Carboxymethyl cellulose-based multifunctional film integrated with polyphenol-rich extract and carbon dots from coffee husk waste for active food packaging applications.

Sustainable carboxymethyl cellulose (CMC)-based active composite films were developed through the addition of polyphenol-rich extract from coffee husk (CHE) and carbon dots (CDs) prepared using the biowaste residue of CHE extraction. The influences of various CDs contents on the physicochemical and functional characteristics of composite films have been researched. The 6% (w/w) CHE and 3% (w/w) CDs were uniformly dispersed within the CMC matrix to produce a homogenous film with enhanced mechanical properties. The CMC/CHE/CDs3% film exhibited outstanding UV-light blocking, improved water and gas barriers, potent antioxidant activity with above 95% DPPH and ABTS scavenging rates, and effective antibacterial capabilities against L. monocytogenes and E. coli. The food packaging experiment demonstrated that this active composite film slowed the rotting of fresh-cut apples and extended their shelf-life to 7 days at 4 °C storage. Therefore, the obtained multifunctional film showed promise as an environmentally friendly food packaging material.

Gelatin-based multifunctional composite films integrated with dialdehyde carboxymethyl cellulose and coffee leaf extract for active food packaging.

In this study, dialdehyde carboxymethyl cellulose (DCMC, 10 wt% based on gelatin) and varying contents of coffee leaf extract (CLE, 1, 3, 5 and 7 wt% based on gelatin) were incorporated into gelatin (GEL) matrix to develop multifunctional food packaging films. DCMC acted as a physical reinforcing filler through crosslinking with GEL matrix by Schiff-base reaction, CLE served as an active filler to confer film functional properties. The micro-morphology, micro-structure, physicochemical and functional properties of the GEL/DCMC/CLE composite film were investigated. The results demonstrated that mechanical, barrier properties and thermal stability of films were significantly improved by incorporation of CLE. Compared with pure GEL film, the GEL/DCMC/5%CLE film exhibited excellent UV light blocking while kept enough transparency, the best mechanical property, water resistance, water vapor and oxygen barrier, as well as thermal stability. GEL/DCMC/5%CLE film also possessed strong antioxidant activity and some antibacterial activity against E. coli and S. aureus. Packaging application testing demonstrated that the resultant GEL/DCMC/5%CLE film effectively delayed the lipid oxidation of walnut oil and preserved the postharvest freshness of fresh walnut kernels under ambient conditions.

Preparation and characterization of chitosan/dialdehyde carboxymethyl cellulose composite film loaded with cinnamaldehyde@zein nanoparticles for active food packaging.

In this study, zein-loaded cinnamaldehyde (Cin@ZN) nanoparticles were incorporated into Chitosan (CS)/dialdehyde carboxymethyl cellulose (DCMC) matrix to fabricate the active food packaging materials possessing outstanding antioxidant and antibacterial properties. The research investigated how varying levels of Cin@ZN nanoparticles affected the morphology, microstructure, physicochemical properties of CS/DCMC composite films. The inclusion of Cin@ZN could significantly improve the mechanical strength, reduce the water vapor and oxygen permeability of CS/DCMC composite films and endow films with UV-light blocking properties. It's worth noting that the antibacterial and antioxidant capacities of CS/DCMC films had an astonishing enhancement with Cin@ZN blending, in which ABTS scavenging ratio of the composite films (100 mg) with different Cin@ZN contents reached >90 %. Furthermore, CS/DCMC/Cin@ZN 35 % composite film has the ability to efficiently protect strawberries from microbial damage and decelerate the spoilage rate of strawberries under ambient condition. Consequently, the CS/DCMC/Cin@ZN composite film can be applied as packaging material to extend the lifespan of fruits.

Comparison of embryo quality and pregnancy outcomes for patients with low ovarian reserve in natural cycles and mildly stimulated cycles: a cohort study.

BACKGROUND: As women with low ovarian reserve embark on the challenging journey of in-vitro fertilisation (IVF) treatment, the choice between natural and mildly stimulated cycles becomes a pivotal consideration. It is unclear which of these two regimens is superior for women with low ovarian reserve. Our study aims to assess the impact of natural cycles on embryo quality and pregnancy outcomes in women with low ovarian reserve undergoing IVF treatment compared to mildly stimulated cycles. METHODS: This retrospective study enrolled consecutive patients with low ovarian reserve who underwent IVF/intracytoplasmic sperm injection (ICSI) at Guangdong Second Provincial General Hospital between January 2017 and April 2021. The primary outcome for pregnancy rate of 478 natural cycles and 448 mild stimulated cycles was compared. Secondary outcomes included embryo quality and oocyte retrieval time of natural cycles. RESULTS: The pregnancy rate in the natural cycle group was significantly higher than that in the mildly stimulated cycle group (51.8% vs. 40.1%, p = 0.046). Moreover, natural cycles exhibited higher rates of available embryos (84.1% vs. 78.6%, p = 0.040), high-quality embryos (61.8% vs. 53.2%, p = 0.008), and utilisation of oocytes (73% vs. 65%, p = 0.001) compared to mildly stimulated cycles. Oocyte retrievals in natural cycles were predominantly performed between 7:00 and 19:00, with 94.9% occurring during this time frame. In natural cycles with high-quality embryos, 96.4% of oocyte retrievals were also conducted between 7:00 and 19:00. CONCLUSION: Natural cycles with appropriately timed oocyte retrieval may present a valuable option for patients with low ovarian reserve.

In the realm of in-vitro fertilisation (IVF) treatment, women with low ovarian reserve often face the crucial decision of opting for natural or mildly stimulated cycles. This retrospective study, conducted between January 2017 and April 2021 at Guangdong Second Provincial General Hospital, delves into the impact of these cycles on pregnancy outcomes. Examining 478 natural cycles and 448 mildly stimulated cycles, the study reveals a notably higher pregnancy rate in the natural cycle group (51.8% vs. 40.1%). Additionally, natural cycles demonstrated higher rates of available embryos, high-quality embryos, and oocyte utilisation compared to their mildly stimulated counterparts. The findings suggest that natural cycles, with proper oocyte retrieval timing, could be a favourable choice for those with low ovarian reserve seeking IVF treatment.

Humidity-adjustable functional gelatin hydrogel/ethyl cellulose bilayer films for active food packaging application.

A sustainable functional bilayer film composed of gelatin hydrogel/ethyl cellulose was fabricated using a simple LBL casting method. The outer layer was hydrophobic ethyl cellulose (EC), while the inner layer was hydrophilic gelatin (GEL) hydrogel. Tannic acid (TA) served as a green cross-linker for GEL hydrogel preparation and as a reductant for AgNPs synthesis in-situ within the hydrogel network. Physicochemical and functional properties of the bilayer films containing different TA content were studied. When 3 wt% TA was added, the AgNPs@GT-3/EC bilayer film exhibited superior UV-light barrier, possessed desirable humidity-adjustable capability and oxygen barrier due to denser hydrogel network structure, and effectively inactivated foodborne pathogens S. aureus and E. coli with bacteriostatic rates of 99 %. The application results indicated that this bilayer film effectively maintained the postharvest quality of white button mushrooms and prolonged their shelf-life to 7 days under ambient storage, demonstrating its promising potential for fresh food packaging.

Crosslinked fish scale gelatin/alginate dialdehyde functional films incorporated with carbon dots derived from pomelo peel waste for active food packaging.

A multifunctional and environmentally friendly composite film was developed by incorporating pomelo peel-derived carbon dots (PCDs) into a fish scale gelatin (FSG)/alginate dialdehyde (ADA) biopolymer matrix. ADA was used to reinforce the physicomechanical properties of the FSG film via Schiff base crosslinking. PCDs with strong antioxidant and antimicrobial activities were synthesized via a hydrothermal method. The effect of various PCDs content on the surface morphological, physicochemical, and functional characteristics of the composite films was investigated. The results showed that the introduction of PCDs into the FSG/ADA matrix effectively reinforced the mechanical performance, enhanced the water vapor and water resistance, increased UV-light blocking, conferred fluorescence properties, and improved the thermal properties of the composite films. Under 3 wt% PCDs content, the FSG/ADA/PCDs-3 % composite film not only presented significant antioxidant capacity with a radical scavenging rate of 91.71 % for DPPH and approximately 100 % for ABTS, but also exhibited excellent antimicrobial ability against bacteria and fungi. Results of a preservation experiment showed that the prepared FSG/ADA/PCDs-3 % film preserved the physiological qualities of strawberries post-harvest and extended their shelf-life to 7 days at room temperature. Overall, the fabricated FSG/ADA/PCDs composite films are promising for use in eco-friendly active food packaging.

[Relationship between trace elements in synovial fluid and cartilage and severity of knee osteoarthritis].

Objective: To investigate the relationship between trace elements in synovial fluid and cartilage and severity of knee osteoarthritis (KOA). Methods: Patients with KOA who underwent knee arthrocentesis or total knee arthroplasty (TKA) were recruited based on inclusion criteria between June 2021 and December 2021. Synovial fluid samples were obtained during knee arthrocentesis and TKA, and participants were divided into the mild group (grading Ⅰ/Ⅱ) and the severe group (grading Ⅲ/Ⅳ) according to the Kellgren-Lawrence grading (K-L grading). Cartilage samples with different degrees of wear were collected during the TKA from the same patient and were divided into mild wear (0-1 point) and severe wear (2-4 points) groups based on the Pelletier score. The contents of copper (Cu), zinc (Zn), and manganese (Mn) in synovial fluid and cartilage were evaluated by inductively coupled plasma mass spectrometry, and the differences between groups were compared. Results: A total of 33 synovial fluid samples were collected, including 19 specimens from 14 patients who underwent knee arthrocentesis of mild group, with 5 bilateral sides knee arthrocentesis in them, and 14 specimens from 14 TKA patients of severe group. The patients were significantly younger in the mild group than in the severe group ( P<0.05), but there was no significant difference in gender or body mass index between the two groups ( P>0.05). Nineteen pairs of cartilage samples with mild and severe wear were collected from severe KOA patients (K-L grading Ⅲ and Ⅳ), including 9 males and 10 females, with an average age of 70.4 years (range, 58-80 years). The body mass index ranged from 21.2 to 30.7 kg/m 2, with an average of 25.6 kg/m 2. The content of Zn in synovial fluid and cartilage from KOA patients was the highest, followed by Cu, and Mn was the lowest. The Cu content in synovial fluid was significantly higher in the severe group than in the mild group ( P<0.05), and in the severe wear group than in the mild wear group ( P<0.05). There was no significant difference in Zn and Mn content between the two groups ( P>0.05). Conclusion: The Cu content increases with the severity of cartilage wear in patients with KOA.

CRISPR editing demonstrates rs10490924 raised oxidative stress in iPSC-derived retinal cells from patients with ARMS2/HTRA1-related AMD.

Genome-wide association studies (GWAS) have identified genetic risk loci for age-related macular degeneration (AMD) on the chromosome 10q26 (Chr10) locus and are tightly linked: the A69S (G>T) rs10490924 single-nucleotide variant (SNV) and the AATAA-rich insertion-deletion (indel, del443/ins54), which are found in the age-related maculopathy susceptibility 2 (ARMS2) gene, and the G512A (G>A) rs11200638 SNV, which is found in the high-temperature requirement A serine peptidase 1 (HTRA1) promoter. The fourth variant is Y402H complement factor H (CFH), which directs CFH signaling. CRISPR manipulation of retinal pigment epithelium (RPE) cells may allow one to isolate the effects of the individual SNV and thus identify SNV-specific effects on cell phenotype. Clustered regularly interspaced short palindromic repeats (CRISPR) editing demonstrates that rs10490924 raised oxidative stress in induced pluripotent stem cell (iPSC)-derived retinal cells from patients with AMD. Sodium phenylbutyrate preferentially reverses the cell death caused by ARMS2 rs10490924 but not HTRA1 rs11200638. This study serves as a proof of concept for the use of patient-specific iPSCs for functional annotation of tightly linked GWAS to study the etiology of a late-onset disease phenotype. More importantly, we demonstrate that antioxidant administration may be useful for reducing reactive oxidative stress in AMD, a prevalent late-onset neurodegenerative disorder.

Knockdown of circ_CLIP2 regulates the proliferation, metastasis and apoptosis of glioma cells through miR-641/EPHA3/STAT3 axis.

A great amount of reaches have confirmed that circular RNAs (circRNAs) are novel regulators in glioma progression. Here, our work aimed to probe the specific role of circ_CLIP2 in glioma. The mRNA and protein expressions were analyzed by qRT-PCR and western blot, respectively. Cell viability, migration, invasion and apoptosis were examined by MTT assay, tranwell and flow cytometry assays, respectively. Moreover, the binding relationships between circ_CLIP2, microRNA (miR)-641 and erythropoietin-producing human hepatocellular (Eph)A3 were verified by dual luciferase reporter gene assay and/or RIP assay. The following data showed that circ_CLIP2 and EPHA3 were markedly increased in glioma tissues and cells, while miR-647 was downregulated. Gain- and loss-of-function experiments discovered that circ_CLIP2 knockdown remarkably inhibited cell proliferation, migration and invasion and promoted cell apoptosis of glioma cells, while these effects of circ_CLIP2 knockdown were abolished by miR-641 inhibition. Circ_CLIP2 was proved as a sponge of miR-641 to competitively upregulate EPHA3 expression. In addition, EPHA3 overexpression could abolish the inhibitory effects of miR-641 overexpression on the malignant behaviors of glioma cells by activating the signal transducer and activator of transcription 3 (STAT3). These findings elucidated that circ_CLIP2 knockdown suppressed glioma development by regulation of the miR-641/EP HA3/STAT3 axis, which provided a novel mechanism for understanding the pathogenesis of glioma.

Fabrication and characterization of waste fish scale-derived gelatin/sodium alginate/carvacrol loaded ZIF-8 nanoparticles composite films with sustained antibacterial activity for active food packaging.

An environmental-friendly composite films containing waste fish scale-derived gelatin (FSG), sodium alginate (SA) and carvacrol loaded ZIF-8 (CV@ZIF-8) nanoparticles were designed and fabricated to develop active food packaging materials capable of sustained antibacterial activity. The microstructure and physicochemical properties of the FSG/SA/CV@ZIF-8 composite films were investigated. The incorporation of CV@ZIF-8 into FSG/SA matrix significantly enhanced the UV-light blocking and the elongation at break, improved water resistance and reduced water vapor permeability, and improved the thermal stability of composite film. The FSG/SA/CV@ZIF-8 film not only exhibited strong antioxidant activity with DPPH radical scavenging rate of 92.35 %, but also showed the satisfactory and long-acting antibacterial ability against E. coli and S. aureus due to slow release of CV from composite film. Strawberry preservation experiment revealed that FSG/SA/CV@ZIF-8 film decelerated the texture deterioration and retarded the growth of spoilage microorganism, resulting in the prolonged shelf-life of 8 days under ambient condition, indicating its promising application prospect in food preservation packaging.

Continuous light exposure influences luteinization and luteal function of ovary in ICR mice.

With the rapid change of people's lifestyle, more childbearing couples live with irregular schedules (i.e., staying up late) and suffer from decreased fertility and abortion, which can be caused by luteal phase defect (LPD). We used continuous light-exposed mice as a model to observe whether continuous light exposure may affect luteinization and luteal function. We showed that the level of progesterone in serum reduced (p < .001), the number of corpus luteum (CL) decreased (p < .01), and the expressions of luteinization-related genes (Lhcgr, Star, Ptgfr, and Runx2), clock genes (Clock and Per1), and Mt1 were downregulated (p < .05) in the ovaries of mice exposed to continuous light, suggesting that continuous light exposure induces defects in luteinization and luteal functions. Strikingly, injection of melatonin (3 mg/kg) could improve luteal functions in continuous light-exposed mice. Moreover, we found that, after 2 h of hCG injection, the level of pERK1/2 in the ovary decreased in the continuous light group, but increased in the melatonin administration group, suggesting that melatonin can improve LPD caused by continuous light exposure through activating the ERK1/2 pathway. In summary, our data demonstrate that continuous light exposure affects ovary luteinization and luteal function, which can be rescued by melatonin.

[Surgical planning and mid-term effectiveness of four major lower extremity arthroplasties in patients with rheumatoid arthritis].

Objective: To investigate the surgical planning and the mid-term effectiveness of four major lower extremity arthroplasties (4JA) in patients with rheumatoid arthritis (RA). Methods: A clinical data of 25 patients with RA, who received 4JA and were followed up more than 3 years between June 2012 and September 2018, was retrospectively analyzed. There were 3 males and 22 females, with an average age of 48.6 years (range, 27-80 years). The body mass index ranged from 16.0 to 28.4 kg/m 2, with an average of 20.48 kg/m 2. The duration of RA ranged from 2 to 35 years (median, 21 years). There were 8 cases (12 sides) of knee valgus, 6 cases (12 side) of acetabular retraction, and 5 cases (10 sides) of hip stiffness. Among them, 20 patients underwent hip surgery first, and 5 patients underwent knee surgery first. Hip joint function was evaluated by Harris score, Hip Disability and Osteoarthritis Outcome Score (HOOS), hip range of motion, and Trendelenburg sign; knee joint function was evaluated by American Hospital for Special Surgery (HSS) score, knee range of motion and muscle strength, and a timed up and go (TUG) test was performed at last follow-up. X-ray films were used to observe whether the prosthesis was loose or displaced. Results: All 25 patients completed 4JA. Only 1 patient (1 side) had incision infection after operation, 3 patients (3 sides) had proximal femur fractures during operation. All patients were followed up 3.0-8.8 years, with an average of 5.8 years. At last follow-up, the Harris score, HOOS score, and range of motion of flexion, extension, and abduction of the hip joint significantly improved when compared with those before operation, and the patients with positive Trendelenburg sign decreased. The HSS score and range of motion of flexion and extension of the knee joint also significantly improved when compared with those before operation. There were significant differences in all indexes between pre- and post-operation ( P<0.05). The muscle strength was grade V. The TUG test ranged from 7.8 to 15.34 seconds (mean,10.79 seconds). X-ray films showed the prosthesis was not loose or displaced. Conclusion: When RA patients receive 4JA, adequate preoperative evaluation, rational selection of the timing and sequence of surgery, and maximal restoration of lower limb alignment can achieve good mid-term effectiveness.

Effects of Maternal Factors and Postpartum Environment on Early Colonization of Intestinal Microbiota in Piglets.

Intestinal microbiota significantly influences the intake, storage, and utilization of body nutrients, as well as animal growth and development. The establishment of microbiota is affected by many factors, such as delivery and feeding modes, antibiotics, disease, and the surrounding environment. In this study, we selected Chinese indigenous Mashen and Jinfen White pigs as the study subjects. To explore the source and factors affecting the piglet intestinal microbiota, 16S rRNA gene sequencing was performed to analyze the microbial composition of the feces, saliva, vaginal secretions, and colostrum of parturient sows, feces and saliva of newborn piglets, and surrounding environment samples. The results showed that the microbiota of the saliva of sows and piglets is structurally similar to that of the environment and is dominated by the phylum Proteobacteria, including Acinetobacter, Actinomyces, and Pseudomonas. The core genus in the vaginal secretions and colostrum of sows was Pseudomonas. Among the fecal samples, the core bacterial genera in sows before and after delivery were Clostridium sensu_stricto_1 and Christensenellaceae_R-7_group, while in piglets at 1 d of age, Pseudomonas and Escherichia-Shigella were most abundant. These results indicate that microbiota in feces, colostrum, and vaginal secretions of sows more easily colonized piglet intestines through a symbiotic effect. The environmental and salivary microbiota could also affect the early colonization and succession of the intestinal microbiota of piglets to some extent. This study provides a theoretical basis for sow delivery protection and early nursing of piglets and background for the research and development of microbial agents to improve piglet intestinal health.

TRIP12 ubiquitination of glucocerebrosidase contributes to neurodegeneration in Parkinson's disease.

Impairment in glucocerebrosidase (GCase) is strongly associated with the development of Parkinson's disease (PD), yet the regulators responsible for its impairment remain elusive. In this paper, we identify the E3 ligase Thyroid Hormone Receptor Interacting Protein 12 (TRIP12) as a key regulator of GCase. TRIP12 interacts with and ubiquitinates GCase at lysine 293 to control its degradation via ubiquitin proteasomal degradation. Ubiquitinated GCase by TRIP12 leads to its functional impairment through premature degradation and subsequent accumulation of α-synuclein. TRIP12 overexpression causes mitochondrial dysfunction, which is ameliorated by GCase overexpression. Further, conditional TRIP12 knockout in vitro and knockdown in vivo promotes the expression of GCase, which blocks α-synuclein preformed fibrils (α-syn PFFs)-provoked dopaminergic neurodegeneration. Moreover, TRIP12 accumulates in human PD brain and α-synuclein-based mouse models. The identification of TRIP12 as a regulator of GCase provides a new perspective on the molecular mechanisms underlying dysfunctional GCase-driven neurodegeneration in PD.

Impaired cholesterol efflux in retinal pigment epithelium of individuals with juvenile macular degeneration.

Macular degeneration (MD) is characterized by the progressive deterioration of the macula and represents one of the most prevalent causes of blindness worldwide. Abnormal intracellular accumulation of lipid droplets and pericellular deposits of lipid-rich material in the retinal pigment epithelium (RPE) called drusen are clinical hallmarks of different forms of MD including Doyne honeycomb retinal dystrophy (DHRD) and age-related MD (AMD). However, the appropriate molecular therapeutic target underlying these disorder phenotypes remains elusive. Here, we address this knowledge gap by comparing the proteomic profiles of induced pluripotent stem cell (iPSC)-derived RPEs (iRPE) from individuals with DHRD and their isogenic controls. Our analysis and follow-up studies elucidated the mechanism of lipid accumulation in DHRD iRPE cells. Specifically, we detected significant downregulation of carboxylesterase 1 (CES1), an enzyme that converts cholesteryl ester to free cholesterol, an indispensable process in cholesterol export. CES1 knockdown or overexpression of EFEMP1R345W, a variant of EGF-containing fibulin extracellular matrix protein 1 that is associated with DHRD and attenuated cholesterol efflux and led to lipid droplet accumulation. In iRPE cells, we also found that EFEMP1R345W has a hyper-inhibitory effect on epidermal growth factor receptor (EGFR) signaling when compared to EFEMP1WT and may suppress CES1 expression via the downregulation of transcription factor SP1. Taken together, these results highlight the homeostatic role of cholesterol efflux in iRPE cells and identify CES1 as a mediator of cholesterol efflux in MD.

Cerebellar oscillations driven by synaptic pruning deficits of cerebellar climbing fibers contribute to tremor pathophysiology.

Essential tremor (ET) is one of the most common movement disorders and the prototypical disorder for abnormal rhythmic movements. However, the pathophysiology of tremor generation in ET remains unclear. Here, we used autoptic cerebral tissue from patients with ET, clinical data, and mouse models to report that synaptic pruning deficits of climbing fiber (CF)-to-Purkinje cell (PC) synapses, which are related to glutamate receptor delta 2 (GluRδ2) protein insufficiency, cause excessive cerebellar oscillations and might be responsible for tremor. The CF-PC synaptic pruning deficits were correlated with the reduction in GluRδ2 expression in the postmortem ET cerebellum. Mice with GluRδ2 insufficiency and CF-PC synaptic pruning deficits develop ET-like tremor that can be suppressed with viral rescue of GluRδ2 protein. Step-by-step optogenetic or pharmacological inhibition of neuronal firing, axonal activity, or synaptic vesicle release confirmed that the activity of the excessive CF-to-PC synapses is required for tremor generation. In vivo electrophysiology in mice showed that excessive cerebellar oscillatory activity is CF dependent and necessary for tremor and optogenetic-driven PC synchronization was sufficient to generate tremor in wild-type animals. Human validation by cerebellar electroencephalography confirmed that excessive cerebellar oscillations also exist in patients with ET. Our findings identify a pathophysiologic contribution to tremor at molecular (GluRδ2), structural (CF-to-PC synapses), physiological (cerebellar oscillations), and behavioral levels (kinetic tremor) that might have clinical applications for treating ET.

Potent Activity of Composite Cyclin Dependent Kinase Inhibition against Hepatocellular Carcinoma.

Alterations in cell cycle regulators are common in hepatocellular carcinoma (HCC). We tested the efficacy of composite inhibition of CDKs 1, 2, 5, and 9 through dinaciclib on HCC. In vitro, dinaciclib exhibited potent antiproliferative activities in HCC cell lines regardless of Rb or c-myc expression levels. Dinaciclib significantly downregulated the phosphorylation of Rb (target of CDKs 1 and 2), ataxia telangiectasia mutated kinase (target of CDK5), and RNA polymerase II (target of CDK9) in the HCC cells. In xenograft studies, mice receiving dinaciclib tolerated the treatment well without significant body weight changes and exhibited a significantly slower tumor growth rate than the mice receiving vehicles. RNA interference (RNAi) of CDKs 1 and 9 was more effective in inhibiting the cell proliferation of HCC cells than RNAi of CDKs 2 and 5. Overexpression of CDK9 significantly reduced the efficacy of dinaciclib in HCC cells, but overexpression of CDK1 did not. In conclusion, composite inhibition of CDKs 1, 2, 5, and 9 through dinaciclib exhibited potent in vitro and in vivo activity against HCC. CDK9 inhibition might be the crucial mechanism.

Mesenchymal stem cells enhance microglia M2 polarization and attenuate neuroinflammation through TSG-6.

Microglia are the primary cells that exert immune function in the central nervous system (CNS), and they play an important role in the pathogenesis and progression of neuroinflammation-related diseases. Mesenchymal stem cells (MSCs) have been demonstrated to promote functional recovery in many neurological diseases. The mechanisms underlying this may be that MSCs can reduce inflammatory responses through various soluble factors. Among these factors, tumor necrosis factor-α-induced gene/protein 6 (TSG-6) is a key factor influencing MSCs immunomodulatory properties; however, the precise mechanisms underlying the anti-inflammatory effects are not fully understood. Here, we aim to investigate the potential effects of MSCs on neuroinflammation and to reveal the underlying mechanisms. First, we confirmed that administration of MSCs could inhibit the lipopolysaccharide (LPS)-induced neuroinflammatory responses in a mouse model. Then, we found that MSCs promoted M2 polarization and inhibited M1 polarization both in vivo and in vitro. Moreover, we demonstrated that the effect of MSCs on microglial polarization was dependent on TSG-6. This study demonstrated that MSCs promoted M2 polarization of microglia via TSG-6, thus conferring anti-neuroinflammatory effects.

Animal Models of Tremor: Relevance to Human Tremor Disorders.

Background: Tremor is the most common movement disorder; however, the pathophysiology of tremor remains elusive. While several neuropathological alterations in tremor disorders have been observed in post-mortem studies of human brains, a full understanding of the relationship between brain circuitry alterations and tremor requires testing in animal models. Additionally, tremor animal models are critical for our understanding of tremor pathophysiology, and/or to serve as a platform for therapy development. Methods: A PubMed search was conducted in May 2018 to identify published papers for review. Results: The methodology used in most studies on animal models of tremor lacks standardized measurement of tremor frequency and amplitude; instead, these studies are based on the visual inspection of phenotypes, which may fail to delineate tremor from other movement disorders such as ataxia. Of the animal models with extensive tremor characterization, harmaline-induced rodent tremor models provide an important framework showing that rhythmic and synchronous neuronal activities within the olivocerebellar circuit can drive action tremor. In addition, dopamine-depleted monkey and mouse models may develop rest tremor, highlighting the role of dopamine in rest tremor generation. Finally, other animal models of tremor have involvement of the cerebellar circuitry, leading to altered Purkinje cell physiology. Discussion: Both the cerebellum and the basal ganglia are likely to play a role in tremor generation. While the cerebellar circuitry can generate rhythmic movements, the nigrostriatal system is likely to modulate the tremor circuit. Tremor disorders are heterogeneous in nature. Therefore, each animal model may represent a subset of tremor disorders, which collectively can advance our understanding of tremor.

Hepatitis C virus core protein potentiates proangiogenic activity of hepatocellular carcinoma cells.

Increased angiogenic activity has been demonstrated in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC), but the mechanism was unclear. To study the role of HCV core protein, we used tube formation and Matrigel plug assays to assess the proangiogenic activity of an HCC cell line, HuH7, and 2 of its stable clones-HuH7-core-high and HuH7-core-low, with high and low HCV core protein expression, respectively. In both assays, HuH7-core-high and HuH7-core-low cells dose-dependently induced stronger angiogenesis than control cells. HuH7 cells with HCV core protein expression showed increased mRNA and protein expression of vascular endothelial growth factor (VEGF). VEGF inhibition by bevacizumab reduced the proangiogenic activity of HuH7-core-high cells. The promotor region of VEGF contains the binding site of activator protein-1 (AP-1). Compared with controls, HuH7-core-high cells had an increased AP-1 activity and nuclear localization of phospho-c-jun. AP-1 inhibition using either RNA knockdown or AP-1 inhibitors reduced the VEGF mRNA expression and the proangiogenic activity of HuH7-core-high cells. Among 131 tissue samples from HCC patients, HCV-related HCC revealed stronger VEGF expression than did hepatitis B virus-related HCC. In conclusion, increased VEGF expression through AP-1 activation is a crucial mechanism underlying the proangiogenic activity of the HCV core protein in HCC cells.