BACKGROUND The prevalence of colorectal cancer(CRC)in younger people is increasing.Despite advances in precision medicine,the challenges of drug resistance and high costs persist.Nitidine chloride(NC)has pharmacologic...BACKGROUND The prevalence of colorectal cancer(CRC)in younger people is increasing.Despite advances in precision medicine,the challenges of drug resistance and high costs persist.Nitidine chloride(NC)has pharmacological potential,and kinesin family member 20A(KIF20A)is overexpressed in various tumors;however,their interaction in CRC remains unexplored.AIM To investigate the KIF20A expression characteristics in CRC cells and determine whether it is a potential target gene for NC in inhibiting CRC treatment.METHODS Single-cell RNA sequencing(scRNA-seq),spatial transcriptomics,and mRNA expression profiling were used to analyze KIF20A expression in CRC cells.Immunohistochemical staining was used to verify KIF20A expression in 416 clinical samples(208 CRC tissue samples and 208 noncancerous control tissue samples).Clustered regularly interspaced short palindromic repeats(CRISPR)technology was used to evaluate the impact of knocking out KIF20A on CRC cell growth.Molecular docking was applied to analyze NC–KIF20A binding.Finally,RNA sequencing and functional enrichment analysis were performed to explore the mechanism of action of NC in CRC cells.RESULTS Treating HCT116 cells with NC was found to significantly downregulate KIF20A(P<0.05),and the molecular docking analysis revealed high-affinity binding between NC and KIF20A(binding energy=-9.6 kcal/mol).The scRNA-seq,spatial transcriptomics,and mRNA expression profiling results confirmed the significantly high expression of KIF20A in CRC tissues(standardized mean difference=1.33,95%confidence interval:0.885-1.77,summary receiver operating characteristic curve area=0.94).The immunohistochemical analysis of the clinical samples showed high KIF20A expression in the CRC tissues(P<0.05),with significant correlation between the level of expression and gender,tumor size,and tumor grade(P<0.05).Knocking out KIF20A significantly inhibited the growth of various CRC cell lines(CRISPR score<-0.3).The functional enrichment analysis indicated that NC may inhibit CRC by disrupting several biological processes,such as mitotic nuclear division,chromosome segregation,and microtubule binding.CONCLUSION Our results indicate that NC binds to KIF20A with high affinity and downregulates its expression in CRC cells,leading to reduced proliferation.Hence,NC has promise as a therapeutic agent in the treatment of CRC,and targeting KIF20A also has potential as a therapeutic strategy.Further KIF20A knockout studies are needed to confirm the binding specificity and mechanistic roles of NC in CRC.展开更多
Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, characterized by a progressive decline in cognitive ability. Around 50 million people worldwide are reportedly affected, with annual los...Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, characterized by a progressive decline in cognitive ability. Around 50 million people worldwide are reportedly affected, with annual losses estimated at about $1 trillion [1]. Nevertheless, there remains unknown about the exact pathological mechanisms of AD and currently available treatments have a lack of efficacy. Thus, experts have reached a consensus that interventions in the preclinical stage of AD should be prioritized [2], especially when the amount of patients is set to reach 78 million by the end of this decade [3]. Recently, the proposition “integrating food and nutrition into healthcare” has been promoted [4]. Prevention from dietary eating and drinking may be an effective and age-friendly method. Nowadays, many beverages have been proven to offer great preventative benefits to AD like coffee, soy milk, tea, and wine. Coffee, consumed by tens of thousands of people every day, has been proven in several epidemiological studies to have a protective effect against AD [5-7]. A study including 411 individuals shows that significant negative correlation between stratified lifetime coffee intake and β-amyloid positivity [8]. In other words, higher coffee intake (≥ 2 cups/day) is associated with lower risk of AD. However, a Mendelian randomization (MR) analysis came to the opposite conclusion, with an additional 1 cup of coffee per day being associated with a 1.16-fold increased risk of developing AD [9]. In meta-analyses of cohort studies, it was proposed that there was a non-linear “U-shaped” link between coffee consumption and AD, with 3-4 cups per day being optimal [10]. In addition to the possibility that different conclusions are due to inconsistent estimations of coffee intake and populations in these studies, research recently proposed a hypothesis that the cytochrome P450 1A2 played an essential role in the metabolism of coffee in the human body [11]. Rs762551 is its most representative and commonly studied single nucleotide polymorphism. In detail, carriers of the rs762551 gene metabolize caffeine more rapidly and are at greater risk of developing AD when they consume large amounts of coffee. Conversely, people with slow caffeine metabolism who consume more coffee would have a preventive effect on AD, which might be a result of being exposed to coffee for a longer duration of time to the point of absorbing more potential beneficial effects of caffeine.展开更多
基金Supported by the Promoting Project of Basic Capacity for Young and Middle-aged University Teachers in Guangxi,No.2025KY0164Youth Science Foundation of Guangxi Medical University,No.GXMUYSF202423Guangxi Zhuang Autonomous Region Health Commission Scientific Research Project,No.Z-A20220415 and No.Z20210442.
文摘BACKGROUND The prevalence of colorectal cancer(CRC)in younger people is increasing.Despite advances in precision medicine,the challenges of drug resistance and high costs persist.Nitidine chloride(NC)has pharmacological potential,and kinesin family member 20A(KIF20A)is overexpressed in various tumors;however,their interaction in CRC remains unexplored.AIM To investigate the KIF20A expression characteristics in CRC cells and determine whether it is a potential target gene for NC in inhibiting CRC treatment.METHODS Single-cell RNA sequencing(scRNA-seq),spatial transcriptomics,and mRNA expression profiling were used to analyze KIF20A expression in CRC cells.Immunohistochemical staining was used to verify KIF20A expression in 416 clinical samples(208 CRC tissue samples and 208 noncancerous control tissue samples).Clustered regularly interspaced short palindromic repeats(CRISPR)technology was used to evaluate the impact of knocking out KIF20A on CRC cell growth.Molecular docking was applied to analyze NC–KIF20A binding.Finally,RNA sequencing and functional enrichment analysis were performed to explore the mechanism of action of NC in CRC cells.RESULTS Treating HCT116 cells with NC was found to significantly downregulate KIF20A(P<0.05),and the molecular docking analysis revealed high-affinity binding between NC and KIF20A(binding energy=-9.6 kcal/mol).The scRNA-seq,spatial transcriptomics,and mRNA expression profiling results confirmed the significantly high expression of KIF20A in CRC tissues(standardized mean difference=1.33,95%confidence interval:0.885-1.77,summary receiver operating characteristic curve area=0.94).The immunohistochemical analysis of the clinical samples showed high KIF20A expression in the CRC tissues(P<0.05),with significant correlation between the level of expression and gender,tumor size,and tumor grade(P<0.05).Knocking out KIF20A significantly inhibited the growth of various CRC cell lines(CRISPR score<-0.3).The functional enrichment analysis indicated that NC may inhibit CRC by disrupting several biological processes,such as mitotic nuclear division,chromosome segregation,and microtubule binding.CONCLUSION Our results indicate that NC binds to KIF20A with high affinity and downregulates its expression in CRC cells,leading to reduced proliferation.Hence,NC has promise as a therapeutic agent in the treatment of CRC,and targeting KIF20A also has potential as a therapeutic strategy.Further KIF20A knockout studies are needed to confirm the binding specificity and mechanistic roles of NC in CRC.
文摘Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, characterized by a progressive decline in cognitive ability. Around 50 million people worldwide are reportedly affected, with annual losses estimated at about $1 trillion [1]. Nevertheless, there remains unknown about the exact pathological mechanisms of AD and currently available treatments have a lack of efficacy. Thus, experts have reached a consensus that interventions in the preclinical stage of AD should be prioritized [2], especially when the amount of patients is set to reach 78 million by the end of this decade [3]. Recently, the proposition “integrating food and nutrition into healthcare” has been promoted [4]. Prevention from dietary eating and drinking may be an effective and age-friendly method. Nowadays, many beverages have been proven to offer great preventative benefits to AD like coffee, soy milk, tea, and wine. Coffee, consumed by tens of thousands of people every day, has been proven in several epidemiological studies to have a protective effect against AD [5-7]. A study including 411 individuals shows that significant negative correlation between stratified lifetime coffee intake and β-amyloid positivity [8]. In other words, higher coffee intake (≥ 2 cups/day) is associated with lower risk of AD. However, a Mendelian randomization (MR) analysis came to the opposite conclusion, with an additional 1 cup of coffee per day being associated with a 1.16-fold increased risk of developing AD [9]. In meta-analyses of cohort studies, it was proposed that there was a non-linear “U-shaped” link between coffee consumption and AD, with 3-4 cups per day being optimal [10]. In addition to the possibility that different conclusions are due to inconsistent estimations of coffee intake and populations in these studies, research recently proposed a hypothesis that the cytochrome P450 1A2 played an essential role in the metabolism of coffee in the human body [11]. Rs762551 is its most representative and commonly studied single nucleotide polymorphism. In detail, carriers of the rs762551 gene metabolize caffeine more rapidly and are at greater risk of developing AD when they consume large amounts of coffee. Conversely, people with slow caffeine metabolism who consume more coffee would have a preventive effect on AD, which might be a result of being exposed to coffee for a longer duration of time to the point of absorbing more potential beneficial effects of caffeine.
