Titanium dioxide-functionalized dendritic mesoporous silica nanoparticles for highly selective isolation of phosphoproteins.

Selective isolation of phosphoproteins is of great significance in biological applications. Herein, titanium dioxide-functionalized dendritic mesoporous silica nanoparticles are prepared via a post-grafting method for selective capture of phosphoproteins. The fabricated nanoparticles possess a unique central-radial pore structure with a surface area of 666.66 m2 /g and a pore size of 22.2 nm. The high-binding affinity of TiO2 with the phosphate groups facilitates the selective adsorption of phosphoproteins. Moreover, the open central-radial pore structure endows the dendritic mesoporous nanoparticles with better adsorption performance toward phosphoproteins with respect to the commercial titanium dioxide nanoparticles and titanium dioxide-functionalized conventional mesoporous silica nanoparticles by providing more accessible affinity sites. At pH 2, an adsorption capacity of 157.2 mg/g is derived for ß-casein. The feasibility of the as-prepared dendritic material in real biological sample assay is demonstrated by the selective isolation of phosphoproteins from defatted milk, as illustrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis assay.

Transjugular intrahepatic portosystemic shunt is effective in patients with chronic portal vein thrombosis and variceal bleeding.

BACKGROUND: Studies about treatment of patients with chronic portal vein thrombosis (CPVT) are still limited, especially in different types of CPVT. This study aimed to evaluate the effect of transjugular intrahepatic portosystemic shunt (TIPS) in all types of CPVT with variceal bleeding. METHODS: Patients with CPVT who received TIPS treatment between January 2011 and June 2019 were divided into four types according to the extent of thrombosis. All patients had a history of variceal bleeding. The characteristics and clinical parameters were collected and recorded. Data on procedure success rate, variation in portal vein pressure, rebleeding, hepatic encephalopathy (HE), stent stenosis, and overall mortality were analyzed. RESULTS: A total of 189 patients were included in this study (39 in type 1, 84 in type 2, 48 in type 3, 18 in type 4). The TIPS procedure success rate was 86.2%. The success rate was significantly different among the four types (89.7% vs. 88.1% vs. 83.3% vs. 77.8%, P = 0.001). In the TIPS success group, portal vein pressure was significantly reduced from 27.15 ± 6.59 to 19.74 ± 6.73 mmHg after the procedure (P < 0.001) and the rebleeding rate was significantly lower than that of the fail group (14.7% vs. 30.8%, P = 0.017). In addition, there were no significant differences in HE rate (30.7% vs. 26.9%, P = 0.912) or overall mortality (12.9% vs. 19.2%, P = 0.403) between the TIPS success group and the fail group. In the TIPS success group, we found that the occurrence of HE was significantly different (P = 0.020) among the four types, while there were no significant differences in rebleeding rate (P = 0.669), stent stenosis rate (P = 0.056), or overall mortality (P = 0.690). CONCLUSIONS: TIPS was safe and effective in decreasing portal vein pressure and rebleeding rate in patients with CPVT.

hMex-3A is associated with poor prognosis and contributes to the progression of hepatocellular carcinoma.

BACKGROUND: HMex-3A, an RNA-binding protein, was found to be associated with tumorigenesis. However, the roles of hMex-3A in hepatocellular carcinoma (HCC) progression remained unclear. METHODS: The different expression of hMex-3A between HCC tissues and non-tumor tissues was evaluated using The Cancer Genome Atlas database. Thereafter, the hMex-3A expression was evaluated in HCC tissues using Western blotting and qRT-PCR. Immunohistochemistry was performed to investigate the association between hMex-3A level and clinicopathological features including prognosis in HCC patients. In addition, we used si-hMex-3A to knockdown hMex-3A in HCC cells to test Cell Counting Kit-8, colony formation, cell migration and invasion. RESULTS: The hMex-3A expression was significantly elevated in HCC tissues. Analysis of the clinicopathological parameters suggested that hMex-3A expression was significantly associated with pathological grade (P = 0.019) and TNM stage (P = 0.001) in HCC. Moreover, univariate and multivariate Cox-regression analyses revealed that high hMex-3A expression (HR = 1.491, 95% CI: 1.107-2.007; P = 0.009) was an independent risk factor for overall survival in HCC patients. Finally, we confirmed that si-hMex-3A could significantly inhibit HCC cell proliferation, migration, and invasion in vitro. CONCLUSIONS: HMex-3A may contribute to the progression of HCC and might be used as a novel therapeutic target and prognostic marker in HCC.

[Correlation between theta-gamma neural oscillations in hippocampal CA3 area and the spatial identifying and cognitive ability in rats].

The present study was aimed to explore the correlation between θ-γ neural oscillations phase-amplitude coupling (PAC) in hippocampal CA3 area and the changes of spatial identifying and cognitive ability before and after shock avoidance training in rats. According to the results of Y-type maze shock avoidance training, the rats were divided into two groups: the fast avoidance response group and the general avoidance response group. The local field potential (LFP) of hippocampal CA3 area was recorded by wireless telemetry before and after shock avoidance training. The variation of θ oscillation (3-7 Hz) and low-γ neural oscillation (30-60 Hz) PAC in hippocampal CA3 area was analyzed by MATLAB wavelet packet extraction technique. The results showed that, compared with the general avoidance response group, the fast avoidance response group exhibited higher θ-γ neural oscillation PAC in hippocampal CA3 area before training. θ-γ oscillation PAC in hippocampal CA3 area was increased in both groups after training. It was also noticed that θ-γ neural oscillation PAC of some frequency bands in the general avoidance response group were significantly higher than those in the fast avoidance response group. The results suggest that certain intensity of training can change the spatial identifying and cognitive ability of rats, and the mechanism may involve the increase of the synchrony of θ-γ neural oscillation, i.e., the enhancement of θ-γ phase-amplitude alternating frequency coupling in hippocampal neurons.

Triplexed Tracking Labile Sulfur-Containing Species on a Single-Molecule "Nezha" Sensor.

Sulfur-containing species (SCS), especially sulfur dioxide-relevant species, play an essential role in ecological balance. Owing to the intrinsically labile and mobile characteristics of SCS, it is still considered to be an insurmountable challenge for multiplexed tracking dynamics of SCS with distinct molecular structure, valence state, and condensed state. To address this key problem, we proposed herein alternative versatile single-molecule sensors (VSMs) that intramolecularly integrate high affinity target-guided multiple recognition units into a single sensory molecule, clarified as molecular Nezha available in triplexed responses to gaseous sulfur dioxide, liquid sulfur trioxide, and aqueous bisulfite through ubiquitous charge transfer and nucleophilic addition. High-performance molecular Nezha remarkably facilitated promising applications in a quantitative visualization of SCS on lab-on-paper and tracking the dynamics transformation of SCS as well comprehensive evaluation of multiphase adsorption science of SCS on an advanced Zeolitic imidazolate framework-8 (ZIF-8).

High temperature damage to fatty acids and carbohydrate metabolism in tall fescue by coupling deep transcriptome and metabolome analysis.

High temperature damage impairs the growth of tall fescue by inhibiting secondary metabolites. Little is known about the regulation pattern of the fatty acids and carbohydrate metabolism at the whole-transcriptome level in tall fescue under high temperature stress. Here, two tall fescue genotypes, heat tolerant PI578718 and heat sensitive PI234881 were subjected to high temperature stress for 36 h. PI 578718 showed higher SPAD chloroplast value, lower EL and leaf injury than PI 234881 during the first 36 h high-temperature stress. Furthermore, by transcriptomic analysis, 121 genes were found to be induced during the second energy production phase in tall fescue exposed to high-temperature conditions, indicating that there may be one energy-sensing system in cool-season turfgrass to adapt high-temperature conditions. PI 578718 showed higher differentially expressed unigenes involved in fatty acids and carbohydrate metabolism compared with PI 234881 for 36 h heat stress. Interestingly, a metabolomic analysis using GC-MS uncovered that the sugars and sugar alcohol accounted for more than 65.06% of the total 41 metabolites content and high-temperature elevated the rate to 82.89-91.16% in PI 578718. High-temperature damage decreased the rate of fatty acid in the total 41 metabolites content and PI 578718 showed lower content than in PI 234881, which might be attributed to the down-regulated genes in fatty acid biosynthesis pathway in tall fescue. The integration of deep transcriptome and metabolome analyses provides systems-wide datasets to facilitate the identification of crucial regulation factors in cool-season turfgrass in response to high-temperature damage.

[RAD51 regulates REV1 recruitment to DNA double-strand break sites].

REV1 is one of the major Y-family DNA polymerases. It not only functions as a scaffold protein to mediate other specialized DNA polymerases to sites of lesions, but also inserts deoxycytidine across the lesion strand during translesion DNA synthesis (TLS). Meanwhile, REV1 has been reported to be involved in homologous recombination (HR) repair. Here we further explore the roles of REV1-interacting proteins RAD51 and RAD51C in REV1-mediated DNA double-strand break (DSB) repair. We found that RAD51 but not RAD51C regulates REV1 recruitment to DSB sites via pulsed laser microirradiation. Interestingly, immunofluorescence staining exhibits that REV1 also regulates RAD51 focus formation in response to CPT treatment. These results suggest that REV1 and RAD51 might be mutually dependent on each other in the REV1-related HR pathway.

Supplementation with high-dose trans-resveratrol improves ultrafiltration in peritoneal dialysis patients: a prospective, randomized, double-blind study.

BACKGROUND: Ultrafiltration (UF) failure mostly contributes to technical failure in peritoneal dialysis (PD) patients, and one of its responsible factors is peritoneal angiogenesis. Resveratrol has been proposed to have an angiogenesis-ameliorating effect on tumor patients. We hypothesize trans-resveratrol has beneficial effects on angiogenesis-related markers in PD patients. METHODS: In this prospective, randomized, and double-blind trial, 72 patients were randomly assigned to 12-week treatment of low-dose or high-dose (150 or 450 mg/d) trans-resveratrol or a placebo. Visits were scheduled at 0, 4, 8, and 12 weeks after treatment. Clinical indices including 24-hour UF volume, UF rate, 24-hour urine volume, residual renal function, and dialysis adequacy (kt/v) were measured. Angiogenesis markers including vascular endothelial growth factor (VEGF), fetal liver kinase-1 (Flk-1), angiopoietin-2 (Ang-2), tyrosine kinase 2 (Tie-2), and thrombospondin-1 (Tsp-1) in peritoneal effluent were also assessed by enzyme-linked immunosorbent assay. RESULTS: Finally, 64 out of 72 patients were analyzed, 18 in the high-dose group, 22 in the low-dose group, and 24 in the placebo group. Over the 12-week period, patients in the high-dose group [mean change from baseline (95% CI): 171.4 (141.3-201.5) (mL), p = 0.003 (Net UF); 11.3(10.5-12.1) (mL/h), p = 0.02 (UF rate)] or the low-dose group [mean change from baseline (95% CI: 98.1 (49.5-146.7) (mL), p = 0.007 (Net UF); 6.5 (4.4-8.6) (mL/h), p = 0.04 (UF rate)] versus the placebo group had a significantly greater improvement in mean net UF volume and UF rate. The appearance rates of VEGF, Flk-1, and Ang-2 were more significantly reduced (appearance rates of Tie-2 and Tsp-1 increased) in the high-dose group versus the placebo group, but not in the low-dose group. CONCLUSION: Supplementation with trans-resveratrol is beneficial to improve ultrafiltration in PD patients, and high-dose supplementation may improve ultrafiltration by ameliorating angiogenesis induced by conventional lactate-buffered PD solutions.

Isoprenaline induces epithelial-mesenchymal transition in gastric cancer cells.

The emerging role of stress-related signaling in regulating cancer development and progression has been recognized. However, whether stress serves as a mechanism to promote gastric cancer metastasis is not clear. Here, we show that the ß2-AR agonist, isoprenaline, upregulates expression levels of CD44 and CD44v8-10 in gastric cancer cells. CD44, a cancer stem cell-related marker, is expressed at high levels in gastric cancer tissues, which strongly correlates with the occurrence of epithelial-mesenchymal transition (EMT)-associated phenotypes both in vivo and in vitro. Combined with experimental observations in two human gastric cancer cell lines, we found that ß2-AR signaling can initiate EMT. It led to an increased expression of mesenchymal markers, such as α-SMA, vimentin, and snail at mRNA and protein levels, and conversely a decrease in epithelial markers, E-cadherin and ß-catenin. Isoprenaline stimulation of ß2-AR receptors activates the downstream target STAT3, which functions as a positive regulator and mediated the phenotypic switch toward a mesenchymal cell type in gastric cancer cells. Our data provide a mechanistic understanding of the complex signaling cascades involving stress-related hormones and their effects on EMT. In light of our observations, pharmacological interventions targeting ß2-AR-STAT3 signaling can potentially be used to ameliorate stress-associated influences on gastric cancer development and progression.

The protease inhibitor atazanavir blocks hERG K(+) channels expressed in HEK293 cells and obstructs hERG protein transport to cell membrane.

AIM: Atazanavir (ATV) is a HIV-1 protease inhibitor for the treatment of AIDS patients, which is recently reported to provoke excessive prolongation of the QT interval and torsades de pointes (TdP). In order to elucidate its arrhythmogenic mechanisms, we investigated the effects of ATV on the hERG K(+) channels expressed in HEK293 cells. METHODS: hERG K(+) currents were detected using whole-cell patch clamp recording in HEK293 cells transfected with EGFP-hERG plasmids. The expression of hERG protein was measured with Western blotting. Two mutants (Y652A and F656C) were constructed in the S6 domain within the inner helices of hERG K(+) channels that were responsible for binding of various drugs. The trafficking of hERG protein was studied with confocal microscopy. RESULTS: Application of ATV (0.01-30 µmol/L) concentration-dependently decreased hERG K(+) currents with an IC50 of 5.7±1.8 µmol/L. ATV (10 µmol/L) did not affect the activation and steady-state inactivation of hERG K(+) currents. Compared with the wild type hERG K(+) channels, both Y652A and F656C mutants significantly reduced the inhibition of ATV on hERG K(+) currents. Overnight treatment with ATV (0.1-30 µmol/L) concentration-dependently reduced the amount of fully glycosylated 155 kDa hERG protein without significantly affecting the core-glycosylated 135 kDa hERG protein in the cells expressing the WT-hERG protein. Confocal microscopy studies confirmed that overnight treatment with ATV obstructed the trafficking of hERG protein to the cell membrane. CONCLUSION: ATV directly blocks hERG K(+) channels via binding to the residues Y652 and F656 in the S6 domain, and indirectly obstructs the transport of the hERG protein to the cell membrane.

Polymorphisms in NF-κB pathway genes & their association with risk of lung cancer in the Chinese population.

OBJECTIVE: To investigate the association of NFKB1 -94 ins/del ATTG, NFKBIA -826C>T and NFKBIA -881A>G polymorphisms with risk of lung cancer in a Chinese population. METHODS: Genotyping of the polymorphisms were performed on 1,436 subjects (718 cases and 718 controls) by using PCR-RFLP technique, followed by DNA sequencing. RESULTS: We found a significant risk reduction associated with heterozygous ins/del (OR=0.705, 95% CI=0.566-0.878, P=0.002) and variant del/del (OR=0.342, 95% CI=0.221-0.528, P<0.001) genotypes of the NFKB1 polymorphism. In contrast, the heterozygous and variantgenotypes of theNFKBIA polymorphisms showed association with increased lung cancer risk (NFKBIA -826 CT,OR=1.256, 95%CI=1.004-1.572, P=0.046; TT,OR=1.773, 95% CI=1.131-2.778, P=0.013; NFKBIA -881 AG,OR=1.277, 95% CI=1.023-1.599, P=0.031; GG,OR=1.801, 95% CI=1.169-2.775, P=0.008). Several genotypic combinations of the three polymorphisms also showed significant association with lung cancer risk. The risk association of NFKB1 polymorphism remained significant when analyses were done according to gender and smoking status (P<0.05). The significance of NFKBIA risk association was not observed when gender-specific analyses were made (P>0.05), while only NFKBIA -881 GG genotype showed significant risk association among smokers when analyzed according to smoking status (P=0.032). CONCLUSIONS: Polymorphisms in NFKB1 and NFKBIAgenes were associated with risk of lung cancer.

The complete mitochondrial genomes of the Fenton's wood white, Leptidea morsei, and the lemon emigrant, Catopsilia pomona.

The complete mitochondrial genomes of Leptidea morsei Fenton (Lepidoptera: Pieridae: Dis-morphiinae) and Catopsilia pomona (F.) (Lepidoptera: Pieridae: Coliadinae) were determined to be 15,122 and 15,142 bp in length, respectively, with that of L. morsei being the smallest among all known butterflies. Both mitogenomes contained 37 genes and an A+T-rich region, with the gene order identical to those of other butterflies, except for the presence of a tRNA-like insertion, tRNA(Leu) (UUR), in C. pomona. The nucleotide compositions of both genomes were higher in A and T (80.2% for L. morsei and 81.3% for C. pomona) than C and G; the A+T bias had a significant effect on the codon usage and the amino acid composition. The protein-coding genes utilized the standard mitochondrial start codon ATN, except the COI gene using CGA as the initiation codon, as reported in other butterflies. The intergenic spacer sequence between the tRNA(Ser) (UCN) and ND1 genes contained the ATACTAA motif. The A+T-rich region harbored a poly-T stretch and a conserved ATAGA motif located at the end of the region. In addition, there was a triplicated 23 bp repeat and a microsatellite-like (TA)9(AT)3 element in the A+T-rich region of the L. morsei mitogenome, while in C. pomona, there was a duplicated 24 bp repeat element and a microsatellite-like (TA)9 element. The phylogenetic trees of the main butterfly lineages (Hesperiidae, Papilionidae, Pieridae, Nymphalidae, Lycaenidae, and Riodinidae) were reconstructed with maximum likelihood and Bayesian inference methods based on the 13 concatenated nucleotide sequences of protein-coding genes, and both trees showed that the Pieridae family is sister to Lycaenidae. Although this result contradicts the traditional morphologically based views, it agrees with other recent studies based on mitochondrial genomic data.

Biomaterial-based mechanical regulation facilitates scarless wound healing with functional skin appendage regeneration.

Scar formation resulting from burns or severe trauma can significantly compromise the structural integrity of skin and lead to permanent loss of skin appendages, ultimately impairing its normal physiological function. Accumulating evidence underscores the potential of targeted modulation of mechanical cues to enhance skin regeneration, promoting scarless repair by influencing the extracellular microenvironment and driving the phenotypic transitions. The field of skin repair and skin appendage regeneration has witnessed remarkable advancements in the utilization of biomaterials with distinct physical properties. However, a comprehensive understanding of the underlying mechanisms remains somewhat elusive, limiting the broader application of these innovations. In this review, we present two promising biomaterial-based mechanical approaches aimed at bolstering the regenerative capacity of compromised skin. The first approach involves leveraging biomaterials with specific biophysical properties to create an optimal scarless environment that supports cellular activities essential for regeneration. The second approach centers on harnessing mechanical forces exerted by biomaterials to enhance cellular plasticity, facilitating efficient cellular reprogramming and, consequently, promoting the regeneration of skin appendages. In summary, the manipulation of mechanical cues using biomaterial-based strategies holds significant promise as a supplementary approach for achieving scarless wound healing, coupled with the restoration of multiple skin appendage functions.

Therapeutic effect of manual massage on early postpartum rectus abdominis separation and postpartum depression.

BACKGROUND: Rectus abdominis separation (DRA) affects pelvic stability and body image. No studies have explored the effects of manual massage on early postpartum DRA and postpartum depression. AIM: To analyze the curative effect of massage on early postpartum DRA and its impact on postpartum depression and thus its ability promote the overall psychosomatic rehabilitation of postpartum women. METHODS: Data were retrospectively collected on 70 primiparous women with postpartum DRA who underwent rehabilitation at the Postpartum Rehabilitation Center of Huzhou Maternal and Child Health Hospital from October 2022 to September 2023. The patients were divided into the Group S (35 cases, biomimetic electrical stimulation treatment) and Group L (35 cases, biomimetic electrical stimulation combined with manual massage treatment). Baseline data, the edinburgh postpartum depression scale (EPDS) score, and the visual analog scale (VAS) scores for rectus abdominis distance, waist circumference, and lower back pain before and after treatment were compared. RESULTS: No significant differences were found in the baseline data, rectus abdominis distance, waist circumference, and VAS and EPDS scores between the two groups before treatment (P > 0.05). After treatment, the distance between rectus abdominis and waist circumference in Group L were significantly smaller than those in Group S (P < 0.05). Furthermore, lower back pain (VAS score) and the EPDS score in Group L were significantly lower than those in Group S (P < 0.05). CONCLUSION: Manual massage can significantly reduce early postpartum DRA, waist circumference, and back pain and improve the patient's mental state and postpartum depression.

Multiplex Profiling of Biomarker and Drug Uptake in Single Cells Using Microfluidic Flow Cytometry and Mass Spectrometry.

To perform multiplex profiling of single cells and eliminate the risk of potential sample loss caused by centrifugation, we developed a microfluidic flow cytometry and mass spectrometry system (µCytoMS) to evaluate the drug uptake and induced protein expression at the single cell level. It involves a microfluidic chip for the alignment and purification of single cells followed by detection with laser-induced fluorescence (LIF) and inductively coupled plasma mass spectrometry (ICP-MS). Biofunctionalized nanoprobes (BioNPs), conjugating ∼3000 6-FAM-Sgc8 aptamers on a single gold nanoparticle (AuNP) (Kd = 0.23 nM), were engineered to selectively bind with protein tyrosine kinase 7 (PTK7) on target cells. PTK7 expression induced by oxaliplatin (OXA) uptake was assayed with LIF, while ICP-MS measurement of 195Pt revealed OXA uptake of the drug in individual cells, which provided further in-depth information about the drug in relation to PTK7 expression. At an ultralow flow of ∼0.043 dyn/cm2 (20 µL/min), the chip facilitates the extremely fast focusing of BioNPs labeled single cells without the need for centrifugal purification. It ensures multiplex profiling of single cells at a throughput speed of 500 cells/min as compared to 40 cells/min in previous studies. Using a machine learning algorithm to initially profile drug uptake and marker expression in tumor cell lines, µCytoMS was able to perform in situ profiling of the PTK7 response to the OXA at single-cell resolution for tests done on clinical samples from 10 breast cancer patients. It offers great potential for multiplex single-cell phenotypic analysis and clinical diagnosis.

Blockage of hERG current and the disruption of trafficking as induced by roxithromycin.

Roxithromycin is an oral macrolide antibiotic agent that has been repeatedly reported to provoke excessive prolongation of the Q-T interval and torsades de pointes in clinical settings. To investigate the mechanisms underlying the arrhythmogenic side effects of roxithromycin, we studied the molecular mechanisms of roxithromycin on human ether-à-go-go-related gene (hERG) K(+) channels expressed in human embryonic kidney (HEK293) cells. Roxithromycin was found to inhibit wild-type (WT) hERG currents in a concentration-dependent manner with a half-maximum block concentration (IC50) of 55.8 ± 9.1 µmol/L. S6 residue hERG mutants (Y652A and F656C) showed reduced levels of hERG current blockage attributable to roxithromycin. Roxithromycin also inhibited the trafficking of hERG protein to the cell membrane, as confirmed by Western blot analysis and confocal microscopy. These findings indicate that roxithromycin may cause acquired long-QT syndrome via direct inhibition of hERG current and by disruption of hERG protein trafficking. Mutations in drug-binding sites (Y652A or F656C) of the hERG channel were found to attenuate hERG current blockage by roxithromycin, but did not significantly alter the disruption of trafficking.

As4S4 targets RING-type E3 ligase c-CBL to induce degradation of BCR-ABL in chronic myelogenous leukemia.

Arsenic, a curative agent for acute promyelocytic leukemia, induces cell apoptosis and degradation of BCR-ABL in chronic myelogenous leukemia (CML). We demonstrated that ubiquitination and degradation of BCR-ABL was mediated by c-CBL, a RING-type E3 ligase that was also shown to be involved in ubiquitination for many other receptor/protein tyrosine kinases. Our data showed that c-CBL protein was considerably up-regulated by arsenic sulfide (As(4)S(4)). Interestingly, arsenic directly bound the RING finger domain of c-CBL to inhibit its self-ubiquitination/degradation without interfering with the enhancement of ubiquitination and subsequent proteolysis of its substrate BCR-ABL. Degradation of BCR-ABL due to c-CBL induction as a result of arsenic treatment was also observed in vivo in CML mice. These findings provide insight into the molecular mechanisms of arsenic and further support its therapeutic applications in CML in combination with tyrosine kinase inhibitors and potentially also in other malignancies involving aberrant receptor/protein tyrosine kinase signaling.

[Influence of methylenetetrahydrofolate reductase gene polymorphisms on antidepressant response].

OBJECTIVE: To assess the influence of polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene on response to antidepressant treatment. METHODS: Two hundred and eight one Chinese Han patients have received single antidepressant drugs for at least 6 weeks, among whom 275 were followed up for 8 weeks. Hamilton depression scale 17 (HAMD-17) was used to evaluate the severity of depressive symptoms and therapeutic effects. Single nucleotide polymorphisms (SNPs) of the MTHFR gene were determined using gene chips. Associations of single loci and haplotypes with response to treatment were analyzed using an Unphased 3.0.13 software. RESULTS: No significant differences in gender, age, year of education, family history, episode times, and antidepressant agents were found between responders and non-responders (all P U+003E 0.05), while the baseline scores of HAMD-17 was significantly different(t=2.891, P=0.004). There was also no significant difference between age, years of education, family history, baseline scores of HAMD-17 and antidepressant agents between remitters and non-remitters (both P U+003E 0.05), while proportion of male patients was significantly higher in non-remission group than remission group (t=2.381, P=0.018), and episode times in non-remission group was significantly higher (t=-1.983, P=0.049). Single locus association analysis has found no significant association between SNPs rs1801131 and rs1801133 in the MTHFR gene with antidepressant response (P U+003E 0.05). On the other hand, haplotype A-C of MTHFR gene (rs1801131 and rs1801133) was significantly associated with antidepressant response in total group (U+03C7 2=11.39, P=0.0007), male subgroup (U+03C7 2=8.767, P=0.003) and serotonin noradrenaline reuptake inhibitors (SNRIs) subgroup (U+03C7 2=10.51, P=0.001). CONCLUSION: Particular haplotype of MTHFR gene may be related with antidepressant effect, in which the haplotype (rs1801131, rs1801133) A-C type may be associated with better antidepressant efficacy, particularly in males and patients receiving SNRIs drugs.

Chemerin Exacerbates Psoriasis by Stimulating Keratinocyte Proliferation and Cytokine Production.

OBJECTIVE: Psoriasis is often combined with metabolic abnormalities, such as obesity and diabetes. The upregulation of chemerin, which is an essential protein produced primarily from white fat, is strongly correlated to the development of psoriasis. However, there is no clarification on its exact function and mechanism in disease pathogenesis. The present study aims to determine its function and mechanism in disease pathogenesis. METHODS: The present study used a psoriasislike inflammatory cell model and imiquimod (IMQ)-induced mouse model to confirm whether chemerin is upregulated in psoriasis patients. RESULTS: Chemerin enhanced the keratinocyte proliferation, inflammatory cytokine secretion, and activation of the MAPK signaling pathway. Crucially, the intraperitoneal injection of neutralizing anti-chemerin antibody (ChAb) diminished the epidermal proliferation and inflammation in the IMQ-induced mouse model. CONCLUSION: The present results indicate that chemerin promotes keratinocyte proliferation, and enhances the production of inflammatory cytokines, thereby aggravating the psoriasis. Thus, chemerin can be a prospective target for the treatment of psoriasis.

Clinical Evaluation of a Vancomycin Dosage Strategy Based on a Serum Trough Concentration Model in Elderly Patients with Severe Pneumonia.

Objective: This study aimed to evaluate the clinical benefits of a vancomycin dosage strategy based on a serum trough concentration model in elderly patients. Methods: This prospective single-center, open-label, randomized controlled trial categorized 66 elderly patients with severe pneumonia into study and control groups. The control group received vancomycin using a regimen decided by the attending physician. Meanwhile, the study group received individualized vancomycin therapy with a dosing strategy based on a serum trough concentration model. The primary endpoint was the proportion of patients with serum trough concentrations reaching the target values. The secondary endpoints were clinical response, vancomycin treatment duration, and vancomycin-associated acute kidney injury (VA-AKI) occurrence. Results: All patients were at least 60 years old (median age = 81 years). The proportion of patients with target trough concentration achievement (≥ 15 mg/L) with the initial vancomycin regimen was significantly higher in the study group compared to the control group (75.8% vs. 42.4%, P = 0.006). Forty-five patients (68.2%) achieved clinical success, the median duration of vancomycin therapy was 10.0 days, and VA-AKI occurred in eight patients (12.1%). However, there were no significant differences in these parameters between the two groups. The model for predicting vancomycin trough concentrations was upgraded to: serum trough concentration (mg/L) = 17.194 - 0.104 × creatinine clearance rate (mL/min) + 0.313 × vancomycin daily dose [(mg/(kg∙d)]. Conclusion: A vancomycin dosage strategy based on a serum trough concentration model can improve the proportion of patients achieving target trough concentrations in elderly patients with severe pneumonia.