long-term management of patients with asthma. We aim to evaluate the role of asthma control test (ACT) in the management of adherence to inhalers in outpatients with asthma. PATIENTS AND METHODS: Six hundred twenty-seven outpatients with asthma admitted to the clinic of respiratory medicine in a tertiary hospital in northwestern China during 2016 to 2019 were randomly divided into observation group (n= 315) and control (n= 312) and received standard inhalant therapy for 6 months and lung function test before and after treatment. The patients in the observation group took ACT questionnaires at the end of each month, while the patients in control only took an ACT at the end of the last month. The 'Test of Adherence to Inhalers' (TAI) questionnaire was used to evaluate the patients' adherence to inhalant therapy. RESULTS: All patients completed the study. The ACT scores in the observation group showed a gradual increase month by month. The TAI results indicated that adherence to inhalers of patients in the observation group was significantly better than that in control and the patients' non-adherence pattern in the observation group, with significantly lower erratic non-adherence, was also different from that in control. After 6 months of treatment, the lung function indexes and their relative improvement and the ACT scores in the observation group were significantly better or higher than those in control. CONCLUSION: The once-monthly self-reported ACT can effectively improve the adherence to inhalers of outpatients with asthma mainly by addressing erratic non-adherence and improve the treatment effects, and thus deserves widespread use in the treatment adherence management in patients with asthma.

Research progress in the application of in situ hydrogel system in tumor treatment.

The in situ hydrogel drug delivery system is a hot research topic in recent years. Combining both properties of hydrogel and solution, in situ hydrogels can provide many advantages for drug delivery application, including easy application, high local drug concentration, prolonged drug retention time, reduced drug dose in vivo, good biocompatibility and improved patient compliance, thus has potential in tumor treatment. In this paper, the related literature reports in recent years were reviewed to summarize and discuss the research progress and development prospects in the application of in situ hydrogels in tumor treatment.

Study of the interaction between self-assembling peptide and mangiferin and in vitro release of mangiferin from in situ hydrogel.

OBJECTIVE: This study aimed to investigate the interaction between the ion-complementary self-assembling peptide RADA16-I and the hydrophobic drug mangiferin (MA), and the potential of the self-assembling peptide to be exploited as a drug carrier of MA. METHODS: The RADA16-I-MA suspension was prepared by magnetic stirring, followed by fluorescence spectrophotometry, particle size determination, rheological properties analysis, and in vitro release assay to characterize the interaction between RADA16-I and MA. Then, the effects of in situ MA-loaded hydrogel on the proliferation of KYSE 30 and DLD-1 tumor cells and the toxic effect of the hydrogel on 293T renal epithelial cells were studied by the Cell Counting Kit 8 method. RESULTS: The RADA16-I-MA suspension was formed in water under magnetic stirring; the in situ hydrogel was formed when the suspension was added to PBS. The particle size in the RADA16-I-MA suspension was around 300-600 nm with an average size of 492 nm. Within 24 h, the cumulative release of MA from the RADA16-I-MA hydrogel was about 80%. The release rate of MA from the hydrogel was dependent on the concentration of RADA16-I and the release can be fitted with a first-order kinetic equation. The results suggested that the self-assembling peptide can stabilize MA in water to form a relatively stable suspension; the results also indicated that controlled release of MA from the RADA16-I-MA in situ hydrogel formed from the RADA16-I-MA suspension can be achieved by adjusting the concentration of the peptide in suspension. The cell viability studies showed that the RADA16-I-MA in situ hydrogel not only can maintain or enhance the intrinsic proliferation inhibition effects of MA on tumor cells, but also can reduce the toxicity of MA to normal cells. CONCLUSION: The self-assembling peptide RADA16-I can be a potential candidate for constructing a delivery system of the hydrophobic drug MA.

The interaction between self - assembling peptides and emodin and the controlled release of emodin from in-situ hydrogel.

Ion-complementary self-assembling peptides have potential in delivering hydrophobic drugs. This study involved two self-assembling peptides, RADA16-I and RVDV16-I, of which RVDV16-I was a novel self-assembling peptide with different hydrophobic side chains designed from RADA16-I. The purpose of this study was to observe the interaction between different self-assembling peptides and emodin through fluorescence spectrophotometry, CD, SEM and AFM; to construct a preliminary suspension in-situ hydrogel delivery system for emodin with the self-assembling peptides; and to investigate the drug-loading and drug-releasing properties of the self-assembling peptides on emodin. The results showed that both peptides can interact with emodin and the interaction was dominated by hydrophobic interaction. The aqueous solutions of both self-assembling peptides can form relatively stable suspensions with emodin under mechanical stirring, and the suspension can form in-situ hydrogel under physiological condition. In vitro release of emodin from the hydrogels showed a manner of sustained release to some extent. Cell viability studies showed inherent proliferation inhibiting effects of emodin on tumor cells was maintained or enhanced through the in-situ hydrogels. The self-assembling peptides RADA16-I and RVDV16-I had showed promising drug-loading and drug-releasing performance for hydrophobic drugs. It is reasonable to exploit self-assembling peptides as drug carriers for their great potential to improve delivery of hydrophobic drugs.