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This study aims to explore the change of intimate relationship between people with Alzheimer's disease and their adult child caregivers as the disease progresses. Twelve adult child caregivers were recruited through purposive sampling. Explanatory phenomenological analysis was conducted to analyse data collected by semi-structured in-depth interviews. This study found a dynamically changing relationship between adult child caregivers and their parents with Alzheimer's disease during care giving that evolved with the progress of the disease. The relationship was the most intimate in the middle stage of the disease for most caregivers and a new reciprocal relationship developed due to caregiving. Caregivers experienced different degrees of self-growth when providing care, though caregiver burdens were common. The positive experience and perception of caregivers were important for improving the quality of life for adult child caregivers of people with Alzheimer's disease., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Treating neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) remains highly challenging. Noninvasive brain stimulation using repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) is of considerable interest in this context., Objective: To investigate the efficacy and safety of a novel technique involving simultaneous application of rTMS and tDCS (rTMS-tDCS) over bilateral angular gyrus (AG, P5/P6 electrode site) for AD-related NPS., Methods: Eighty-four AD patients were randomized to receive rTMS-tDCS, single-rTMS, single-tDCS, or sham stimulation for 4 weeks, with evaluation at week-4 (W4, immediately after treatment) and week-12 (W12, follow-up period) after initial examination. Primary outcome comprising Neuropsychiatric Inventory (NPI) score and secondary outcomes comprising mini-mental state examination (MMSE), AD assessment scale-cognitive subscale (ADAS-cog), and Pittsburgh sleep quality index (PSQI) scores were collected and analyzed by a two-factor (time and treatment), mixed-design ANOVA., Results: rTMS-tDCS produced greater improvement in NPI scores than single-tDCS and sham at W4 and W12 (both P < 0.017) and trended better than single-rTMS (W4: P = 0.058, W12: P = 0.034). rTMS-tDCS improved MMSE scores compared with single-tDCS at W4 (P = 0.011) and sham at W4 and W12 (both P < 0.017). rTMS-tDCS also significantly improved PSQI compared with single-rTMS and sham (both P < 0.017). Interestingly, rTMS-tDCS-induced NPI/PSQI improvement was significantly associated with MMSE/ADAS-cog improvement. tDCS- and/or rTMS-related adverse events appeared slightly and briefly., Conclusions: rTMS-tDCS application to bilateral AG can effectively improve AD-related NPS, cognitive function, and sleep quality with considerable safety., Competing Interests: Declaration of competing interest 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 © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Cholinergic neurons are ubiquitous and involved in various higher brain functions including learning and memory. Patients with Alzheimer's disease exhibit significant dysfunction and loss of cholinergic neurons. Meanwhile, such cholinergic deficits can be potentially relieved pharmacologically by increasing acetylcholine. Acetylcholinesterase (AChE) inhibitors have been used to improve cholinergic transmission in the brain for two decades and have proven effective for alleviating symptoms in the early stages of Alzheimer's disease. Therefore, the search for AChE inhibitors for drug development is ongoing. The enzymatic pocket of AChE has long been the target of several drug designs over the last two decades. The peripheral and catalytic sites of AChE are simultaneously bound by several dimeric molecules, enabling more-efficient inhibition. Here, we used 6-chlorotacrine and the tetrahydroquinolone moiety of huperzine A to design and synthesize a series of heterodimers that inhibit AChE at nanomolar potency. Specifically, compound 7b inhibits AChE with an IC 50  < 1 nM and spares butyrylcholinesterase. Administration of 7b to mouse brain slices restores synaptic activity impaired by pirenzepine, a muscarinic M1-selective antagonist. Moreover, oral administration of 7b to C57BL/6 mice enhances hippocampal long-term potentiation in a dose-dependent manner and is detectable in the brain tissue. All these data supported that 7b is a potential cognitive enhancer and is worth for further exploration., Competing Interests: Declaration of competing interest 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 Elsevier Masson SAS. All rights reserved.)

Background: Surgical treatment remains the best option for patients with hepatocellular carcinoma (HCC) caused by chronic hepatitis B virus (HBV) infection. However, there is no optimal tool based on readily accessible clinical parameters to predict postoperative complications. Herein, our study aimed to develop models that permitted risk of severe complications to be assessed before and after liver resection based on conventional variables., Methods: A total of 1,047 patients treated by hepatectomy for HCC with HBV infection at three different centers were recruited retrospectively between July 1, 2014, and July 1, 2018. All surgical complications were recorded and scored by the Comprehensive Complication Index (CCI). A CCI ≥26.2 was used as a threshold to define patients with severe complications. We built two models for the CCI, one using preoperative and one using preoperative and postoperative data. Besides, CCI and other potentially relevant factors were evaluated for their ability to predict early recurrence and metastasis. All the findings were internally validated in the Hangzhou cohort and then externally validated in the Lanzhou and Urumqi cohorts., Results: Multivariable analysis identified National Nosocomial Infections Surveillance (NNIS) index, tumor number, gamma-glutamyltransferase (GGT), total cholesterol (TC), potassium, and thrombin time as the key preoperative parameters related to perioperative complications. The nomogram based on the preoperative model [preoperative CCI After Surgery for Liver tumor (CCIASL-pre)] showed good discriminatory performance internally and externally. A more accurate model [postoperative CCI After Surgery for Liver tumor (CCIASL-post)] was established, combined with the other four postoperative predictors including leukocyte count, basophil count, erythrocyte count, and total bilirubin level. No significant association was observed between CCI and long-term complications., Conclusion: Based on the widely available clinical data, statistical models were established to predict the complications after hepatectomy in patients with HBV infection. All the findings were extensively validated and shown to be applicable nationwide. Such models could be used as guidelines for surveillance follow-up and the design of post-resection adjuvant therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bao, Zhu, Aji, Wei, Tuergan, Ha, Tulahong, Hu and Hu.)

Background: Recent studies report that hospital staff at the forefront of caring for COVID-19 patients experience increased psychological distress. To effectively manage the outbreak of COVID-19, China established COVID-19 designated and non-designated hospitals. To date, few studies have examined the impacts of COVID-19 on psychological health of staff working at non-designated hospitals. This study is to explore factors affecting psychological health of non-designated hospital staff in China during the COVID-19 pandemic. Methods: Data were collected through an online questionnaire between February and March 2020. The questionnaire consists of General Health Questionnaire (GHQ-20), Social Support Rating Scale (SSRS), Simplified Coping Style Questionnaire (SCSQ), sociodemographic characteristics, employment history, health status, and contact history of COVID-19. The questionnaire was distributed through hospital WeChat groups and work colleague referrals. A total of 470 non-designated hospital staff members completed the questionnaire. Multiple Linear Regression analysis was used to interpret the associations among social support, coping styles, sociodemographic factors, job roles, and psychological status. Data were analyzed using SPSS version 21.0. Results: The non-designated hospital staff differed significantly in anxiety and depression subscores of the GHQ-20 by their job roles, levels of social support, and history of mental disorders. Staff with medical job roles, good self-reported health status, no previous mental disorders, adequate social support, and positive coping styles scored lower in GHQ-20 total score, which indicated healthier psychological status. Conclusions: The results indicate that history of mental health disorders, non-medical job roles, and inadequate social support are associated with greater psychological distress. Personalized support should be provided to those who are vulnerable and in need of social and psychological support., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer HW declared a shared affiliation with several of the authors, DY, JL, ZM, ML, WL, HM, YH, to the handling editor at time of review., (Copyright © 2021 Yao, Lyu, Ma, Champ, Xiong, Li, Li, Mu, Hu, Gao and Jia.)

Amyloid-beta peptides generated by β-secretase- and γ-secretase-mediated successive cleavage of amyloid precursor protein are believed to play a causative role in Alzheimer's disease. Thus, reducing amyloid-beta generation by modulating γ-secretase remains a promising approach for Alzheimer's disease therapeutic development. Here, we screened fruit extracts of Ligustrum lucidum Ait. (Oleaceae) and identified active fractions that increase the C-terminal fragment of amyloid precursor protein and reduce amyloid-beta production in a neuronal cell line. These fractions contain a mixture of two isomeric pentacyclic triterpene natural products, 3- O - cis - or 3- O - trans - p -coumaroyl maslinic acid (OCMA), in different ratios. We further demonstrated that trans -OCMA specifically inhibits γ-secretase and decreases amyloid-beta levels without influencing cleavage of Notch. By using photoactivatable probes targeting the subsites residing in the γ-secretase active site, we demonstrated that trans -OCMA selectively affects the S1 subsite of the active site in this protease. Treatment of Alzheimer's disease transgenic model mice with trans -OCMA or an analogous carbamate derivative of a related pentacyclic triterpene natural product, oleanolic acid, rescued the impairment of synaptic plasticity. This work indicates that the naturally occurring compound trans -OCMA and its analogues could become a promising class of small molecules for Alzheimer's disease treatment.

Ovarian cancer (OV) is one of the leading causes of cancer deaths in women worldwide. Late diagnosis and heterogeneous treatment result to poor survival outcomes for patients with OV. Therefore, we aimed to develop novel biomarkers for prognosis prediction from the potential molecular mechanism of tumorigenesis. Eight eligible data sets related to OV in GEO database were integrated to identify differential expression genes (DEGs) between tumour tissues and normal. Enrichment analyses discovered DEGs were most significantly enriched in G2/M checkpoint signalling pathway. Subsequently, we constructed a multi-gene signature based on the LASSO Cox regression model in the TCGA database and time-dependent ROC curves showed good predictive accuracy for 1-, 3- and 5-year overall survival. Utility in various types of OV was validated through subgroup survival analysis. Risk scores formulated by the multi-gene signature stratified patients into high-risk and low-risk, and the former inclined worse overall survival than the latter. By incorporating this signature with age and pathological tumour stage, a visual predictive nomogram was established, which was useful for clinicians to predict survival outcome of patients. Furthermore, SNRPD1 and EFNA5 were selected from the multi-gene signature as simplified prognostic indicators. Higher EFNA5 expression or lower SNRPD1 indicated poorer outcome. The correlation between signature gene expression and clinical characteristics was observed through WGCNA. Drug-gene interaction was used to identify 16 potentially targeted drugs for OV treatment. In conclusion, we established novel gene signatures as independent prognostic factors to stratify the risk of OV patients and facilitate the implementation of personalized therapies., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Tai Chi exercise is a non-pharmacological therapy that has received increased attention in recent years. A Tai Chi program has been specifically modified for older people with cognitive impairments by the research team., Objective: We aim to assess the effects of this Tai Chi program on mild dementia., Methods: Eighty older people with mild dementia were recruited and randomly assigned to a Tai Chi group or a control group. The Tai Chi group practiced the Tai Chi program three times a week for 10 months, while the control group continued receiving routine treatments. All participants were assessed for cognitive function, behavior/mood, and activities of daily living at baseline, 5 months, and 10 months., Results: The Tai Chi group performed better than the control group. Repeated measures ANOVA revealed a significant group×time interaction in the Montreal Cognitive Assessment (MoCA). Further analysis of sub-items of the MoCA showed a significant time effect in naming and abstraction. It was statistically significant in both main effect of time and group×time interaction in the Neuropsychiatric Inventory (NPI) and Geriatric Depression Scale (GDS). Paired sample t test showed the Tai Chi group scored lower at 5 and 10 months in the NPI and at 10 months in the GDS compared with baseline. The Tai Chi group scored lower than the control group at 10 months in the NPI and GDS., Conclusion: The results suggest this Tai Chi program may help improve cognitive function and mental well-being for older adults with mild dementia.

Background: Indole-3-acetic acid (IAA) extraction and purification are of great importance in auxin research, which is a hot topic in the plant growth and development field. Solid-phase extraction (SPE) is frequently used for IAA extraction and purification. However, no IAA-specific SPE columns are commercially available at the moment. Therefore, the development of IAA-specific recognition materials and IAA extraction and purification methods will help researchers meet the need for more precise analytical methods for research on phytohormones., Results: Since the AUXIN RESISTANT/INDOLE-3-ACETIC ACID INDUCIBLE (Aux/IAA) proteins show higher specific binding capability with auxin, recombinant IAA1, IAA7 and IAA28 proteins were used as sorbents to develop an IAA extraction and purification method. A GST tag was used to solidify the recombinant protein in a column. Aux/IAA proteins solidified in a column have successfully trapped trace IAA in aqueous solutions. The IAA7 protein showed higher IAA binding capability than the other proteins tested. In addition, expression of the IAA7 protein in Drosophila Schneider 2 (S2) cells produced better levels of binding than IAA7 expressed in E. coli ., Conclusion: This work validated the potential of Aux/IAA proteins to extract and purify IAA from crude plant extracts once we refined the techniques for these processes.

Brassinosteroids (BRs) are steroidal phytohormones that regulate various physiological processes, such as root development and stress tolerance. In the present study, we showed that brassinolide (BL) affects potato root in vitro growth in a dose-dependent manner. Low BL concentrations (0.1 and 0.01  μ g/L) promoted root elongation and lateral root development, whereas high BL concentrations (1-100  μ g/L) inhibited root elongation. There was a significant ( P < 0.05) positive correlation between root activity and BL concentrations within a range from 0.01 to 100  μ g/L, with the peak activity of 8.238 mg TTC·g -1 FW·h -1 at a BL concentration of 100  μ g/L. Furthermore, plants treated with 50  μ g/L BL showed enhanced salt stress tolerance through in vitro growth. Under this scenario, BL treatment enhanced the proline content and antioxidant enzymes' (superoxide dismutase, peroxidase, and catalase) activity and reduced malondialdehyde content in potato shoots. Application of BL maintain K + and Na + homeostasis by improving tissue K + /Na + ratio. Therefore, we suggested that the effects of BL on root development from stem fragments explants as well as on primary root development are dose-dependent and that BL application alleviates salt stress on potato by improving root activity, root/shoot ratio, and antioxidative capacity in shoots and maintaining K + /Na + homeostasis in potato shoots and roots.

Objective. To investigate the efficacy and safety of traditional Chinese medicine Duliang soft capsule (DSC) in prophylactic treatment for patients with chronic daily headache (CDH). Methods. A multicenter, double-blind, randomized, placebo-controlled clinical study was conducted at 18 Chinese clinical centers. The participants received either DSC or placebo for 4 weeks. The primary efficacy measure was headache-free rate (HFR) in a 4-week period between the pretreatment and posttreatment stages. The secondary efficacy measures were the decrease of headache days, the duration of headache attacks, the frequency of analgesic usage, quality of life, disability, and the headache severity (VAS scores). The accompanying symptoms and adverse events were also assessed. Results. Of 584 CDH patients assessed, 468 eligible patients were randomized. 338 patients received DSC, while 111 patients were assigned in the placebo group. Following treatment, there was a 16.56% difference in HFR favoring DSC over placebo (P < 0.01). Significant differences were also observed between DSC and placebo groups in the secondary measures. However, no statistical difference was found between the two groups in the associated symptoms. No severe adverse effects were observed in the study. Conclusions. DSC might be an effective and well-tolerated option for the prophylactic treatment of patients with CDH.

A series of substituted isoquinolinones were synthesized and their binding affinities and functional activities towards human melatonin MT1 and MT2 receptors were evaluated. Structure-activity relationship analysis revealed that substituted isoquinolinones bearing a 3-methoxybenzyloxyl group at C5, C6 or C7 position respectively (C5>C6>C7 in terms of their potency) conferred effective binding and selectivity toward the MT2 receptor, with 15b as the most potent compound. Most of the tested compounds were MT2-selective agonists as revealed in receptor-mediated cAMP inhibition, intracellular Ca2+ mobilization and phosphorylation of extracellular signal-regulated protein kinases. Intriguingly, compounds 7e and 7f bearing a 4-methoxybenzyloxyl group or 4-methylbenzyloxyl at C6 behaved as weak MT2-selective antagonists. These results suggest that substituted isoquinolinones represent a novel family of MT2-selective melatonin ligands. The position of the substituted benzyloxyl group, and the substituents on the benzyl ring appeared to dictate the functional characteristics of these compounds.

Background: The existence of an association between migraine and essential tremor has long been controversial. The prevalence of migraine in essential tremor patients was surveyed to explore the association between the two diseases., Methods: A case-control clinical study was conducted to investigate the prevalence of migraine in 150 consecutive essential tremor patients and in 150 matched controls without tremor. Detailed information about essential tremor and migraine was obtained using a structured questionnaire at a face-to-face interview. Moreover, a functional variant of the dopamine receptor D3 gene (Ser9Gly, rs6280) was studied in 46 essential tremor patients with and without migraine using direct sequencing analysis., Results: The prevalence of lifetime migraine in essential tremor patients was significantly higher than that in controls (22.0% vs. 12.7%; p=0.035; odds ratio=1.95; 95% confidence interval=1.05-3.60). No significant difference was found in the migraine features between the essential tremor and control groups and most tremor characteristics were no different in essential tremor patients with and without migraine. A higher male prevalence of essential tremor patients without migraine was observed. Moreover, 44 of 46 (95.7%) essential tremor patients had the dopamine receptor D3 Ser9Gly variant, but no significant difference was found in the frequencies of the variant between essential tremor patients with and without migraine (87.5% vs. 100.0%; p=0.22)., Conclusion: Our data suggest that essential tremor patients have a higher risk of lifetime migraine than do controls and the dopamine receptor D3 Ser9Gly variant may be lower in essential tremor with migraine than the general essential tremor patients., (© International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Huntington's disease (HD) is associated with diabetes mellitus (DM) in population studies, but no case has been reported in a large HD family. We report a case of a five-generation Chinese family who is afflicted by both HD and DM. The prevalence of DM in HD of this family was high (72.7%). The diagnosis of HD in 11 family members was confirmed by the genetic test of the proband who had 42 CAG repeats. Furthermore, the proband's daughter had abnormal locus at G3460T in MT-ND1 among mtDNA genome. Our case report suggests a genetic link between HD and DM.

The comorbidity between migraine and depression not only provides a major treatment challenge, but also represents a heavy burden on society. However, the relationship between depression and migraine and their molecular biological mechanisms remain unclear. This study investigated the effects of depression elicited by unpredictable chronic mild stress (UCMS) on trigeminovascular nociception in conscious rats and detected a concentration of calcitonin gene-related peptide (CGRP) and substance P (SP) in the external jugular vein. We divided the rats into four groups: control-stimulated (C/S), control-nonstimulated (C/NS), UCMS-stimulated (U/S), and UCMS-nonstimulated (U/NS). We stimulated the dura mater adjacent to the superior sagittal sinus of rats in the C/S and U/S groups and observed their nociceptive behaviors. We found significant differences between the UCMS and control groups in weight, sucrose preference, and locomotor behavior. Nociceptive behaviors (number of head flicks and head-turning time) were significantly increased in the U/S compared with the C/S group, and head-turning time correlated with depressive-like behaviors. The plasma level of SP was increased significantly in the U/NS compared with the C/NS group. However, no significant differences involving the other groups were observed. UCMS-induced depression can exacerbate trigeminovascular nociception, making rats more sensitive to pain., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Oleanolic acid (3β-hydroxy-olea-12-en-28-oic acid) is a natural pentacyclic triterpenoic acid found in many fruits, herbs and medicinal plants. In the past decade, increasing evidence has suggested that oleanolic acid exhibits inhibitory activities against different types of cancer including skin cancer and colon cancer, but not leukemia. We report here that a derivative of oleanolic acid, olean-12-eno[2,3-c] [1], [2], [5]oxadiazol-28-oic acid (designated OEOA) effectively blocks the proliferation of human leukemia cells. OEOA significantly reduces cell proliferation without inducing cell death in three types of leukemia cell lines, including K562, HEL and Jurket. Moreover, exposure of K562 cells to OEOA results in G1 cell cycle arrest, with a concomitant induction of cyclin-dependent kinase inhibitor p27 and downregulation of cyclins and Cdks that are essential for cell cycle progression. Interestingly, OEOA also enhances erythroid differentiation in K562 cells through suppressing the expression of Bcr-Abl and phosphorylation of Erk1/2. These findings identify a novel chemical entity for further development as therapeutics against leukemia.

Four series of novel heterodimers comprised of donepezil and huperzine A (HupA) fragments were designed, synthesized, and evaluated in search of potent acetylcholinesterase (AChE) inhibitors as potential therapeutic treatment for Alzheimer's disease. Heterodimers comprised of dimethoxyindanone (from donepezil), hupyridone (from HupA), and connected with a multimethylene linker, were identified as potent and selective inhibitors of AChE. Diastereomeric heterodimers (RS,S)-17b (with a tetramethylene linker) exhibited the highest potency of inhibition towards AChE with an IC(50) value of 9 nM and no detectable inhibitory effect on butyrylcholinesterase at 1mM., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A series of novel and selective N-[3-(6-benzyloxy-3-methoxyphenyl)propyl] amides has recently been shown to possess sub-nanomolar range binding affinity to the type 2 melatonin receptor (MT(2)). Pharmacokinetics studies suggested that these compounds were subject to vigorous CYP450-mediated metabolism, resulting in a series of metabolites with significantly decreased or diminished binding affinities toward MT(2) receptor. The ether bonds were found to be the major positions susceptible to metabolism. In this study, the benzyl ether bond was either removed or replaced with a carbon-carbon bond in an attempt to improve metabolic stability and enhance their resistance towards phase I oxidation. The synthesis, receptor binding affinity, intrinsic potency and metabolic stability of modified structures are reported in this article. By removal or replacement of metabolic labile ether linkerage with carbon linkers, a novel compound was identified with good potency and MT(2) selectivity, and with increased metabolic stability., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Melatonin is a widely distributed hormone that regulates several major physiological processes, including the circadian rhythm and seasonal adaptation. The two subtypes of mammalian G protein-coupled melatonin receptors are primarily responsible for mediating the actions of melatonin. Because synthetic melatonin agonists have considerable therapeutic potentials in modulating insomnia and circadian- related sleep disorders, it is highly desirable to develop subtype-selective melatoninergic compounds. The pharmacological potencies of a series of substituted N-[3-(3-methoxyphenyl)propyl] amides towards human melatonin MT(1) and MT(2) receptors were evaluated by the FLIPR high-throughput screening assay, whilst their subtype-selectivity was subsequently verified with ERK phosphorylation and cAMP assays. Structure-activity relationship analysis of highly potent subtype-selective ligands (MT(2) EC(50) 10-90 pM) revealed that a benzyloxyl substituent incorporated at C6 position of the 3-methoxyphenyl ring dramatically enhanced the MT(2) potency and at the same time decreased MT(1) potency. Incorporation of structural moieties conferring the subtype selectivity produced several extremely potent MT(2)-selective ligands. The most potent subtype-selective ligand, 2q had a substantially higher potency for MT(2) receptor than melatonin for elevation of [Ca(2+)]i and inhibition of forskolin-elevated cAMP. Representative MT(2)-selective ligands also induced ERK phosphorylation in both recombinant and native cell lines, and no cross-reactivity to 17 other GPCRs could be detected. These ligands represent invaluable tools for delineating the functional roles of distinct melatonin receptor subtypes and are viable candidates for drug development.

7-Methoxy-6-(3-methoxy-benzyloxy)-2-methylisoquinolin-1(2H)-one (named as IS0042) is a newly identified melatoninergic agonist which exhibits selectivity to the type 2 melatonin receptor. Here, we examined the in vitro and in vivo pharmacokinetics properties of IS0042 in rats. IS0042 was considerably lipophilic with a modest aqueous solubility of 27.3 µg/mL. It was stable in simulated gastrointestinal fluid, and readily penetrated across differentiated Caco-2 cell model of intestinal barrier, suggesting good oral absorption. IS0042 underwent metabolism in rat intestinal and liver microsomes with an in vitro half-life of 367.5 ± 36.6 and 17.5 ± 2.7 min, respectively. Metabolite identification suggested that the major biotransformation pathways included the cleavage of ether bond, hydroxylation and demethylation. The same metabolites were also present in blood circulation following oral administration, indicating a good correlation between in vitro and in vivo metabolism. The pharmacokinetics parameters of IS0042 were evaluated after intravenous administration (10 or 25 mg/kg) and oral administration (100 mg/kg) of the drug to rats. IS0042 showed moderate clearance (0.73-1.02 L/h/kg), large volume of distribution (1.76-3.16 L/kg) and long elimination half-life (3.11-6.04 h) after intravenous administration. The absolute oral bioavailability of IS0042 was relatively low (9.8-18.6%). Overall, these results provide important parameters for the further development of this novel class of melatoninergic ligands.

Two Chinese herb-derived small molecule telomerase activators, astragaloside IV (AG-IV) and cycloastragenol (CAG), have recently been shown to improve the proliferative response of CD8+ T lymphocytes from HIV-infected patients by upregulating telomerase activity. Here, we examined the signaling mechanism of AG-IV and CAG. Telomerase activity in human embryonic kidney HEK293 fibroblasts was increased upon treatment with increasing concentrations of AG-IV or CAG. Both compounds induced the phosphorylation of extracellular signal-regulated protein kinase (ERK) in a time- and dose-dependent manner in HEK293 cells and HEK-neo keratinocytes. AG-IV and CAG also stimulated ERK phosphorylation in other cell lines of lung, brain, mammary, endothelial, and hematopoietic origins. Use of selective inhibitors and dominant negative mutants revealed the involvement of c-Src, MEK (ERK kinase), and epidermal growth factor receptor in CAG-induced ERK phosphorylation. Our data indicate that AG-IV and CAG may exert their cellular effects through the activation of the Src/MEK/ERK pathway., (© Georg Thieme Verlag KG Stuttgart · New York.)

Developing subtype-selective melatoninergic ligands has been a subject of considerable interest in drug discovery. A series of 3-methoxyphenylpropyl amide derivatives showing selective binding capacity to type 2 melatonin receptor with subnanomolar range of affinities has been identified recently by our laboratory. In the present study, their physicochemical properties, Caco-2 cell and mdr1-MDCK cell permeability, plasma protein binding, and metabolic stability were investigated. The selected compounds are lipophilic in nature, exhibiting aqueous solubility ranging from 40 to 200 microg/mL. Cell permeability studies on Caco-2 and mdr1-MDCK model revealed that they were readily transported through intestinal epithelium and possessed high penetration potential through blood-brain barrier, implying good oral absorption and central nervous system (CNS) distribution potential. They also showed substantial binding to human plasma protein ranging from 78.5% to 92.3%. These compounds were, however, subjected to rapid cytochrome P450-mediated degradation in rat and human liver microsomes with in vitro half-life of 9.5-31.9 min in rat and 5.5-66.7 min in human, which were much shorter than that of melatonin (approximately 73 min). Metabolite profiling unveiled that C6-ether linkage and methoxy substituents were likely the major metabolic soft spots in their structures, which provided important information for further improvement of their structural stability.

A series of substituted N-[3-(3-methoxyphenyl)propyl] amides were synthesized and their binding affinities towards human melatonin MT(1) and MT(2) receptors were evaluated. It was discovered that a benzyloxyl substituent incorporated at C6 position of the 3-methoxyphenyl ring dramatically enhanced the MT(2) binding affinity and at the same time decreased MT(1) binding affinity., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Cycloastragenol (CAG) is the aglycone derivative of astragaloside IV which has recently been demonstrated to activate telomerase and represents a potential drug candidate for the treatment of degenerative diseases. In the present study, intestinal absorption and metabolism of CAG were examined using the Caco-2 model and liver microsomes, respectively. The results showed that CAG rapidly passes through the Caco-2 cell monolayer by passive diffusion. Four different glucuronide conjugates and two oxidized CAG metabolites were found in the apical and basolateral sides of Caco-2 monolayer, suggesting that first-pass intestinal metabolism of CAG might occur upon passage through the intestinal epithelium. CAG underwent extensive metabolism in rat and human liver microsomes with only 17.4% and 8.2%, respectively, of the starting amount of CAG remaining after 30 min of incubation. Monohydroxylation of the parent and oxidization of the hydroxylated CAG were found in the liver samples. The present study indicates that CAG is efficiently absorbed through intestinal epithelium. However, extensive first-pass hepatic metabolism would limit the oral bioavailability of this compound.

Melatonin, the pineal gland hormone, is widely distributed in mammalian tissues and exerts its action via two melatonin receptor sub-types, MT(1) and MT(2). Melatonin is known to play functional roles in regulating circadian rhythms and seasonal reproduction. In recent years, growing evidence has also linked melatonin to a variety of other body systems and disease states, thus highlighting its significance as a therapeutic agent. However, due to its properties, melatonin is ineffective in clinical use, thus prompting the development of melatoninergic ligands that mimic the actions of melatonin but in a manner that is more potent and specific for melatonin receptors. An additional focus has been to develop ligands that exhibit receptor subtype selectivity. While there are over seventy patents on melatoninergic ligands, success in developing therapeutically effective melatoninergic ligands have been varied. However, the recent approval of Ramelteon for treatment of sleep disorders and the evaluation of other compounds in clinical trials have highlighted their clinical importance. In this review an overview of recently developed novel melatoninergic ligands is provided including recently filed patents and compounds undergoing clinical evaluation.

Polyene macrolide antibiotics are naturally occurring antifungal agents. Members of this class include amphotericin B, which has been used widely to treat systemic fungal infections. A general synthetic strategy has been devised to prepare polyol chains associated with the polyene macrolides. Cyanohydrin acetonide alkylations were used to assemble the carbon skeleton, and a simple modification of the strategy allowed an advanced intermediate to be converted to either the candidin polyol or the nystatin polyol. The candidin polyol was further elaborated to a protected candidin aglycone. This strategy will be applicable to other members of the polyene macrolide natural products.

Development of structure-activity relationship of cyclic guanines I lead us to discovery of a potent and selective series of phosphodiesterase 5 inhibitors 52-59 (IC50=1.3-11.0 nM, PDE6/5=116-600).