Impact of PNPLA3 I148M on alpha-1 antitrypsin deficiency-dependent liver disease progression.

BACKGROUND AND AIMS: Genetic risk factors are major determinants of chronic liver disease (CLD) progression. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M polymorphism and alpha-1 antitrypsin (AAT) E342K variant, termed PiZ, are major modifiers of metabolic CLD. Both variants are known to affect metabolic CLD through increased endoplasmic reticulum stress, but their combined effect on CLD progression remains largely unknown. Here, we aimed to test our working hypothesis that their combined incidence triggers CLD disease progression. APPROACH AND RESULTS: We showed that patients with PiZZ/PNPLA3 I148M from the European alpha-1-antitrypsin deficiency (AATD) liver consortium and the UK Biobank had a trend towards higher liver enzymes, but no increased liver fat accumulation was evident between subgroups. After generating transgenic mice that overexpress the PiZ variant and simultaneously harbor the PNPLA3 I148M knockin (designated as PiZ/PNPLA3 I148M ), we observed that animals with PiZ and PiZ/PNPLA3 I148M showed increased liver enzymes compared to controls during aging. However, no significant difference between PiZ and PiZ/PNPLA3 I148M groups was observed, with no increased liver fat accumulation over time. To further study the impact on CLD progression, a Western-styled diet was administered, which resulted in increased fat accumulation and fibrosis in PiZ and PiZ/PNPLA3 I148M livers compared to controls, but the additional presence of PNPLA3 I148M had no impact on liver phenotype. Notably, the PiZ variant protected PNPLA3 I148M mice from liver damage and obesity after Western-styled diet feeding. CONCLUSION: Our results demonstrate that the PNPLA3 polymorphism in the absence of additional metabolic risk factors is insufficient to drive the development of advanced liver disease in severe AATD.

Genome-wide identification and analysis of WD40 proteins reveal that NtTTG1 enhances drought tolerance in tobacco (Nicotiana tabacum).

BACKGROUND: WD40 proteins, which are highly prevalent in eukaryotes, play important roles in plant development and stress responses. However, systematic identification and exploration of WD40 proteins in tobacco have not yet been conducted. RESULTS: In this study, a total of 399 WD40 regulatory genes were identified in common tobacco (Nicotiana tabacum). Gene structure and motif analysis revealed structural and functional diversity among different clades of tobacco WD40 regulatory genes. The expansion of tobacco WD40 regulatory genes was mainly driven by segmental duplication and purifying selection. A potential regulatory network of NtWD40s suggested that NtWD40s might be regulated by miRNAs and transcription factors in various biological processes. Expression pattern analysis via transcriptome analysis and qRT-PCR revealed that many NtWD40s exhibited tissue-specific expression patterns and might be involved in various biotic and abiotic stresses. Furthermore, we have validated the critical role of NtTTG1, which was located in the nuclei of trichome cells, in enhancing the drought tolerance of tobacco plants. CONCLUSIONS: Our study provides comprehensive information to better understand the evolution of WD40 regulatory genes and their roles in different stress responses in tobacco.

Genome-wide identification of the N6-methyladenosine regulatory genes reveals NtFIP37B increases drought resistance of tobacco (Nicotiana tabacum L.).

BACKGROUND: N6-methyladenosine (m6A) is one of the common internal RNA modifications found in eukaryotes. The m6A modification can regulate various biological processes in organisms through the modulation of alternative splicing, alternative polyadenylation, folding, translation, localization, transport, and decay of multiple types of RNA, without altering the nucleotide sequence. The three components involved in m6A modification, namely writer, eraser, and reader, mediate the abundance of RNA m6A modification through complex collaborative actions. Currently, research on m6A regulatory genes in plants is still in its infancy. RESULTS: In this study, we identified 52 candidate m6A regulatory genes in common tobacco (Nicotiana tabacum L.). Gene structure, conserved domains, and motif analysis showed structural and functional diversity among different subgroups of tobacco m6A regulatory genes. The amplification of m6A regulatory genes were mainly driven by polyploidization and dispersed duplication, and duplicated genes evolved through purified selection. Based on the potential regulatory network and expression pattern analysis of m6A regulatory genes, a significant number of m6A regulatory genes might play important roles in growth, development, and stress response processes. Furthermore, we have confirmed the critical role of NtFIP37B, an m6A writer gene in tobacco, in enhancing drought resistance. CONCLUSIONS: This study provides useful information for better understanding the evolution of m6A regulatory genes and the role of m6A modification in tobacco stress response, and lays the foundation for further elucidating the function of m6A regulatory genes in tobacco.

A Novel Multi-Functional Fluorescence Probe for the Detection of Al3+/Zn2+/Cd2+ and its Practical Applications.

A novel multi-functional fluorescence probe HMIC based on hydrazide Schiff base has been successfully synthesized and characterized. It can distinguish Al3+/Zn2+/Cd2+ in ethanol, in which fluorescence emission with different colors (blue for Al3+, orange for Zn2+, and green for Cd2+) were presented. The limits of detection of HMIC towards three ions were calculated from the titration curve as 7.70 × 10- 9 M, 4.64 × 10- 9 M, and 1.35 × 10- 8 M, respectively. The structures of HMIC and its complexes were investigated using UV-Vis spectra, Job's plot, infrared spectra, mass spectrometry, 1H-NMR and DFT calculations. Practical application studies have also demonstrated that HMIC can be applied to real samples with a low impact of potential interferents. Cytotoxicity and cellular imaging assays have shown that HMIC has good cellular permeability and potential antitumor effects. Interestingly, HMIC can image Al3+, Zn2+ and Cd2+ in the cells with different fluorescence signals.

Ultrasound characteristics of breast fibromatosis mimicking carcinoma.

PURPOSE: To explore the value of ultrasound (US) characteristics in diagnosing breast fibromatosis (BF) and evaluate their differences from breast carcinoma. METHODS: A total of 121 patients with BF (n = 24, 29 lesions) or invasive ductal carcinoma (IDC) (n = 97, 102 lesions) of the breast were included. Their clinical and US findings were recorded and analyzed. RESULTS: The mean age of BF was younger than that of IDC (28.75 ± 5.55 vs. 50.19 ± 9.87, p < 0.001). The mean size of the BF was smaller than that of IDC (2.09 ± 0.91 vs. 2.71 ± 1.20, p = 0.011). Compared to IDC, BF had more frequency of posterior echo attenuation (p < 0.001), less frequency of peripheral hyperechoic halo (p = 0.002), calcification (p = 0.001), US reported axillary lymph node positive (p = 0.025), and grade 2-3 vascularity (p < 0.001). The Breast Imaging Reporting and Data System categorized BF at a lower level than IDC (p < 0.001). After adjusting for age, the peripheral hyperechoic halo, posterior echo feature, and vascularity could independently identify the differences between these two entities. CONCLUSION: Some differences were observed between BF and IDC in terms of patient age, lesion size, and US characteristics.

An ultrasound-based histogram analysis model for prediction of tumour stroma ratio in pleomorphic adenoma of the salivary gland.

OBJECTIVES: Preoperative identification of different stromal subtypes of pleomorphic adenoma (PA) of the salivary gland is crucial for making treatment decisions. We aimed to develop and validate a model based on histogram analysis (HA) of ultrasound (US) images for predicting tumour stroma ratio (TSR) in salivary gland PA. METHODS: A total of 219 PA patients were divided into low-TSR (stroma-low) and high-TSR (stroma-high) groups and enrolled in a training cohort (n = 151) and a validation cohort (n = 68). The least absolute shrinkage and selection operator regression algorithm was used to screen the most optimal clinical, US, and HA features. The selected features were entered into multivariable logistic regression analyses for further selection of independent predictors. Different models, including the nomogram model, the clinic-US (Clin + US) model, and the HA model, were built based on independent predictors using logistic regression. The performance levels of the models were evaluated and validated on the training and validation cohorts. RESULTS: Lesion size, shape, cystic areas, vascularity, HA_mean, and HA_skewness were identified as independent predictors for constructing the nomogram model. The nomogram model incorporating the clinical, US, and HA features achieved areas under the curve of 0.839 and 0.852 in the training and validation cohorts, respectively, demonstrating good predictive performance and calibration. Decision curve analysis and clinical impact curves further confirmed its clinical usefulness. CONCLUSIONS: The nomogram model we developed offers a practical tool for preoperative TSR prediction in PA, potentially enhancing clinical decision-making.

Efficacy of intramedullary bridge fixation for midshaft clavicle fractures: a retrospective analysis of a novel technique.

BACKGROUND: The aim of this study was to explore the efficacy of a novel intramedullary fixation technique using the ortho-bridge system (OBS) for midshaft clavicle fractures. METHODS: A total of 63 patients were included in this study: 35 underwent plate internal fixation (LP group) and 28 underwent OBS intramedullary fixation (OBS group). Surgical time, intraoperative blood loss, incision length, fracture healing time, removal of the internal fixation agent, visual analog scale (VAS) score for shoulder pain, Constant-Murley shoulder score and complication occurrence were compared between the two groups. RESULTS: Preoperative general data, such as sex, age and fracture type, were not significantly different between the two groups (P > 0.05). However, the OBS group exhibited better outcomes than the LP group exhibited in terms of surgical time, intraoperative blood loss and total incision length (P < 0.05). Additionally, the OBS group exhibited a significantly shorter fracture healing time and internal-fixation removal time than the LP group exhibited (P < 0.05). The VAS scores on postoperative day 1, week 1, month 1 and month 3 were lower in the OBS group than in the LP group (P < 0.05). Furthermore, the Constant-Murley shoulder scores at 1, 3, and 6 months postoperatively were higher in the OBS group than in the LP group (P < 0.05), with no significant difference at 1 year after surgery (P > 0.05). None of the patients in the OBS group experienced scarring of the surgical incision, and 6 patients in the LP group experienced scarring of the surgical incision. Finally, the complication incidence in the OBS group was lower than that in the LP group. CONCLUSION: For midshaft clavicle fractures, OBS intramedullary fixation is better than locking-plate internal fixation because it led to less trauma, a faster recovery, better efficacy, and better esthetic outcomes and comfort. Therefore, this technique may have potential as a novel treatment for midshaft clavicle fractures. LEVEL OF EVIDENCE: III, retrospective observational study.

Intermittent Fasting Primes the Tumor Microenvironment and Improves Nanomedicine Delivery in Hepatocellular Carcinoma.

Fasting has many health benefits, including reduced chemotherapy toxicity and improved efficacy. It is unclear how fasting affects the tumor microenvironment (TME) and tumor-targeted drug delivery. Here the effects of intermittent (IF) and short-term (STF) fasting are investigated on tumor growth, TME composition, and liposome delivery in allogeneic hepatocellular carcinoma (HCC) mouse models. To this end, mice are inoculated either subcutaneously or intrahepatically with Hep-55.1C cells and subjected to IF for 24 d or to STF for 1 d. IF but not STF significantly slows down tumor growth. IF increases tumor vascularization and decreases collagen density, resulting in improved liposome delivery. In vitro, fasting furthermore promotes the tumor cell uptake of liposomes. These results demonstrate that IF shapes the TME in HCC towards enhanced drug delivery. Finally, when combining IF with liposomal doxorubicin treatment, the antitumor efficacy of nanochemotherapy is found to be increased, while systemic side effects are reduced. Altogether, these findings exemplify that the beneficial effects of fasting on anticancer therapy outcomes go beyond modulating metabolism at the molecular level.

Pyroptosis is involved in maternal nicotine exposure-induced metabolic associated fatty liver disease progression in offspring mice.

We have investigated whether inflammasomes and pyroptosis are activated in maternal nicotine exposure (MNE) offspring mice and whether they are involved in MNE-promoted metabolic associated fatty liver disease (MAFLD) in adult offspring. We injected pregnant mice subcutaneously with saline vehicle or nicotine twice a day on gestational days 11-21. Offspring mice from both groups were fed with a normal diet (ND) or a high-fat diet (HFD) for 6 months at postnatal day 21 to develop the MAFLD model. Serum biochemical indices were analyzed, and liver histology was performed. The expression levels of inflammasome and pyroptosis proteins were detected by western blot. We found MNE significantly aggravated the injury of MAFLD in adult offspring mice. MNE activated inflammasomes and pyroptosis in both infant and adult offspring mice. HFD treatment activated inflammasomes but not pyroptosis at 3 months, while it showed no effect at 6 months. However, pyroptosis was more severe in MNE-HFD mice than in MNE-ND mice at 6 months. Taken together, our data suggest MNE promotes MAFLD progression in adult offspring mice. MNE also induces NLRP3 and NLRP6 inflammasome activation and pyroptosis in both infant and adult offspring mice, which may be involved in MNE-promoted progression of MAFLD.

Long-term hypercaloric diet exacerbates metabolic liver disease in PNPLA3 I148M animals.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is a major health burden associated with the metabolic syndrome leading to liver fibrosis, cirrhosis and ultimately liver cancer. In humans, the PNPLA3 I148M polymorphism of the phospholipase patatin-like phospholipid domain containing protein 3 (PNPLA3) has a well-documented impact on metabolic liver disease. In this study, we used a mouse model mimicking the human PNPLA3 I148M polymorphism in a long-term high fat diet (HFD) experiment to better define its role for NAFLD progression. METHODS: Male mice bearing wild-type Pnpla3 (Pnpla3WT ), or the human polymorphism PNPLA3 I148M (Pnpla3148M/M ) were subjected to HFD feeding for 24 and 52 weeks. Further analysis concerning basic phenotype, inflammation, proliferation and cell death, fibrosis and microbiota were performed in each time point. RESULTS: After 52 weeks HFD Pnpla3148M/M animals had more liver fibrosis, enhanced numbers of inflammatory cells as well as increased Kupffer cell activity. Increased hepatocyte cell turnover and ductular proliferation were evident in HFD Pnpla3148M/M livers. Microbiome diversity was decreased after HFD feeding, changes were influenced by HFD feeding (36%) and the PNPLA3 I148M genotype (12%). Pnpla3148M/M mice had more faecal bile acids. RNA-sequencing of liver tissue defined an HFD-associated signature, and a Pnpla3148M/M specific pattern, which suggests Kupffer cell and monocytes-derived macrophages as significant drivers of liver disease progression in Pnpla3148M/M animals. CONCLUSION: With long-term HFD feeding, mice with the PNPLA3 I148M genotype show exacerbated NAFLD. This finding is linked to PNPLA3 I148M-specific changes in microbiota composition and liver gene expression showing a stronger inflammatory response leading to enhanced liver fibrosis progression.

Polar Vessel: A New Ultrasound Sign for Complementary Diagnosis of Major Salivary Gland Adenoid Cystic Carcinoma.

OBJECTIVES: To investigate the characteristic ultrasonographic findings of adenoid cystic carcinoma (ACC) in major salivary glands and identify the value of polar vessel in color Doppler flow imaging (CDFI) for the diagnosis of ACC. METHODS: From January 2017 to December 2021, 76 patients with parotid and submandibular gland tumors, including 14 patients with ACC, as confirmed by surgery and histopathology, were enrolled. Their clinicopathologic information and ultrasound (US) features were recorded and analyzed. The performance of polar vessel in CDFI for differentiating ACC from non-ACC (benign tumors and mucoepidermoid carcinoma [MEC]) was analyzed. RESULTS: ACC in the major salivary gland was more likely to be associated with pain symptoms (P = .027) and unclear borders and rough edges in grayscale US (P = .002, .015, respectively) than benign tumors. Compared to MEC, ACC tended to feature a homogeneous internal echo (P = .008). ACC of the major salivary gland had a significantly higher incidence of polar vessel sign than that of non-ACC (benign tumors and MEC) (P < .0001, .0001, respectively). The polar vessel sign showed good performance in distinguishing between ACC and non-ACC, with an area under the receiver operating characteristic curve of 0.857, a sensitivity of 71.4%, a specificity of 100%, and an accuracy of 94.7%. Positive predictive value and negative predictive value were calculated at 100% and 93.9%, respectively. CONCLUSIONS: The US sign of polar vessel has high diagnostic efficiency, and it may have important potential for use as a new complementary sign for the diagnosis of ACC in major salivary glands.

Biomechanical study of the stiffness of the femoral locking compression plate of an external fixator for lower tibial fractures.

BACKGROUND: A locking compression plate (LCP) of the distal femur is used as an external fixator for lower tibial fractures. However, in clinical practice, the technique lacks a standardized approach and a strong biomechanical basis for its stability. METHODS: In this paper, internal tibial LCP fixator (Group IT-44), external tibial LCP fixator (Group ET-44), external distal femoral LCP fixator (Group EF-44, group EF-33, group EF-22), and conventional external fixator (Group CEF-22) frames were used to fix unstable fracture models of the lower tibial segment, and anatomical studies were performed to standardize the operation as well as to assess the biomechanical stability and adjustability of the distal femoral LCP external fixator by biomechanical experiments. RESULTS: It was found that the torsional and flexural stiffnesses of group EF-44 and group EF-33 were higher than those of group IT-44 and group ET-44 (p < 0.05); the flexural stiffness of group EF-22 was similar to that of group IT-44 (p > 0.05); and the compressive stiffness of all three EF groups was higher than that of group ET-44 (p < 0.05). In addition, the flexural and compressive stiffnesses of the three EF groups decreased with the decrease in the number of screws (p < 0.05), while the torsional stiffness of the three groups did not differ significantly between the two adjacent groups (p > 0.05). Group CEF-22 showed the highest stiffnesses, while group ET-44 had the lowest stiffnesses (P < 0.05). CONCLUSIONS: The study shows that the distal femoral LCP has good biomechanical stability and adjustability and is superior to the tibial LCP as an external fixator for distal tibial fractures, as long as the technique is used in a standardized manner according to the anatomical studies in this article.

Meso-substituted boron-dipyrromethene compounds: synthesis, tunable solid-state emission, and application in blue-driven LEDs.

In this work, we depict the synthesis and characterization of a series of meso-substituted boron-dipyrromethene (BODIPY) compounds. Their optical and electrochemical properties were investigated systematically. All these compounds exhibited intense absorption bands in the ultraviolet (UV) and visible regions, which arise from the π-π* transitions based on their BODIPY core segments. By comparing electron-withdrawing substituents and electron-donating substituents, we found that these compounds exhibited some similar photophysical properties but exhibited different fluorescence in the solid state. All compounds were highly emissive in dichloromethane at room temperature (λem = 512-523 nm, ΦPL > 0.9). When these compounds were applied in blue-driven light-emitting diodes (LEDs) as light-emitting materials, the devices showed luminescence efficiency ranging from 1.09 to 34.13 lm/W. Their luminescence and electrochemical properties could be used for understanding the structure-property relationship of BODIPY compounds and developing functional fluorescent materials.

A review of the association between oral bacterial flora and obstructive sleep apnea-hypopnea syndrome comorbid with cardiovascular disease.

PURPOSE: Obstructive sleep apnea-hypopnea syndrome (OSAHS), a common sleep disorder, has been shown to be an independent risk factor for cardiovascular disease (CVD). Recent studies have focused on the important roles of microorganisms in human health; for example, microorganisms are reportedly associated with obesity, metabolic disorders, and CVD. The number of oral bacteria in patients with OSAHS is considerably higher than that in healthy individuals, and infection with oral bacterial pathogens is associated with the development of CVD. However, whether changes in the oral microbiota mediate the development of OSAHS and CVD remains unknown. METHODS: Therefore, we attempted to review the association between changes in oral microbiota in patients with OSAHS and the development of CVD. RESULTS: Oral microbiota possibly acts via multiple pathways including direct invasion, platelet aggregation, immune response, inflammatory response, and oxidative stress response, leading to the development of CVD in patients with OSAHS. In particular, the strains Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Prevotella intermedia have demonstrated profound effects. OSAHS leads to changes in the oral bacterial flora and thus may facilitate the occurrence and development of CVD. CONCLUSION: We propose that the underlying mechanism of CVDs resulting from oral microbiota in patients with OSAHS should be elucidated in further studies.

Stabilization and destabilization of nonlinear systems via aperiodically intermittent stochastic noises: Average techniques and scalar functions.

In this paper, almost sure exponential stabilization and destabilization criteria for nonlinear systems are obtained via aperiodically intermittent stochastic noises based on average techniques and piecewise continuous scalar functions. Compared with existing results on almost sure exponential stability of stochastic systems, the requirement on the upper bound of the diffusion operator of a Lyapunov function is released. The upper bound is allowed to be a scalar function and even be unbounded. Simultaneously, by means of putting forward new concepts "average noise control rate" and "average noise control period," assumptions on infimum of control time and supremum of rest time in the previous references about aperiodically intermittent control can be removed without implementing in the upper limit of the uncontrolled rate, which reduces the conservativeness of stabilization criteria resulting from non-uniform distribution of control time and rest time. In addition, the main results are applied to coupled and uncoupled nonlinear spring-mass-damper oscillator systems, respectively, and corresponding numerical simulations are carried out to demonstrate the validity of the theoretical analysis.

Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis.

OBJECTIVE: There is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut-liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2-/-) model resembling human primary sclerosing cholangitis (PSC). DESIGN: Male Mdr2-/-, Mdr2-/- crossed with hepatocyte-specific deletion of caspase-8 (Mdr2-/- /Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2-/- -associated intestinal dysbiosis was studied by microbiota transfer experiments. RESULTS: Mdr2-/- mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut-liver axis. Intestinal dysbiosis in Mdr2-/- mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2-/- microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature. CONCLUSIONS: MDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.

Gut microbiota in obstructive sleep apnea-hypopnea syndrome: disease-related dysbiosis and metabolic comorbidities.

Gut microbiota alterations manifest as intermittent hypoxia and fragmented sleep, thereby mimicking obstructive sleep apnea-hypopnea syndrome (OSAHS). Here, we sought to perform the first direct survey of gut microbial dysbiosis over a range of apnea-hypopnea indices (AHI) among patients with OSAHS. We obtained fecal samples from 93 patients with OSAHS [5 < AHI ≤ 15 (n=40), 15 < AHI ≤ 30 (n=23), and AHI ≥ 30 (n=30)] and 20 controls (AHI ≤ 5) and determined the microbiome composition via 16S rRNA pyrosequencing and bioinformatics analysis of variable regions 3-4. We measured fasting levels of homocysteine (HCY), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). Results revealed gut microbial dysbiosis in several patients with varying severities of OSAHS, reliably separating them from controls with a receiver operating characteristic-area under the curve (ROC-AUC) of 0.789. Functional analysis in the microbiomes of patients revealed alterations; additionally, decreased in short-chain fatty acid (SCFA)-producing bacteria and increased pathogens, accompanied by elevated levels of IL-6. Lactobacillus levels correlated with HCY levels. Stratification analysis revealed that the Ruminococcus enterotype posed the highest risk for patients with OSAHS. Our results show that the presence of an altered microbiome is associated with HCY among OSAHS patients. These changes in the levels of SCFA affect the levels of pathogens that play a pathophysiological role in OSAHS and related metabolic comorbidities.

Neuroprotective effects of berberine in animal models of Alzheimer's disease: a systematic review of pre-clinical studies.

BACKGROUND: Berberine is an isoquinoline alkaloid extracted from various Berberis species which is widely used in East Asia for a wide range of symptoms. Recently, neuroprotective effects of berberine in Alzheimer's disease (AD) animal models are being extensively reported. So far, no clinical trial has been carried out on the neuroprotective effects of berberine. However, a review of the experimental data is needed before choosing berberine as a candidate drug for clinical experiments. We conducted a systematic review on AD rodent models to analyze the drug effects with minimal selection bias. METHODS: Five online literature databases were searched to find publications reporting studies of the effect of berberine treatment on animal models of AD. Up to March 2018, 15 papers were identified to describe the efficacy of berberine. RESULTS: The included 15 articles met our inclusion criteria with different quality ranging from 3 to 5. We analyzed data extracted from full texts with regard to pharmacological effects and potential anti-Alzheimer's properties. Our analysis revealed that in multiple memory defects animal models, berberine showed significant memory-improving activities with multiple mechanisms, such as anti-inflammation, anti-oxidative stress, cholinesterase (ChE) inhibition and anti-amyloid effects. CONCLUSION: AD is likely to be a complex disease driven by multiple factors. Yet, many therapeutic strategies based on lowering ß-amyloid have failed in clinical trials. This suggest that the threapy should not base on a single cause of Alzheimer's disease but rather a number of different pathways that lead to the disease. Overall we think that berberine can be a promising multipotent agent to combat Alzheimer's disease.

Inactivation of caspase 8 in liver parenchymal cells confers protection against murine obstructive cholestasis.

BACKGROUND & AIMS: Caspase 8 (CASP8) is the apical initiator caspase in death receptor-mediated apoptosis. Strong evidence for a link between death receptor signaling pathways and cholestasis has recently emerged. Herein, we investigated the role of CASP8-dependent and independent pathways during experimental cholestasis. METHODS: Liver injury was characterized in a cohort of human sera (n = 28) and biopsies from patients with stage IV primary biliary cholangitis. In parallel, mice with either specific deletion of Casp8 in liver parenchymal cells (Casp8Δhepa) or hepatocytes (Casp8Δhep), and mice with constitutive Ripk3 (Ripk3-/-) deletion, were subjected to surgical ligation of the common bile duct (BDL) from 2 to 28 days. Floxed (Casp8fl/fl) and Ripk3+/+ mice were used as controls. Moreover, the pan-caspase inhibitor IDN-7314 was used, and cell death mechanisms were studied in primary isolated hepatocytes. RESULTS: Overexpression of activated caspase 3, CASP8 and RIPK3 was characteristic of liver explants from patients with primary biliary cholangitis. Twenty-eight days after BDL, Casp8Δhepamice showed decreased necrotic foci, serum aminotransferase levels and apoptosis along with diminished compensatory proliferation and ductular reaction. These results correlated with a decreased inflammatory profile and ameliorated liver fibrogenesis. A similar phenotype was observed in Ripk3-/- mice. IDN-7314 treatment decreased CASP8 levels but failed to prevent BDL-induced cholestasis, independently of CASP8 in hepatocytes. CONCLUSION: These findings show that intervention against CASP8 in liver parenchymal cells - specifically in cholangiocytes - might be a beneficial option for treating obstructive cholestasis, while broad pan-caspase inhibition might trigger undesirable side effects. LAY SUMMARY: Loss of caspase 8 - a protein involved in programmed cell death - in liver parenchymal cells protects against experimental cholestasis. Therefore, specific pharmacological intervention against caspase 8 might be a valid alternative for the treatment of obstructive cholestasis in the clinic, whereas broad pan-caspase inhibiting drugs might trigger undesirable side effects.

Synchronization of coupled stochastic complex-valued dynamical networks with time-varying delays via aperiodically intermittent adaptive control.

This paper deals with the synchronization problem of a class of coupled stochastic complex-valued drive-response networks with time-varying delays via aperiodically intermittent adaptive control. Different from the previous works, the intermittent control is aperiodic and adaptive, and the restrictions on the control width and time delay are removed, which lead to a larger application scope for this control strategy. Then, based on the Lyapunov method and Kirchhoff's Matrix Tree Theorem as well as differential inequality techniques, several novel synchronization conditions are derived for the considered model. Specially, impulsive control is also considered, which can be seen as a special case of the aperiodically intermittent control when the control width tends to zero. And the corresponding synchronization criteria are given as well. As an application of the theoretical results, a class of stochastic complex-valued coupled oscillators with time-varying delays is studied, and the numerical simulations are also given to demonstrate the effectiveness of the control strategies.