Genetic variation in ZmKW1 contributes to kernel weight and size in dent corn and popcorn.

Kernel weight is a critical factor that essentially affects maize (Zea mays) yield. In natural inbred lines, popcorn kernels exhibit overtly smaller sizes compared to dent corn kernels, and kernel weight, which is controlled by multiple genetic loci, varies widely. Here, we characterized a major quantitative trait locus on chromosome 1, responsible for controlling kernel weight (qKW1) and size. The qKW1 locus encodes a protein containing a seven in absentia domain with E3 ubiquitin ligase activity, expressed prominently from the top to the middle region of the endosperm. The presence and function of qKW1 were confirmed through ZmKW1 gene editing, where the mutations in ZmKW1 within dent corn significantly increased kernel weight, consistent with alterations in kernel size, while overexpression of ZmKW1 had the opposite effect. ZmKW1 acts as a negative regulator of kernel weight and size by reducing both the number and size of the endosperm cells and impacting endosperm filling. Notably, the popcorn allele qKW1N and the dent corn allele qKW1D encode identical proteins; however, the differences in promoter activity arise due to the insertion of an Indel-1346 sequence in the qKW1N promoter, resulting in higher expression levels compared to qKW1D, thus contributing to the variation in kernel weight and size between popcorn and dent corn kernels. Linkage disequilibrium analysis of the 2.8 kb promoter region of ZmKW1 in a dataset comprising 111 maize association panels identified two distinct haplotypes. Our results provide insight into the mechanisms underlying kernel development and yield regulation in dent corn and popcorn, with a specific focus on the role of the ubiquitination system.

ZmMPK6, a mitogen-activated protein kinase, regulates maize kernel weight.

Kernel weight is a critical agronomic trait in maize production. Many genes are related to kernel weight but only a few of them have been applied to maize breeding and cultivation. Here, we identify a novel function of maize mitogen-activated protein kinase 6 (ZmMPK6) in the regulation of maize kernel weight. Kernel weight was reduced in zmmpk6 mutants and increased in ZmMPK6-overexpressing lines. In addition, starch granules, starch content, protein content, and grain-filling characteristics were also affected by the ZmMPK6 expression level. ZmMPK6 is mainly localized in the nucleus and cytoplasm, widely distributed across various tissues, and is expressed during kernel development, which is consistent with its role in kernel weight. Thus, these results provide new insights into the role of ZmMPK6, a mitogen-activated protein kinase, in maize kernel weight, and could be applied to further molecular breeding for kernel quality and yield in maize.

Intermittent hypoxia induces hepatic senescence through promoting oxidative stress in a mouse model.

PURPOSE: Metabolic-associated fatty liver disease (MAFLD) is an aging-related disease. Obstructive sleep apnea (OSA) may cause MAFLD. This study aimed to explore whether or not intermittent hypoxia (IH), the hallmark of OSA, induces liver aging through oxidative stress. METHODS: C57BL/6J male mice were administered normal air (control), IH, or antioxidant tempol + IH daily for 6 weeks before the collection of serum and liver tissue samples. A histological examination was conducted to assess liver aging. ELISA was performed to measure liver function indicator levels in the serum and oxidative stress indicator activities in the liver. Western blot analysis was carried out to determine the protein expression of the markers related to oxidative stress, inflammation, and senescence. RESULTS: Compared with control, IH resulted in significant increases in serum ALT, AST, and TG levels in mice (all P < 0.001), along with lobular inflammation and accumulation of collagen and fat in the liver. The protein levels of inflammatory factors and senescent markers were significantly increased in the IH mouse liver compared with those in the control mouse liver. Meanwhile, IH significantly reduced SOD and CAT activities while enhancing p22phox and Nrf2 protein expression in mouse liver compared with control. Importantly, antioxidant therapy with tempol effectively abrogated the effects of IH on oxidative stress response and aging-related liver injury. CONCLUSIONS: Our findings suggest that IH induces liver inflammation and aging through oxidative stress. OSA may exacerbate target organ aging and participate in target organ damage. Strategies targeting oxidative stress may prevent and treat OSA-related MAFLD.

Multifunctional N, Fe-doped carbon dots with peroxidase-like activity for the determination of H2O2 and ascorbic acid and cell protection against oxidation.

Multifunctional N, Fe-doped carbon dots (N, Fe-CDs) were synthesized by the one-step hydrothermal method using ferric ammonium citrate and dicyandiamide as raw materials. The N, Fe-CDs exhibited peroxidase-like (POD) activity by catalyzing the oxidization of 3,3',5,5'-tetramethylbenzidine (TMB) to the green oxidation state ox-TMB in the presence of hydrogen peroxide (H2O2). Subsequently, based on the POD activity of N, Fe-CDs, an efficient and sensitive colorimetric method for the detection of H2O2 and ascorbic acid (AA) was established with a limit of detection of 0.40 µM and 2.05 µM. The proposed detection method has been successfully applied to detect AA in fruit juice, vitamin C tablets, and human serum samples and has exhibited excellent application prospects in biotechnology and food fields. Furthermore, N, Fe-CDs also showed a protective effect on the cell damage caused by H2O2 and could be used as an antioxidant agent.

Effect of information-motivation-behavior skills on adherence of continuous positive airway pressure therapy in patients with obstructive sleep apnea hypopnea syndrome. / 信息-动机-è¡Œä¸ºæŠ€å·§å¯¹é˜»å¡žæ€§ç¡çœ å‘¼å¸æš‚åœä½Žé€šæ°”ç»¼åˆå¾æ‚£è€ æŒç»­æ°”é“æ­£åŽ‹é€šæ°”æ²»ç–—ä¾ä»Žæ€§çš„å½±å“.

OBJECTIVES: Obstructive sleep apnea hypopnea syndrome (OSAHS) is a common disease that seriously affects health. Continuous positive airway pressure (CPAP) therapy is the preferred treatment for moderate-to-severe OSAHS patients. However, poor adherence to CPAP is a major obstacle in the treatment of OSAHS. Information-motivation-behavioral (IMB) skills, as a kind of mature technology to change the behavior, has been used in various health areas to improve treatment adherence. This study aims to explore the effects of the IMB skills intervention on CPAP adherence in OSAHS patients. METHODS: Patients who were primary diagnosed with moderate-to-severe OSAHS were randomly divided into the IMB group (n=62) and the control group (n=58). The patients in the IMB group received CPAP therapy and the IMB skills intervention for 4 weeks. The patients in the control group received CPAP therapy and a usual health care provided by a registered nurse. We collected the baseline data of the general information, including age, sex, body mass index (BMI), the Epworth Sleepiness Scale (ESS) score, the Hospital Anxiety and Depression Scale (HADS) score, and indicators about disease severity [apnea-hypopnea index (AHI), percentage of time with arterial oxygen saturation SaO2<90% (T90), average SaO2, lowest SaO2, arousal index]. After CPAP titration, we collected CPAP therapy-relevant parameters (optimal pressure, maximum leakage, average leakage, 95% leakage, and residual AHI), score of satisfaction and acceptance of CPAP therapy, and score of willingness to continue CPAP therapy. After 4 weeks treatment, we collected the ESS score, HADS score, CPAP therapy-relevant parameters, effective CPAP therapy time per night, CPAP therapy days within 4 weeks, CPAP adherence rate, score of satisfaction and acceptance of CPAP therapy, and score of willingness to continue CPAP therapy. Visual analog scale (VAS) of 0-5 was used to evaluate the satisfaction and acceptance of IMB intervention measures in the IMB group. RESULTS: There were no significant differences in the baseline level of demographic parameters, ESS score, HADS score, disease severity, and CPAP therapy related parameters between the IMB group and the control group (all P>0.05). There were no significant differences in score of willingness to continue CPAP therapy, as well as score of satisfaction and acceptance of CPAP therapy after CPAP titration between the IMB group and the control group (both P>0.05). After 4 weeks treatment, the ESS score, HADS score, maximum leakage, average leakage, and 95% leakage of the IMB group were significantly decreased, while the score of satisfaction and acceptance of CPAP therapy and willingness to continue CPAP therapy of the IMB group were significantly increased (all P<0.05); while the above indexes in the control group were not different before and after 4 weeks treatment (all P<0.05). Compared with the control group, the ESS score, HADS score, maximum leakage, average leakage, and 95% leakage of the IMB group after 4 weeks treatment were significantly lower (all P<0.05); the effective CPAP therapy time, CPAP therapy days within 4 weeks, score of satisfaction and acceptance of CPAP therapy, score of willingness to continue CPAP therapy of the IMB group were significantly higher (all P<0.05). The rate of CPAP therapy adherence in 4 weeks of the IMB group was significantly higher than that of the control group (90.3% vs 62.1%, P<0.05). The VAS of overall satisfaction with IMB skills intervention measures was 4.46±0.35. CONCLUSIONS: IMB skills intervention measures can effectively improve the adherence of CPAP therapy in OSAHS patients, and is suitable for clinical promotion.

Mindfulness may be a novel factor associated with CPAP adherence in OSAHS patients.

BACKGROUND: Poor adherence to continuous positive airway pressure (CPAP) remains the greatest obstacle to effective treatment of obstructive sleep apnea-hypopnea syndrome (OSAHS). The purpose of the present study was to identify if mindfulness is associated with CPAP adherence of OSAHS patients. METHODS: Newly diagnosed patients with OSAHS completed questionnaires including the Epworth Sleepiness Scale (ESS), the Mindful Attention Awareness Scale (MAAS), and the Hospital Anxiety and Depression Scale (HADS) and had experienced an overnight CPAP titration. Participants returned to the sleep center for a scheduled research visit after 30-day CPAP treatment at home. Demographics, disease severity, and device-related variables were collected. Multiple linear regression analysis was performed to build a multivariate predictive model for the outcome variable, mean daily CPAP use over 30 days. RESULTS: Mean CPAP use was 4.7 ± 2.4 h/night for the study sample of 100 patients and 67% were classified as CPAP adherent. MAAS scale was 45.2 ± 18.8, whereas only 13% of patients expressed anxiety or depression. MAAS scales were significantly higher in the CPAP adherent group compared to the non-adherent group (49.5 ± 14.5 vs 40.8 ± 14.2, p < 0.001) with mean hours of daily CPAP use over 30 days for the adherent group (5.7 ± 1.4 h/night) compared to the non-adherence group (3.0 ± 1.7 h/night). There were differences between the two groups in HADS depression, AHI, lowest SaO2, optimal CPAP pressure, residual AHI, mean days over 30 days, and mean daily CPAP use in the first week. Univariate analyses identified an unadjusted association between mean daily CPAP use over 30 days and HADS depression, MAAS, AHI, lowest SaO2, optimal pressure, and mean daily CPAP use in the first week. Multiple linear regression analysis demonstrated only MAAS and AHI were associated (p < 0.05) with mean daily CPAP use. MAAS and AHI uniquely explained 10.1% (p < 0.001) and 8.7% (p < 0.001) of mean daily CPAP use respectively. CONCLUSIONS: This study found a significant independent association of dispositional mindfulness with CPAP adherence. As a novel factor, mindfulness may play an important role in CPAP adherence.

Coronavirus disease 2019 in the elderly: Clinical characteristics, diagnosis and treatment strategies. / 老年2019å† çŠ¶ç— æ¯’ç— çš„ä¸´åºŠç‰¹ç‚¹ä¸Žè¯Šç–—ç­–ç•¥.

Many countries in the world have faced with coronavirus disease 2019 (COVID-19) epidemic since December 2019, while the proportion of elderly patients with COVID-19 in severe and death cases is relatively high. At present, China is in the rapid development stage of population aging, and the demand of the elderly for medical care, health care, nursing and life services far exceeds that of other people. Especially in the period of COVID-19, it is particularly urgent to summarize more experience and methods in time to reduce the infection rate, the incidence of critical illness, and the mortality rate. Therefore, this review combines the existing research results with clinic experience of diagnosis and treatment for senile infectious diseases, summarizes the clinical characteristics and puts forward the prevention strategies of elderly COVID-19 patients, which provide evidence for effective prevention and treatment of COVID-19 in elderly patients, improvement of cure rate, and reduction of severe incidence rate and mortality.

The benefit of HH during the CPAP titration in the cool sleeping environment.

PURPOSE: Upper airway symptom associated with continuous positive airway pressure (CPAP) treatment is an important factor influencing CPAP adherence. There are conflicting data on the effect of a heated humidifier (HH) during CPAP titration for patients with obstructive sleep apnea hypopnea syndrome (OSAHS). This study investigated the effects of HH during CPAP titration in the cool sleeping environment. METHODS: Forty newly diagnosed OSAHS patients who received CPAP titration in the cool sleeping environment were randomly assigned to HH and non-HH groups. A questionnaire was used to evaluate upper airway symptoms, satisfaction with initial CPAP treatment, and willingness to further use CPAP. Some therapy parameters including leak, apnea hypopnea index (AHI) reduction, and optimal CPAP pressure level were analyzed. We compared these subjective and objective data between the two groups. RESULTS: In subjective sensation, the use of HH can alleviate upper airway symptoms associated with CPAP titration (P < 0.001). The HH group has benefit in satisfaction with initial CPAP treatment (P < 0.001) and further willingness to use CPAP (P < 0.01), although there were no significant differences in leak, AHI reduction, and optimal CPAP pressure between the two groups. CONCLUSIONS: The use of HH is recommended during CPAP titration in the cool sleeping environment because of its benefit in the treatment of upper airway symptoms associated with CPAP therapy and improvement of the CPAP acceptance.

HRD1-mediated ubiquitination of HDAC2 regulates PPARα-mediated autophagy and alleviates metabolic-associated fatty liver disease.

BACKGROUND: Metabolic-associated fatty liver disease (MAFLD) is a leading cause of chronic liver disease worldwide. Autophagy plays a pivotal role in lipid metabolism; however, the mechanism underlying the reduced autophagic activity in MAFLD remains elusive. METHODS: Autophagy was monitored by TUNEL assay and immunofluorescence staining of LC3. The expression of autophagy-related proteins, PPARα, HDAC2, and HRD1 was detected by Western blot. The association between HDAC2 and PPARα promoter was assessed by chromatin immunoprecipitation (ChIP) and dual-luciferase assays, and the HRD1-mediated ubiquitin-proteasomal degradation of HDAC2 was detected by co-immunoprecipitation (co-IP). The in vitro findings were validated in a hypoxia-induced MAFLD mouse model. Histological changes, fibrosis, and apoptosis in liver tissues were detected by hematoxylin and eosin staining, Masson's trichrome staining, and TUNEL assay. The immunoreactivities of key molecules were examined by IHC analysis. RESULTS: Hypoxia-suppressed autophagy in hepatocytes. Hypoxic exposure downregulated HRD1 and PPARα, while upregulating HDAC2 in hepatocytes. Overexpression of PPARα promoted hepatic autophagy, while knocking down HDAC2 or overexpressing HRD1 reduced hypoxia-suppressed autophagy in hepatocytes. Mechanistically, HDAC2 acted as a transcriptional repressor of PPARα, and HRD1 mediated the degradation of HDAC2 through the ubiquitin-proteasome pathway. Functional studies further showed that hypoxia-suppressed hepatic autophagy via the HRD1/HDAC2/PPARα axis in vitro and in vivo. CONCLUSION: HRD1-mediated ubiquitination of HDAC2 regulates PPARα-mediated autophagy and ameliorates hypoxia-induced MAFLD.

Saccharomyces boulardii alleviates allergic asthma by restoring gut microbiota and metabolic homeostasis via up-regulation of METTL3 in an m6A-dependent manner.

BACKGROUND: Allergic asthma is a heterogeneous disease and new strategies are needed to prevent or treat this disease. Studies have shown that probiotic interventions are effective in preventing asthma. Here, we investigated the impact of Saccharomyces boulardii (S. boulardii) on ovalbumin (OVA)-induced allergic asthma in mice, as well as the underlying mechanisms. METHODS: First, we constructed a mouse asthma model using OVA and given S. boulardii intervention. Next, we measured N6-methyladenosine (m6A) levels in lung injury tissues. 16 s rRNA was employed to identify different gut microbiota in fecal samples. The analysis of differential metabolites in feces was performed by non-targeted metabolomics. Pearson correlation coefficient was utilized to analyze correlation between gut microbiota, metabolites and methyltransferase-like 3 (METTL3). Finally, we collected mouse feces treated by OVA and S. boulardii intervention for fecal microbiota transplantation (FMT) and interfered with METTL3. RESULTS: S. boulardii improved inflammation and oxidative stress and alleviated lung damage in asthmatic mice. In addition, S. boulardii regulated m6A modification levels in asthmatic mice. 16 s rRNA sequencing showed that S. boulardii remodeled gut microbiota homeostasis in asthmatic mice. Non-targeted metabolomics analysis showed S. boulardii restored metabolic homeostasis in asthmatic mice. There was a correlation between gut microbiota, differential metabolites, and METTL3 analyzed by Pearson correlation. Additionally, through FMT and interference of METTL3, we found that gut microbiota mediated the up-regulation of METTL3 by S. boulardii improved inflammation and oxidative stress in asthmatic mice, and alleviated lung injury. CONCLUSIONS: S. boulardii alleviated allergic asthma by restoring gut microbiota and metabolic homeostasis via up-regulation of METTL3 in an m6A-dependent manner.

Elevated fractalkine in patients with obstructive sleep apnea hypopnea syndrome.

BACKGROUND: Obstructive sleep apnea hypopnea syndrome (OSAHS) has been increasingly linked to cardiovascular disease. Inflammatory processes associated with OSAHS may contribute to atherosclerosis in these patients. Fractalkine is a unique chemokine which has both adhesive and chemoattractant functions. We tested the hypothesis that OSAHS patients have increased fractalkine. METHODS AND RESULTS: We studied 20 patients (18 males and 2 females) with newly diagnosed OSAHS, who were free of other diseases, had never been treated for OSAHS, and were taking no medications. We compared fractalkine measurements in these patients to measurements obtained in 15 control subjects (14 males and 1 female) who were matched for age and body mass index, and in whom occult OSAHS was excluded. Plasma fractalkine levels were significantly higher in patients with OSAHS than in controls (463.15 ± 110.78 versus 364.67 ± 64.81 pg/mL, F = 2.58, P = 0.004). Fractalkine were associated with AHI (r = 0.756, P < 0.0001), lowest oxygen saturation (r = -0.466, P = 0.005), and mean oxygen saturation (r = -0.344, P = 0.043). Plasma fractalkine levels were significantly decreased in patients with OSAHS after four nights nCPAP (463.15 ± 110.78 versus 416.75 ± 97.67 pg/mL, P = 0.001). CONCLUSIONS: OSAHS is associated with elevated levels of fractalkine, a marker of inflammation related to atherosclerosis. The severity of OSAHS is proportional to the fractalkine level.

[Effect of chronic intermittent hypoxia on the expression of fractalkine in rat liver].

OBJECTIVE: To investigate the effect of chronic intermittent hypoxia (CIH) on liver injury and the expression of fractalkine in rats and explore its possible mechanism. METHODS: A CIH murine model was established to mimic the pathophysiology of obstructive sleep apnea-hypopnea syndrome (OSAHS) in humans. Thirty healthy male Spraque-Dawley rats were randomly assigned to 3 groups: a 5% CIH group, a 5% CIH+RH (removal of hypoxia) group and a control group ( 10 rats in each group). The 5% CIH and 5% CIH+RH groups were exposed to CIH for 3 weeks, 8 h/d, and the frequency of hypoxia was 20 times/h. The 5% CIH+RH group was then exposed to normal gaseous environment for another 3 weeks. After the experiment, liver sections were stained with hematoxylin-eosin (HE) and the liver pathology was observed. The expression of fractalkine in the liver tissues was detected by immunohistochemical method. RESULTS: 1) Compared with the control group, the hepatic steatosis and inflammatory activities in the 5% CIH and 5% CIH+RH groups were more severe (all P<0.01 ); compared with the 5% CIH group, the hepatic steatosis and inflammatory activity in the 5% CIH+RH group were dramatically reduced (P<0.01 ). 2) Compared with the control group, the fractalkine expression in the 5% CIH and 5% CIH+RH groups was increased (both P<0.01). The fractalkine expression in the 5% CIH+RH group was dramatically downregulated compared with that in the 5% CIH group (P<0.01). CONCLUSION: CIH can induce liver injury and high fractalkine expression in rat liver tissues.

Nano-Resveratrol Liposome: Physicochemical Stability, In Vitro Release, and Cytotoxicity.

Nano-resveratrol liposome (RES-LIP) was prepared by the thin film rotary-evaporated method combined with ultrasonication and characterized by transmission electron microscopy (TEM), zeta potential, dynamic light scattering (DLS), and Fourier-transform infrared (FT-IR). The physicochemical stability, in vitro release, antioxidant activity, and cytotoxicity of RES-LIP were studied. Data showed that RES-LIP was a spherical vesicle with a diameter of less than 100 nm, the zeta potential was - 60 mV and the encapsulation efficiency was 86.78%. The physicochemical stability of RES-LIP was determined by Ea, ΔG, ΔH, and ΔS, which suggested that the process of RES-LIP degradation was spontaneous and endothermic. The in vitro release of RES-LIP was pH-dependent, belonged to the Weibull model, and was non-Fick diffusion. The antioxidant activity of RES-LIP was stronger than free resveratrol. The MTT assay and flow cytometry results suggested that resveratrol decreased cytotoxicity after being encapsulated by liposome. The prepared RES-LIP had high encapsulation efficiency, was sustained-release, had low cytotoxicity, was pH-targeted, and had potential usage in food and medicine fields.

High Drug Capacity of Nano-Levodopa-Liposomes: Preparation, In Vitro Release and Brain-Targeted Research.

In this work, nano-levodopa-liposomes (L-dopa-Lip) suspension was prepared by rotary-evaporated film-ultrasonic method, and freeze-drying powders of L-dopa-Lip were also obtained to improve the stability. The products were characterized by TEM, DLS, and TG-DSC, and the phase-transition temperature (Tm) and encapsulation efficiency were calculated. The brain-targeting and in vitro release of the drug was also studied. The results showed that L-dopa-Lip were well-formed spherical vesicles, and the sizes were about 100 nm, and the encapsulation efficiency was higher than 90%. The drug release temperature of L-dopa-Lip was 68 °C, and the in vitro release property and mathematical model were also studied. The brain targeting of L-dopa-Lip in vivo was explored by injecting the gold nanoparticles (AuNPs) labeled L-dopa-Lip (AuNPs-L-dopa-Lip) through the tail vein. ICP-MS and TEM showed that L-dopa-Lip had brain targeting, suggesting the potential treatment of L-dopa-Lip on brain dysfunction. The results of this work might be helpful for designing drug-loaded liposomes for the treatment of central nervous system (CNS) diseases and monitoring their distributions in vivo.

CX3CL1 represses autophagy via CX3CR1/ CaMKIIδ/HDAC4/Rubicon axis and exacerbates chronic intermittent hypoxia induced Kupffer cell apoptosis.

BACKGROUND: Nocturnal hypoxemia is an established factor in the pathogenesis and exacerbation of term metabolic (dysfunction) associated fatty liver disease (MAFLD). Kupffer cells (KCs) are resident macrophages in the liver, and their activity is closely related to the progress of MAFLD. KC insufficient autophagy is involved in MAFLD pathogenesis. Herein, the regulatory mechanism of KC autophagy under chronic intermittent hypoxia (CIH) condition was investigated. METHODS: Primary KCs and hepatic stellate cells (HSCs) were isolated from mouse liver. Immunofluorescence was employed to detect immunofluorescence intensity of LC3 protein and HDAC4 distribution. KC apoptosis was measured by TUNEL staining. Dual-luciferase reporter and ChIP assays were performed to analyze the interactions between HDAC4, MEF2C and RUBCN. RESULTS: Herein, our results revealed that CIH-induced increased CX3CL1 in HSCs inhibited KC autophagy and promoted cell apoptosis by interacting with CX3CR1. Meanwhile, CX3CL1 treatment inhibited KC autophagy (p < 0.001, fold change: 0.059) and promoted cell apoptosis (p < 0.001, fold change: 8.18). Rubicon knockdown promoted KC autophagy (p < 0.001, fold change: 2.90) and inhibited cell apoptosis (p < 0.05, fold change: 0.23), while these effects were reversed by CX3CL1 treatment (p < 0.01, fold change: 6.59; p < 0.001, fold change: 0.35). Our mechanistic experiments demonstrated that HDAC4 overexpression transcriptionally inhibited RUBCN expression by interacting with MEF2C, thereby promoting KC autophagy and inhibiting cell apoptosis. Moreover, CaMKIIδ inhibition promoted the translocation of HDAC4 from the cytosol to the nucleus to promote KC autophagy and inhibit the apoptosis. CONCLUSION: Taken together, CIH-induced increased CX3CL1 expression in HSCs inhibited KC autophagy and promoted apoptosis by regulating the CX3CR1/ CaMKIIδ/HDAC4/Rubicon axis.

Antimalarial ß-carboline and indolactam alkaloids from Marinactinospora thermotolerans, a deep sea isolate.

Four new ß-carboline alkaloids, designated marinacarbolines A-D (1-4), two new indolactam alkaloids, 13-N-demethyl-methylpendolmycin (5) and methylpendolmycin-14-O-α-glucoside (6), and the three known compounds 1-acetyl-ß-carboline (7), methylpendolmycin (8), and pendolmycin (9) were obtained from the fermentation broth of Marinactinospora thermotolerans SCSIO 00652, a new actinomycete belonging to the family Nocardiopsaceae. Their structures were elucidated by extensive MS and 1D and 2D NMR spectroscopic data analyses. The structure of compound 1 was further confirmed by single-crystal X-ray crystallography. The new compounds 1-6 were inactive against a panel of eight tumor cell lines (IC50>50 µM) but exhibited antiplasmodial activities against Plasmodium falciparum lines 3D7 and Dd2, with IC50 values ranging from 1.92 to 36.03 µM.

Clinicopathological characteristics of intrahepatic cholangiocarcinoma in patients with cirrhosis.

BACKGROUND/AIMS: The purpose of this study was to explore the clinicopathological characteristics of intrahepatic cholangiocarcinoma (ICC) in patients with cirrhosis. METHODOLOGY: A total of 155 patients with ICC were divided into those with cirrhosis (n=52) and those without cirrhosis (n=103). We compared the clinicopathological features of patients in both groups. RESULTS: The prevalence of HBsAg seropositivity and hepatolithiasis in ICC patients with cirrhosis was higher than that in patients without cirrhosis. Compared with noncirrhotic patients, cirrhotic patients had a higher incidence of reduced albumin (46.1% vs. 25.2%, p<0.008) and elevated total bilirubin (TBIL) levels (44.2% vs. 24.3%, p=0.011). The resectability rate in cirrhotic patients was lower than that in noncirrhotic patients (63.7% vs. 80.6%, p=0.033). CONCLUSIONS: Among ICC patients, we found marked differences in clinicopathological characteristics and therapeutic approaches between cirrhotic and noncirrhotic patients. ICC patients with cirrhosis may have poorer prognosis than those without cirrhosis.

Synergy of the antiretroviral protease inhibitor indinavir and chloroquine against malaria parasites in vitro and in vivo.

Many malaria-endemic areas are also associated with high rates of human immunodeficiency virus (HIV) infection. An understanding of the chemotherapeutic interactions that occur during malaria and HIV co-infections is important. Our previous studies have demonstrated that some antiretroviral protease inhibitors are effective in inhibiting Plasmodium falciparum growth in vitro. Currently, studies examining the interactions between antiretroviral protease inhibitors and antimalarial drugs are being conducted, but the data are limited. In this study, we examined the synergistic interactions between the antiretroviral protease inhibitor indinavir and chloroquine (CQ) in chloroquine-resistant and chloroquine-sensitive malaria parasites in vitro and in vivo. In vitro, by using modified fixed-ratio isobologram method, fractional inhibitory concentrations index (FICI) was calculated to indicate the interaction between the two drugs. The results demonstrated that indinavir interacted synergistically with chloroquine against both chloroquine-sensitive P. falciparum clone 3D7 (mean FICI 0.784) and multidrug-resistant P. falciparum clone Dd2 (mean FICI 0.599). In vivo drug interactions were measured using a 4-day suppressive test in a rodent malaria model infected with Plasmodium chabaudi. We observed that indinavir enhanced the antimalarial activity of chloroquine against both the chloroquine-sensitive line P. chabaudi ASS and the chloroquine-resistant line P. chabaudi ASCQ. More importantly, chloroquine had a 100% clearance of asexual parasites when used in combination with indinavir at an appropriate dose ratio (10 mg/kg CQ + 1.8 g/kg indinavir) where there was no obvious toxicity. We conclude from this study that the combination of indinavir and chloroquine may become a novel antimalarial drug regimen.

Obstructive Sleep Apnea-hypopnea Syndrome as a Novel Potential Risk for Aging.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a common sleep disorder, negatively influencing individuals' quality of life and socioeconomic burden. In recent years, OSAHS has been reported in not only constituting an aging-associated disease, but also in accelerating and/or potentiating aging mechanisms. However, the negative impacts of OSAHS on aging are underestimated because of low level of public awareness about this disease and high rates of undiagnosed cases, which are more critical in developing countries or economically disadvantaged regions. Hence, reviewing previously reported observations may assist scholars to better indicate that OSAHS is likely a novel potential risk for aging. Further understanding of the pathophysiological mechanism of OSAHS and its role in procession of aging may markedly highlight the importance of this common sleep disorder.