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Benzimidazole compounds and use thereof for treating alzheimer's disease or huntington's disease
No full text[[abstract]]Benzimidazole compounds of formula (I), shown below, are disclosed. The compounds are potent human glutaminyl cyclase inhibitors. Also disclosed is a pharmaceutical composition containing one of these compounds and a pharmaceutical acceptable carrier, as well as a method of treating Alzheimer's disease or Huntington's disease by administering to a subject in need thereof an effective amount of such a compound
Tetrahydroisoquinolines for use as MOR/NOP dual agonists
No full text[[abstract]]Disclosed are compounds of formula (I) below or pharmaceutically acceptable salts thereof:in which each of variables R1-R6, L, m, and n is defined herein. Also disclosed are a method for treating an opioid receptor-associated condition with a compound of formula (I) and a pharmaceutical composition containing same
Thiazolidinone compounds and use thereof
No full text[[abstract]]A pharmaceutical composition containing a compound of Formula (I) for treating an opioid receptor-associated condition. Also disclosed is a method for treating an opioid receptor-associated condition using such a compound. Further disclosed are two sets of thiazolidinone compounds of formula (I): (i) compounds each having an enantiomeric excess greater than 90% and (ii) compounds each being substituted with deuterium
[[alternative]]Anti-rspo3 antibodies
No full text[[abstract]]一種分離的抗體，包含：重鏈可變區序列的重鏈互補決定區CDR1、CDR2和CDR3，該重鏈可變區序列係選自SEQ ID NOs：2、6、10和14；以及輕鏈可變區序列的輕鏈互補決定區CDR1、CDR2和CDR3，該輕鏈可變區序列係選自SEQ ID NOs：4、8、12和16；其中，該抗體與RSPO3蛋白特異性地結合
Opioid receptor modulators and use thereof
No full text[[abstract]]Disclosed is an in vitro screening method for identifying an antagonist-to-agonist allosteric modifier of a mu-opioid receptor and an in vivo method for confirming that a test compound is such a modifier of a mu-opioid receptor. Also disclosed is a method for treating an opioid receptor-associated condition using a compound of Formula (I) and a pharmaceutical composition containing the same
아미노티아졸 화합물 및 이의 용도
No full text[[abstract]]본원에 기재된 화학식 (I)의 아미노티아졸 화합물 및 상기 화합물 중 하나를 포함하는 약학 조성물. 또한, 아미노티아졸 화합물 중 하나를 사용하여 단백질 키나아제를 억제하거나 단백질 키나아제와 관련된 암을 치료하는 각각의 방법이 개시되어 있다
The cross-talk between FTH1 & PYCR1 plays a pivotal role in driving the progression of KRAS-mutated pancreatic cancer
No full text[[abstract]]Ferritin consists of heavy (FTH1) and light (FTL) chains, and the expression of each subunit is associated with cancer risk, although this association varies by cancer type. In this study, we aimed to investigate the mechanism underlying ferritin involved in KRAS-mutated pancreatic ductal adenocarcinoma (PDAC) progression and metabolism reprogramming. We revealed that high FTH1 expression is associated with KRAS-mutant pancreatic cancer, where knockdown of FTH1 reduced SUIT-2 and Mia PaCa-2 PDAC cell viability and colony forming ability in vitro and xenograft tumor growth in vivo . Metabolomics analysis has shown that proline metabolism is significantly altered in SUIT-2 cells after FTH1 knockdown, which we further found that FTH1 is positively correlated with the level of pyrroline-5-carboxylate reductase 1 (PYCR1), but not proline dehydrogenase (PRODH), and its cross-talk contributes to KRAS-mutated PDAC cell progression. Our study, therefore, suggests that FTH1 and its cross-talk with PYCR1 may be a potential target for pancreatic cancer research and developing related metabolite-based therapeutic strategies are needed to improve the prognosis of PDAC patients
FOXO3a/miR-4259-driven LDHA expression as a key mechanism of gemcitabine sensitivity in pancreatic ductal adenocarcinoma
No full text[[abstract]]BackgroundLactate dehydrogenase A (LDHA) can regulate tumorigenesis and cancer progression. Nevertheless, whether the regulation of LDHA is involved in the development of gemcitabine resistance in PDAC has not yet been fully elucidated. Increasing studies have shown that cancer acquired drug resistance led to treatment failure is highly attributed to the cancer stem cell (CSC) properties. Therefore, we aim to demonstrate the functions and regulatory mechanisms of LDHA on cancer stem cell (CSC) properties and gemcitabine resistance in PDAC.MethodsWe investigate the metabolite profiles by liquid chromatography-mass spectrometry between gemcitabine-resistant PDAC and parental PDAC cells. Additionally, gain-of-function and loss-of-function experiments were conducted to examine the roles of LDHA on CSC properties and gemcitabine resistance in the gemcitabine-resistant PDAC and parental PDAC cells. To investigate regulators involved in LDHA-mediated gemcitabine resistance and CSC of pancreatic cancer cells, we further used a combination of the miRNA microarray results and software predictions and confirmed that miR-4259 is a direct target of LDHA by luciferase assay. Furthermore, we constructed serial miR-4259 promoter reporters and searched for response elements using the TESS 2.0/TFSEARCH software to find the transcription factor binding site in the promoter region of miR-4259.ResultsWe observed that elevated LDHA expression significantly correlates with recurrent pancreatic cancer patients following gemcitabine treatment and with CSC properties. We further identify that FOXO3a-induced miR-4259 directly targets the 3'untranslated region of LDHA and reduced LDHA expression, leading to decreased gemcitabine resistance and a reduction in the CSC phenotypes of pancreatic cancer.ConclusionOur results demonstrated that LDHA plays a critical role in cancer stemness and gemcitabine resistance of pancreatic cancer, and indicate that targeting the FOXO3a/miR-4259/LDHA pathway might serve as a new treatment for pancreatic cancer patients with a poor response to gemcitabine chemotherapy
Time allocation to physical activity and sedentary behaviour and its iImpact on sarcopenia risk: A systematic review and meta-analysis
No full text[[abstract]]AimTo evaluate the relationship between time spent in sedentary behaviour and physical activity and sarcopenia in older adults, and to analyse the effect of reallocating time between different intensities of activities on sarcopenia.DesignSystematic review and meta-analysis.MethodsFollowing PRISMA guidelines, data were synthesised using a random-effects model, with heterogeneity assessed via Cochran's Q test and the I2 statistic. Study quality was evaluated using the Newcastle-Ottawa Scale by two independent reviewers.Data SourcesA comprehensive search was conducted in PubMed, Web of Science, Embase, CINAHL and Cochrane databases for studies published up to November 5, 2024, with no language or date restrictions. Relevant reference lists were also manually screened.ResultsThe present review included six studies involving 9914 older adults. Three studies suggested that older adults without sarcopenia spent more time performing light physical activities (SMD: 0.35; 95% CI: 0.24-0.45) and moderate to vigorous physical activity (SMD: 0.61; 95% CI: 0.49-0.74) and had less sedentary behaviour (SMD: -0.34; 95% CI: -0.51 to -0.16) than did older adults with sarcopenia. Replacing sedentary behaviour with an equivalent amount of moderate to vigorous physical activity (10, 30, or 60 min) each day can reduce the risk of sarcopenia, with 30 min showing the best preventive effect. However, research findings on the relationship between substituting sedentary behaviour time with light physical activities and sarcopenia are inconsistent.Implications for the ProfessionEncouraging older adults to engage in moderate to vigorous physical activity, even in short bouts of 10 min, can significantly reduce the risk of sarcopenia. Healthcare professionals should tailor activity recommendations to individual preferences and physical conditions to promote overall health and reduce sedentary behaviour.Patient and Public ContributionNo Patient or Public Contribution.Trial RegistrationCRD4202341616
Effects of sodium benzoate on behavioral and synaptic deficits induced by subchronic ketamine exposure in mice
No full text[[abstract]]Background: Ketamine, an N-methyl-D-aspartate receptor (NMDAR) blocker, has been used as a dissociative anesthetic and currently become a popular recreational abused substance. Repeated and chronic use of ketamine leads to behavioral disturbances, including social deficits and cognitive impairments in memory. Previous studies indicate that enhancement of NMDAR function reveals the beneficial effects on ketamine-induced abnormal behavioral and neurochemical responses. Sodium benzoate (SB), a D-amino acid oxidase inhibitor, has been reported to improve several neurological disorders, such as depression and schizophrenia, which may be associated with increasing NMDAR function. Aims & Objectives: This study aimed to investigate the therapeutic effects of SB on ketamine- induced psychotomimetic behaviors and neuronal activity. Method: The male ICR mice received intraperitoneal injection (i.p.) of either ketamine (20 mg/kg) or vehicle twice per day successively during postnatal days (PN) 32-46. Subsequently, SB (30 &100 mg/kg, i.p.) was given during PN55-69. The novel location/object recognition task, reciprocal social interaction, three-chamber social test, tail suspension test and forced swimming test were monitored. Moreover, a serotonergic hallucinogen was administered to induce head-twitch responses. After animal behavioral tests, the hippocampal synaptic function was determined. Results: The data showed that the enduring behavioral abnormalities after repeated ketamine exposure, including social deficits, recognition memory impairments, and increased depression- like and hallucinogen-induced head-twitch responses, were ameliorated by SB post-treatment. In addition, SB reversed the reduced hippocampal synaptic activity after repeated ketamine treatment. Discussion & Conclusion: These results demonstrated that post-treatment with SB could effectively reverse the adverse behavioral manifestations and hippocampal synaptic plasticity after repeated ketamine use, suggesting that SB can be used as a novel adjunct therapy with ketamine for treatment- resistant depression and provide benefits for ketamine use disorders