FXR Regulates Intestinal Cancer Stem Cell Proliferation.

Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal cancer (CRC). Here, we show that the convergence of dietary factors (high-fat diet) and dysregulated WNT signaling (APC mutation) alters BA profiles to drive malignant transformations in Lgr5-expressing (Lgr5+) cancer stem cells and promote an adenoma-to-adenocarcinoma progression. Mechanistically, we show that BAs that antagonize intestinal farnesoid X receptor (FXR) function, including tauro-ß-muricholic acid (T-ßMCA) and deoxycholic acid (DCA), induce proliferation and DNA damage in Lgr5+ cells. Conversely, selective activation of intestinal FXR can restrict abnormal Lgr5+ cell growth and curtail CRC progression. This unexpected role for FXR in coordinating intestinal self-renewal with BA levels implicates FXR as a potential therapeutic target for CRC.

Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBα Degradation.

Defects in circadian rhythm influence physiology and behavior with implications for the treatment of sleep disorders, metabolic disease, and cancer. Although core regulatory components of clock rhythmicity have been defined, insight into the mechanisms underpinning amplitude is limited. Here, we show that REV-ERBα, a core inhibitory component of clock transcription, is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7. By relieving REV-ERBα-dependent repression, FBXW7 provides an unrecognized mechanism for enhancing the amplitude of clock gene transcription. Cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation of REV-ERBα is necessary for FBXW7 recognition. Moreover, targeted hepatic disruption of FBXW7 alters circadian expression of core clock genes and perturbs whole-body lipid and glucose levels. This CDK1-FBXW7 pathway controlling REV-ERBα repression defines an unexpected molecular mechanism for re-engaging the positive transcriptional arm of the clock, as well as a potential route to manipulate clock amplitude via small molecule CDK1 inhibition.

Obesity alters pathology and treatment response in inflammatory disease.

Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system1-7, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 inflammation. We also observed divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo TH response towards a TH2-predominant state and prevent aberrant non-TH2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of TH17 pathology and unlocked therapeutic responsiveness to targeted anti-TH2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.

Autocrine FGF1 signaling promotes glucose uptake in adipocytes.

Fibroblast growth factor 1 (FGF1) is an autocrine growth factor released from adipose tissue during over-nutrition or fasting to feeding transition. While local actions underlie the majority of FGF1's anti-diabetic functions, the molecular mechanisms downstream of adipose FGF receptor signaling are unclear. We investigated the effects of FGF1 on glucose uptake and its underlying mechanism in murine 3T3-L1 adipocytes and in ex vivo adipose explants from mice. FGF1 increased glucose uptake in 3T3-L1 adipocytes and epididymal WAT (eWAT) and inguinal WAT (iWAT). Conversely, glucose uptake was reduced in eWAT and iWAT of FGF1 knockout mice. We show that FGF1 acutely increased adipocyte glucose uptake via activation of the insulin-sensitive glucose transporter GLUT4, involving dynamic crosstalk between the MEK1/2 and Akt signaling proteins. Prolonged exposure to FGF1 stimulated adipocyte glucose uptake by MEK1/2-dependent transcription of the basal glucose transporter GLUT1. We have thus identified an alternative pathway to stimulate glucose uptake in adipocytes, independent from insulin, which could open new avenues for treating patients with type 2 diabetes.

A20 functions as a negative regulator of the lipopolysaccharide-induced inflammation in corneal epithelial cells.

A20, also called TNFAIP3, is a crucial regulator of inflammation in various diseases but has not evidenced its function in the cornea. We aimed to evaluate the existence and the functions of A20 in human corneal epithelial (HCE-T) cells. After being treated with lipopolysaccharide (LPS) in different concentrations or at separate times, cells were collected to analyze A20 expressions. We then constructed the A20 knockdown system by siRNA and the A20 overexpressing system by lentivirus transduction. Systems were further exposed to medium with or without LPS for indicated times. Next, we evaluated the production of inflammatory cytokines (IL-6 and IL-8) by qRT-PCR and ELISA. Also, the translocation of P65 and the phosphorylation of P65, P38 and JNK were observed in two systems. In addition, we used the nuclear factor kappa-B (NF-κB) antagonist TPCA-1 for the pretreatment in cells and then detected the A20 expressions. We found a low basal expression of A20 in HCE-T cells, and the expressions could be dose-dependently induced by LPS, peaking at 4 h in protein level after stimulation. Both the A20 knockdown and A20 overexpressing systems were confirmed to be effective. After the LPS treatment, productions of IL-6 and IL-8 were enhanced in the A20 knockdown system and reduced in the A20 overexpressing system. A20 reduced the translocation of P65 into the nucleus and the phosphorylation of P65, P38 and JNK. Furthermore, TPCA-1 pretreatment reduced the expression of A20 in cells. We concluded that A20 is a potent regulator for corneal epithelium's reaction to inflammation, and it thus is expected to be a potential therapy target for ocular surface diseases.

Dihydroartemisinin induces cell apoptosis through repression of UHRF1 in prostate cancer cells.

Prostate cancer (PCa) seriously jeopardizes men's health worldwide. Dihydroartemisinin, which is an effective antimalarial agent, has shown potential anticancer effects in various human cancer cell lines, including PCa cells. However, the mechanisms underlying the anticancer activity of dihydroartemisinin are not fully understood. Ubiquitin-like with plant homeodomain and ring finger domain 1 (UHRF1) is highly expressed in a variety of tumors and is negatively correlated with the prognosis of various tumors. We reported previously that UHRF1 is downregulated during apoptosis induced by dihydroartemisinin in PC-3 PCa cells. In this study, we transfected PC-3 cells with lentiviruses containing UHRF1 or shRNA-UHRF1. Then, the cells were treated with dihydroartemisinin at different concentrations. Our data showed that overexpression of UHRF1 promoted cell proliferation and migration in PC-3 cells, inhibited cell apoptosis, increased cell proportion in G2 phase, increased DNA methyltransferase 1 and decreased p16INK4A expression at mRNA and protein levels. Downregulation of UHRF1 produces the opposite results. Moreover, the phenomena caused by overexpression of UHRF1 were inhibited after dihydroartemisinin treatment. Compared with control cells, cells overexpressing UHRF1 can resist the proapoptotic and antiproliferative effects of dihydroartemisinin to a certain extent. The effects of UHRF1 knockdown were further aggravated by dihydroartemisinin treatment, but no statistically significant effect was observed with increasing drug concentration. Our results suggested that dihydroartemisinin decreases proliferation and migration but enhances apoptosis of PCa cells, likely by downregulating UHRF1 and upregulating p16INK4A.

Foldable Bulk Anti-adhesive Polyacrylic Intraocular Lens Material Design and Fabrication for Posterior Capsule Opacification Prevention.

Posterior capsular opacification (PCO) is a primary complication after phacoemulsification combined with intraocular lens (IOL) implantation, which is attributed to adhesion, proliferation, and migration of residual lens epithelial cells on IOL. Although surface hydrophilic coating is considered to be a powerful way to inhibit PCO incidence after surgery, it requires complex post-production processes, thus limiting their applicability. In comparison, bulk modification is a stable, effective, and facile IOL synthesis method for PCO prevention. Herein, a new anti-adhesive IOL material was designed and successfully synthesized by radical copolymerization of ethylene glycol phenyl ether methacrylate (EGPEMA) and 2-(2-ethoxyethoxy) ethyl acrylate (EA). The physicochemical properties of P(EGPEMA-co-EA) copolymer materials, including chemical structure, mechanical, thermal, surface, and optical properties, were analyzed by using 1H NMR spectroscopy, FT-IR spectroscopy, tensile test, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), water contact angle measurement, and UV-vis spectroscopy. The elongation at break and the modulus of elasticity of the copolymer were tunable through the change of the composition of monomers. Compared to other components, the tensile results showed that P(EGPEMA-co-EA) materials (70% EGPEMA in mass ratio, F7) are suitable for the preparation of foldable intraocular lens with lower elastic modulus and higher elongation at break. TGA and DSC showed that the material has high thermal stability, and the glass transition temperature of F7 material is 16.1 °C. The water contact angle measurement results showed that the introduction of EA improved the hydrophilicity of the material. The percentage of transmittance of all copolymers at 400-800 nm is above 85%. Then, the biocompatibility of the materials was evaluated by in vitro assay and subcutaneous implantation. Both in vitro results and subcutaneous implantation experiments showed that the designed IOL materials exhibited a good anti-adhesion effect and no cytotoxicity. Finally, phacoemulsification and IOL intraocular implantation were performed, and the in vivo results confirmed the good PCO prevention ability as well as the biocompatibility of the new IOL materials.

Depletion of fat-resident Treg cells prevents age-associated insulin resistance.

Age-associated insulin resistance (IR) and obesity-associated IR are two physiologically distinct forms of adult-onset diabetes. While macrophage-driven inflammation is a core driver of obesity-associated IR, the underlying mechanisms of the obesity-independent yet highly prevalent age-associated IR are largely unexplored. Here we show, using comparative adipo-immune profiling in mice, that fat-resident regulatory T cells, termed fTreg cells, accumulate in adipose tissue as a function of age, but not obesity. Supporting the existence of two distinct mechanisms underlying IR, mice deficient in fTreg cells are protected against age-associated IR, yet remain susceptible to obesity-associated IR and metabolic disease. By contrast, selective depletion of fTreg cells via anti-ST2 antibody treatment increases adipose tissue insulin sensitivity. These findings establish that distinct immune cell populations within adipose tissue underlie ageing- and obesity-associated IR, and implicate fTreg cells as adipo-immune drivers and potential therapeutic targets in the treatment of age-associated IR.

Stromal cues regulate the pancreatic cancer epigenome and metabolome.

A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap of stroma-induced changes in vitro with those previously shown to be regulated by oncogenic Kras in vivo suggests that oncogenic Kras signaling-a hallmark and key driver of PDAC-is contingent on stromal inputs. Mechanistically, stroma-activated cancer cells show widespread increases in histone acetylation at transcriptionally enhanced genes, implicating the PDAC epigenome as a presumptive point of convergence between these pathways and a potential therapeutic target. Notably, inhibition of the bromodomain and extraterminal (BET) family of epigenetic readers, and of Bromodomain-containing protein 2 (BRD2) in particular, blocks stroma-inducible transcriptional regulation in vitro and tumor progression in vivo. Our work suggests the existence of a molecular "AND-gate" such that tumor activation is the consequence of mutant Kras and stromal cues, providing insight into the role of the tumor microenvironment in the origin and treatment of Ras-driven tumors.

A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use.

Food intake increases the activity of hepatic de novo lipogenesis, which mediates the conversion of glucose to fats for storage or use. In mice, this program follows a circadian rhythm that peaks with nocturnal feeding and is repressed by Rev-erbα/ß and an HDAC3-containing complex during the day. The transcriptional activators controlling rhythmic lipid synthesis in the dark cycle remain poorly defined. Disturbances in hepatic lipogenesis are also associated with systemic metabolic phenotypes, suggesting that lipogenesis in the liver communicates with peripheral tissues to control energy substrate homeostasis. Here we identify a PPARδ-dependent de novo lipogenic pathway in the liver that modulates fat use by muscle via a circulating lipid. The nuclear receptor PPARδ controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific PPARδ activation increases, whereas hepatocyte-Ppard deletion reduces, muscle fatty acid uptake. Unbiased metabolite profiling identifies phosphatidylcholine 18:0/18:1 (PC(18:0/18:1) as a serum lipid regulated by diurnal hepatic PPARδ activity. PC(18:0/18:1) reduces postprandial lipid levels and increases fatty acid use through muscle PPARα. High-fat feeding diminishes rhythmic production of PC(18:0/18:1), whereas PC(18:0/18:1) administration in db/db mice (also known as Lepr(-/-)) improves metabolic homeostasis. These findings reveal an integrated regulatory circuit coupling lipid synthesis in the liver to energy use in muscle by coordinating the activity of two closely related nuclear receptors. These data implicate alterations in diurnal hepatic PPARδ-PC(18:0/18:1) signalling in metabolic disorders, including obesity.

In vivo monitoring of microwave ablation in a porcine model using ultrasonic differential attenuation coefficient intercept imaging.

In this study, the feasibility of using ultrasonic differential attenuation coefficient intercept (Δα0) imaging to evaluate thermal lesions induced by microwave ablation (MWA) was explored using an in vivo porcine model. The attenuation coefficient intercept (Δα0 is estimated by subtracting an initial value of Δα0 images. Receiver operating characteristic (ROC) curves and the area under ROC curve (AUC) were employed to statistically assess the predictability of ultrasonic imaging. Ultrasonic Δα0 values were approximately 0.13 dB/cm and 0.16 dB/cm in a normal liver and kidney, respectively, increasing to 2.9 dB/cm and 2.55 dB/cm in ablated regions after MWA. The CNR values of the ultrasonic Δα0 images (0.9 dB and 0.6 dB in the liver and kidney, respectively) were significantly higher (p < 0.05) than the values of B-mode images (0.6 dB and 0.3 dB). The AUC value of the ultrasonic Δα0 image was higher than the B-mode image value, 0.95 compared with 0.88. This in vivo study suggests that ultrasonic Δα0 imaging has the potential to evaluate thermal lesions with high accuracy and better image contrast for monitoring MWA.

Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance.

Mammalian acyl-CoA thioesterases (Acots) catalyze the hydrolysis of fatty acyl-CoAs to form free fatty acids plus CoA, but their metabolic functions remain undefined. Thioesterase superfamily member 1 (Them1; synonyms Acot11, StarD14, and brown fat inducible thioesterase) is a long-chain fatty acyl-CoA thioesterase that is highly expressed in brown adipose tissue and is regulated by both ambient temperature and food consumption. Here we show that Them1(-/-) mice were resistant to diet-induced obesity despite greater food consumption. Them1(-/-) mice exhibited increased O(2) consumption and heat production, which were accompanied by increased rates of fatty acid oxidation in brown adipose tissue and up-regulation of genes that promote energy expenditure. Them1(-/-) mice were also protected against diet-induced inflammation in white adipose tissue, as well as hepatic steatosis, and demonstrated improved glucose homeostasis. The absence of Them1 expression in vivo and in cell culture led to markedly attenuated diet- or chemically induced endoplasmic reticulum stress responses, providing a mechanism by which Them1 deficiency protects against insulin resistance and lipid deposition. Taken together, these data suggest that Them1 functions to decrease energy consumption and conserve calories. In the setting of nutritional excess, the overproduction of free fatty acids by Them1 provokes insulin resistance that is associated with inflammation and endoplasmic reticulum stress.

Iron loading impairs lipoprotein lipase activity and promotes hypertriglyceridemia.

Iron loading is associated with altered lipid metabolism, but underlying mechanisms remain unknown. We compared serum iron and triglycerides (TGs) in Belgrade rats, a genetic model of iron-loading anemia. Homozygous b/b rats had greater serum iron (68 vs. 28 µM; P=0.0004) and TG levels (180 vs. 84 mg/dl; P=0.014) compared to +/b controls. To confirm the association between iron loading and high TGs, Fischer rats were fed chow containing 1% carbonyl iron. Compared to controls pair-fed normal chow, carbonyl iron-fed rats had elevated serum iron (42 vs. 21 µM; P=0.007) and TGs (190 vs. 115 mg/dl; P=0.009). Despite normal hepatic production and secretion, TG clearance was lower in b/b than +/b rats due to reduced serum lipoprotein lipase (LPL) activity (3.1 vs. 5.0 mM/min; P=0.026). Likewise, LPL was lower in carbonyl iron-fed rats compared to controls (2.4 vs. 3.7 mM/min; P=0.017). Direct addition of iron to serum ex vivo or recombinant LPL in vitro decreased enzymatic activity in a dose-dependent manner. Lowering serum iron in Belgrade rats reduced TG levels (274 to 67 mg/dl, P=0.001). This study explains the relationship between iron status and lipid metabolism and provides mechanistic support for interventions that reduce serum iron levels in individuals at risk for hypertriglyceridemia.

Expression of Concern: Surface modification of intraocular lenses via photodynamic coating for safe and effective PCO prevention.

Expression of Concern for 'Surface modification of intraocular lenses via photodynamic coating for safe and effective PCO prevention' by Junmei Tang et al., J. Mater. Chem. B, 2021, 9, 1546-1556, https://doi.org/10.1039/D0TB02802A.

Correlation analysis of balance function with plantar pressure distribution and gait parameters in patients with cerebral infarction in the basal ganglia region.

Objective: To analyze the correlation between balance function and gait parameters of patients with basal ganglia infarction. And to observe the influence of balance function on plantar pressure and hemiplegia gait based on the Berg Balance Scale (BBS) score. Methods: One hundred and forty patients with cerebral infarction hemiplegia in the basal ganglia region (a study group, n = 140) and healthy people (a control group, n = 140) were enrolled. The study group was evaluated with the BBS, the 10 m walking test (10MWT), and the timed up-and-go test (TUGT). The gait parameters and the peak plantar pressure were measured in both groups while walking, and the differences between the groups were compared. In addition, the characteristics of the plantar pressure curve of the hemiplegic and non-hemiplegic sides during walking and the correlation between the 10MWT, the TUGT, the plantar pressure peak, the gait parameters,and the BBS score were analyzed in the study group. Results: The peak plantar pressure of the forefoot and heel, stride length, lateral symmetry, stand phase, swing phase, and dual stand phase of both sides in the study group were significantly lower than those in the control group (P < 0.05). The BBS score negatively correlated with the 10MWT, the TUGT, the peak plantar pressure of the hemiplegic forefoot, midfoot, and the non-hemiplegic midfoot, the anterior to posterior position (ant/post position), hemiplegic stand phase, and the dual stand phase (P < 0.05). The BBS score positively correlated with the hemiplegic swing phase and stride length (P < 0.05). Conclusion: A correlation was found between the forefoot plantar pressure and the stand phase of the hemiplegic limbs, the ant/post position, and the balance function after basal ganglion cerebral infarction. This association can be used in walking and balance assessment for stroke rehabilitation. Correcting forefoot pressure or the front and ant/post position can improve balance function.

Role of tear exosomes in the spread of herpes simplex virus type 1 in recurrent herpes simplex keratitis.

BACKGROUND: Herpes simplex keratitis (HSK) is the most common but serious infectious keratitis with high recurrence. It is predominantly caused by herpes simplex virus type 1 (HSV-1). The spread mechanism of HSV-1 in HSK is not entirely clear. Multiple publications indicate that exosomes participate in the intercellular communication process during viral infections. However, there is rare evidence that HSV-1 spreads in HSK by exosomal pathway. This study aims to investigate the relationship between the spread of HSV-1 and tear exosomes in recurrent HSK. METHODS: Tear fluids collected from total 59 participants were included in this study. Tear exosomes were isolated by ultracentrifugation, then identified by silver staining and western blot. The size was determined by dynamic light scattering (DLS). The viral biomarkers were identified by western blot. The cellular uptake of exosomes was studied using labelled exosomes. RESULTS: Tear exosomes were indeed enriched in tear fluids. Collected exosomes own normal diameters consistent with related reports. The exosomal biomarkers existed in tear exosomes. Labelled exosomes were successfully taken up by human corneal epithelial cells (HCEC) in large numbers in a short time. After cellular uptake, HSK biomarkers were detectable by western blot in infected cells. CONCLUSIONS: Tear exosomes should be the latent sites of HSV-1 in recurrent HSK and might be involved in the spread of HSV-1. Besides, this study verifies HSV-1 genes can be indeed transferred between cells by exosomal pathway, providing new inspiration for the clinical intervention and treatment as well as the drug discovery of recurrent HSK.

Anticancer effect of Dihydroartemisinin via dual control of ROS-induced apoptosis and protective autophagy in prostate cancer 22Rv1 cells.

BACKGROUND: Dihydroartemisinin (DHA), a natural agent, exhibits potent anticancer activity. However, its biological activity on prostate cancer (PCa) 22Rv1 cells has not been previously investigated. OBJECTIVE: In this study, we demonstrate that DHA induces anticancer effects through the induction of apoptosis and autophagy. METHODS: Cell viability and proliferation rate were assessed using the CCK-8 assay and cell clone formation assay. The generation of reactive oxygen species (ROS) was detected by flow cytometry. The molecular mechanism of DHA-induced apoptosis and autophagy was examined using Western blot and RT-qPCR. The formation of autophagosomes and the changes in autophagy flux were observed using transmission electron microscopy (TEM) and confocal microscopy. The effect of DHA combined with Chloroquine (CQ) was assessed using the EdU assay and flow cytometry. The expressions of ROS/AMPK/mTOR-related proteins were detected using Western blot. The interaction between Beclin-1 and Bcl-2 was examined using Co-IP. RESULTS: DHA inhibited 22Rv1 cell proliferation and induced apoptosis. DHA exerted its anti-prostate cancer effects by increasing ROS levels. DHA promoted autophagy progression in 22Rv1 cells. Inhibition of autophagy enhanced the pro-apoptotic effect of DHA. DHA-induced autophagy initiation depended on the ROS/AMPK/mTOR pathway. After DHA treatment, the impact of Beclin-1 on Bcl-2 was weakened, and its binding with Vps34 was enhanced. CONCLUSION: DHA induces apoptosis and autophagy in 22Rv1 cells. The underlying mechanism may involve the regulation of ROS/AMPK/mTOR signaling pathways and the interaction between Beclin-1 and Bcl-2 proteins. Additionally, the combination of DHA and CQ may enhance the efficacy of DHA in inhibiting tumor cell activity.

The Effect of Continuous Theta Burst Stimulation over the Right Dorsolateral Prefrontal Cortex on Cognitive Function and Emotional Regulation in Patients with Cerebral Small Vessel Disease.

OBJECTIVES: Cognitive impairment in cerebral small vessel disease (CSVD) is a common cause of vascular dementia and is often accompanied by mental disorders. The purpose of this study was to investigate the effect of continuous theta burst stimulation (cTBS) over the right dorsolateral prefrontal cortex (DLPFC) on the cognitive function and Hamilton depression (HAMD) scores in patients with CSVD. METHODS: A total of 30 CSVD patients who met the inclusion criteria were randomly assigned to either the sham or cTBS group. The patients in both groups received routine cognitive function training. All the patients were under treatment for 14 sessions, with one session per day (each cTBS conditioning session consisted of three-pulse bursts at 50 Hz repeated at 5 Hz, 80% MT, and 600 pulses). Before and after the treatment, the patients in both groups were evaluated using the Montreal Cognitive Assessment (MoCA), Stroop Color-Word Test (SCWT), Trail Marking Test (TMT), Digital Span Test (DST), and HAMD test. The time to complete the SCWT and TMT were recorded. The scores of the MoCA, DST and HAMD test were recorded. RESULTS: The HAMD scores in the cTBS group decreased significantly compared to the control (p < 0.05). There were no significant differences in the MoCA (including the MoCA subitems) or DST scores or in the SCWT or TMT completion times between the two groups (p > 0.05). For the HAMD scores and the MoCA subitem visuospatial/executive scores, the SCWT-B and SCWT-C completion times in the two groups both improved significantly before and after treatment (p < 0.05). For the MoCA scores, the DST-backward scores and the TMT-B completion times in the cTBS group improved significantly before and after treatment (p < 0.05). There was no significant difference in the SCWT-A, TMT-A completion times and MoCA subitems naming, attention, language, abstraction, delayed recall, and orientation scores either before or after treatment in the two groups or between the two groups (p > 0.05). CONCLUSIONS: In this study, cTBS over the right DLPFC decreased the HAMD scores significantly in patients with CSVD but had no significant improvement or impairment effects on cognitive function. cTBS over the right DLPFC could be used to treat CSVD patients with depression symptoms.

Role of peroxisome proliferator-activated receptor {delta}/{beta} in hepatic metabolic regulation.

Pharmacological activation of peroxisome proliferator-activated receptor δ/ß (PPARδ/ß) improves glucose handling and insulin sensitivity. The target tissues of drug actions remain unclear. We demonstrate here that adenovirus-mediated liver-restricted PPARδ activation reduces fasting glucose levels in chow- and high fat-fed mice. This effect is accompanied by hepatic glycogen and lipid deposition as well as up-regulation of glucose utilization and de novo lipogenesis pathways. Promoter analyses indicate that PPARδ regulates hepatic metabolic programs through both direct and indirect transcriptional mechanisms partly mediated by its co-activator, PPARγ co-activator-1ß. Assessment of the lipid composition reveals that PPARδ increases the production of monounsaturated fatty acids, which are PPAR activators, and reduces that of saturated FAs. Despite the increased lipid accumulation, adeno-PPARδ-infected livers exhibit less damage and show a reduction in JNK stress signaling, suggesting that PPARδ-regulated lipogenic program may protect against lipotoxicity. The altered substrate utilization by PPARδ also results in a secondary effect on AMP-activated protein kinase activation, which likely contributes to the glucose-lowering activity. Collectively, our data suggest that PPARδ controls hepatic energy substrate homeostasis by coordinated regulation of glucose and fatty acid metabolism, which provide a molecular basis for developing PPARδ agonists to manage hyperglycemia and insulin resistance.

A polydopamine-based photodynamic coating on the intraocular lens surface for safer posterior capsule opacification conquering.

Intraocular lens (IOL) is the indispensable implant for cataract surgery. However, posterior capsular opacification (PCO) happens in high incidence after IOL implantation. PCO is caused by adhesion, proliferation, and trans-differentiation of the residual human lens epithelial cells (HLECs). Despite the great achievements in surface coating and antiproliferative drug loading on the intraocular lens (IOL) for effective PCO prevention, the complex fabrication process and potential toxicity of the drugs still limit their clinical applications and commercial mass production. In this investigation, a convenient and efficient photodynamic therapy (PDT) coating fabricated by facile yet economical and practical dopamine self-polymerization was applied to IOL surface modification for PCO prevention. The optical properties of IOL, such as light transmittance, imaging quality and refractive index, remain unchanged after modification. Using an in vitro cell assay, the parameters of PDT were optimized. The PDT coating shows excellent biocompatibility in darkness and eliminates LECs significantly under irradiation. The research on the cell elimination mechanism showed that reactive oxygen species (ROS) mainly induced cell apoptosis. In vivo experiments demonstrated that the implantation of modified IOLs can prevent PCO effectively. As a result, this work provides a safe, simple and effective PDT coating for the IOL surface to reduce the incidence of PCO.