Antidepressant effect of repeated ketamine administration on kynurenine pathway metabolites in patients with unipolar and bipolar depression.

Ketamine has rapid antidepressant effects on treatment-resistant depression, but the biological mechanism underpinning this effect is less clear. Our aims were to examine whether kynurenine pathway metabolites were altered by six infusions of ketamine and whether these biological factors could act as potential biomarkers to predict ketamine's antidepressant effects. Six intravenous infusions of ketamine (0.5 mg/kg) were administered to 84 patients with unipolar and bipolar depression over a 12-d period. Symptom severity and response were assessed using the Montgomery-Asberg Scale (MADRS), and blood samples were collected at baseline and 24 h following the first infusion and at 24 h and 14 d after the sixth infusion (24 h, 13 d and 26 d). Blood samples from sixty healthy controls were collected for comparison with samples from the patients. Serum concentrations of tryptophan (TRP), kynurenine (KYN) and kynurenic acid (KYNA) were measured by the liquid chromatography-tandem mass spectrometry method. At baseline, serum levels of TRP and KYNA and the KYNA/KYN ratio were lower and the KYN/TRP ratio was greater in depressed patients than in healthy controls. Overall, fifty (59.5%) patients responded to ketamine at 13 d. Ketamine responders had a greater KYNA level and KYNA/KYN ratio than nonresponders at 24 h and 13 d (all P < 0.05). Elevations in the KYNA levels and KYNA/KYN ratio at 24 h were significantly associated with reductions in MADRS scores at 24 h, 13 d and 26 d in the linear regression analysis (all P < 0.05). Our results showed a possible involvement of the kynurenine pathway in the rapid antidepressant effect of ketamine. Early changes in serum KYNA levels and the KYNA/KYN ratio could be potential predictors of antidepressanteffects of repeated ketamine administration.

Quantitative evaluation of human bone mesenchymal stem cells rescuing fulminant hepatic failure in pigs.

OBJECTIVE: Stem cell transplantation provides a promising alternative for the treatment of fulminant hepatic failure (FHF). However, it lacks fundamental understanding of stem cells' activities. Our objective was to clarify stem cell-recipient interactions for overcoming barriers to clinical application. DESIGN: We used an in-house large-animal (pig) model of FHF rescue by human bone marrow mesenchymal stem cells (hBMSCs) and profiled the cells' activities. The control and transplantation groups of pigs (n=15 per group) both received a D-galactosamine (D-Gal) injection (1.5 g/kg). The transplantation group received hBMSCs via intraportal vein infusion (3×106 cells/kg) immediately after D-Gal administration. The stem cell-recipient interactions were quantitatively evaluated by biochemical function, cytokine array, metabolite profiling, transcriptome sequencing and immunohistochemistry. RESULTS: All pigs in the control group died within an average of 3.22 days, whereas 13/15 pigs in the transplantation group lived >14 days. The cytokine array and metabolite profiling analyses revealed that hBMSC transplantation suppressed D-Gal-induced life-threatening cytokine storms and stabilised FHF within 7 days, while human-derived hepatocytes constituted only ∼4.5% of the pig hepatocytes. The functional synergy analysis of the observed profile changes indicated that the implanted hBMSCs altered the pigs' cytokine responses to damage through paracrine effects. Delta-like ligand 4 was validated to assist liver restoration in both pig and rat FHF models. CONCLUSIONS: Our results delineated an integrated model of the multifaceted interactions between stem cells and recipients, which may open a new avenue to the discovery of single molecule-based therapeutics that simulate stem cell actions.

Profiling, clinicopathological correlation and functional validation of specific long non-coding RNAs for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent and aggressive malignancies worldwide. Studies seeking to advance the overall understanding of lncRNA profiling in HCC remain rare. METHODS: The transcriptomic profiling of 12 HCC tissues and paired adjacent normal tissues was determined using high-throughput RNA sequencing. Fifty differentially expressed mRNAs (DEGs) and lncRNAs (DELs) were validated in 21 paired HCC tissues via quantitative real-time PCR. The correlation between the expression of DELs and various clinicopathological characteristics was analyzed using Student's t-test or linear regression. Co-expression networks between DEGs and DELs were constructed through Pearson correlation co-efficient and enrichment analysis. Validation of DELs' functions including proliferation and migration was performed via loss-of-function RNAi assays. RESULTS: In this study, we identified 439 DEGs and 214 DELs, respectively, in HCC. Furthermore, we revealed that multiple DELs, including NONHSAT003823, NONHSAT056213, NONHSAT015386 and especially NONHSAT122051, were remarkably correlated with tumor cell differentiation, portal vein tumor thrombosis, and serum or tissue alpha fetoprotein levels. In addition, the co-expression network analysis between DEGs and DELs showed that DELs were involved with metabolic, cell cycle, chemical carcinogenesis, and complement and coagulation cascade-related pathways. The silencing of the endogenous level of NONHSAT122051 or NONHSAT003826 could significantly attenuate the mobility of both SK-HEP-1 and SMMC-7721 HCC cells. CONCLUSION: These findings not only add knowledge to the understanding of genome-wide transcriptional evaluation of HCC but also provide promising targets for the future diagnosis and treatment of HCC.

Lactococcus cremoris D2022 alleviates hyperuricemia and suppresses renal inflammation via potential gut-kidney axis.

Hyperuricemia (HUA) is a widespread metabolic disorder. Probiotics have drawn increasing attention as an adjunctive treatment with fewer side effects. However, thus far the effective strains are limited and the mechanisms for their serum uric acid (SUA)-lowering effect are not well understood. Along this line, we conducted the current study using a hyperuricemia mouse model induced by potassium oxonate and adenine. A novel strain of Lactococcus cremoris named D2022 was identified to have significant SUA-lowering capability. Lactococcus cremoris D2022 significantly reduced SUA levels by inhibiting uric acid synthesis and regulating uric acid transportation. It was also found that Lactococcus cremoris D2022 alleviated HUA-induced renal inflammatory injury involving multiple signaling pathways. By focusing on the expression of NLRP3-related inflammatory genes, we found correlations between the expression levels of these genes and free fatty acid receptors (FFARs). In addition, oral administration of Lactococcus cremoris D2022 increased short-chain fatty acids (SCFAs) in cecal samples, which may be one of the mechanisms by which oral probiotics alleviate renal inflammation. Serum untargeted metabolomics showed changes in a variety of serum metabolites associated with purine metabolism and inflammation after oral administration of Lactococcus cremoris D2022, further confirming its systemic bioactivity. Finally, it was proved that Lactococcus cremoris D2022 improved intestinal barrier function. In conclusion, Lactococcus cremoris D2022 can alleviate HUA and HUA-induced nephropathy by increasing the production of SCFAs in the gut and systemic metabolism.

Ultrasound-triggered piezocatalytic composite hydrogels for promoting bacterial-infected wound healing.

Wound healing has become one of the basic issues faced by the medical community because of the susceptibility of skin wounds to bacterial infection. As such, it is highly desired to design a nanocomposite hydrogel with excellent antibacterial activity to achieve high wound closure effectiveness. Here, based on ultrasound-triggered piezocatalytic therapy, a multifunctional hydrogel is designed to promote bacteria-infected wound healing. Under ultrasonic vibration, the surface of barium titanate (BaTiO3, BT) nanoparticles embedded in the hydrogel rapidly generate reactive oxygen species (ROS) owing to the established strong built-in electric field, endowing the hydrogel with superior antibacterial efficacy. This modality shows intriguing advantages over conventional photodynamic therapy, such as prominent soft tissue penetration ability and the avoidance of serious skin phototoxicity after systemic administration of photosensitizers. Moreover, the hydrogel based on N-[tris(hydroxymethyl)methyl]acrylamide (THM), N-(3-aminopropyl)methacrylamide hydrochloride (APMH) and oxidized hyaluronic acid (OHA) exhibits outstanding self-healing and bioadhesive properties able to accelerate full-thickness skin wound healing. Notably, compared with the widely reported mussel-inspired adhesive hydrogels, OHA/THM-APMH hydrogel due to the multiple hydrogen bonds from unique tri-hydroxyl structure overcomes the shortage that catechol groups are easily oxidized, giving it long-term and repeatable adhesion performance. Importantly, this hybrid hydrogel confines BT nanoparticles to wound area and locally induced piezoelectric catalysis under ultrasound to eradicate bacteria, markedly improving the therapeutic biosafety and exhibits great potential for harmless treatment of bacteria-infected tissues.

Lactiplantibacillus pentosus P2020 protects the hyperuricemia and renal inflammation in mice.

Introduction: Hyperuricemia (HUA) is a common metabolic disease, and its prevalence has been increasing worldwide. Pharmaceutical drugs have been used for controlling HUA but they all have certain side effects, which thus calls for discovering alternative options including using treatment of probiotics to prevent the development of HUA. Methods: We established HUA mice model induced by potassium oxonate and adenine and performed in vivo experiments to verify the ability to lower serum uric acid of Lactiplantibacillus pentosus P2020 (LPP), a probiotics stain extracted from Chinese pickle. We also tried to discussed the underlying mechanisms. Results: Oral administration with LPP significantly decreased serum uric acid and reduced renal inflammatory response by downregulating multiple inflammation pathways including NK-kB, MAPK, and TNFα. We also found that LPP administration significantly promoted uric acid excretion by regulating expression of transporters in the kidney and ileum. In addition, LPP intake improved intestinal barrier function and modulated the composition of gut microbiota. Discussion: These results suggest that probiotics LPP may have a promising potential to protect against development of HUA and HUA-related renal damage, and its working mechanisms involve regulation of inflammation pathways and expression of transporters in the kidney and ileum.

Thermal management of chips by a device prototype using synergistic effects of 3-D heat-conductive network and electrocaloric refrigeration.

With speeding up development of 5 G chips, high-efficient thermal structure and precise management of tremendous heat becomes a substantial challenge to the power-hungry electronics. Here, we demonstrate an interpenetrating architecture of electrocaloric polymer with highly thermally conductive pathways that achieves a 240% increase in the electrocaloric performance and a 300% enhancement in the thermal conductivity of the polymer. A scaled-up version of the device prototype for a single heat spot cooling of 5 G chip is fabricated utilizing this electrocaloric composite and electromagnetic actuation. The continuous three-dimensional (3-D) thermal conductive network embedded in the polymer acts as nucleation sites of the ordered dipoles under applied electric field, efficiently collects thermal energy at the hot-spots arising from field-driven dipolar entropy change, and opens up the high-speed conduction path of phonons. The synergy of two components, thus, tackles the challenge of sluggish heat dissipation of the electroactive polymers and their contact interfaces with low thermal conductivity, and more importantly, significantly reduces the electric energy for switching the dipolar states during the electrocaloric cycles, and increases the manipulable entropy at the low fields. Such a feasible solution is inevitable to the precisely fixed-point thermal management of next-generation smart microelectronic devices.

Skin-Inspired Pressure Sensor with MXene/P(VDF-TrFE-CFE) as Active Layer for Wearable Electronics.

Multi-functional electronic skin is of paramount significance for wearable electronics in health monitoring, medical analysis, and human-machine interfacing systems. In order to achieve the function of natural skin, mechanical sensing with high sensitivity is an important feature of electronic skin. Inspired by the spinosum structure under the skin, herein, we fabricate a new capacitive pressure sensor with two-dimensional transition-metal carbides and nitrides (MXene) and ferroelectric polymer (P(VDF-TrFE-CFE)) as an active layer and micropatterned Cr-Au deposited on polydimethylsiloxane as flexible electrodes. Such a method is facile, effective, easily operated, and low-cost. The device design provides great capacitive change as a consequence of large deformation under pressure. Benefiting from the randomly distributed microstructure and high dielectric constant of the active layer, the device demonstrates high sensitivity with great linearity (16.0 kPa-1 for less than 10 kPa), that is, a low detection limit of 8.9 Pa, and quick response. A series of dynamic physiological signals, including typing, knuckle motion, and voice recognition can be facilely detected, making it a competitive candidate in the field of wearable electronics.

Baseline insomnia as a predictor of antidepressant efficacy to repeated intravenous ketamine for unipolar and bipolar depression: A preliminary study.

OBJECTIVE: Ketamine has been demonstrated to have robust and rapid antidepressant effects, and few studies have focused on the relationship between insomnia and the efficacy of ketamine. The objective of this study was to examine whether baseline insomnia predicted the antidepressant efficacy of repeated intravenous ketamine infusions for unipolar and bipolar depression. METHOD: Patients with high insomnia (n = 64) or low insomnia (n = 68) received six intravenous infusions of ketamine (0.5 mg/kg over 40 min) over 12 days (Monday-Wednesday-Friday). The Montgomery-Asberg Depression Rating Scale (MADRS) without sleep item was used to assess depressive symptoms. Response was defined as a MADRS total score ≥ 50%, and remission was defined as a MADRS total score ≤ 10. RESULT: There were no differences in response or remission rates between patients with high and low insomnia. However, the logistic regression model showed that high insomnia predicted an increased likelihood of response and remission. Cox proportional hazards models showed a reduced latency to respond and remit in patients with high insomnia. A linear mixed model showed that the high insomnia subgroup had greater improvement than the low insomnia subgroup (all p < 0.05). LIMITATION: The major limitation of this study is the open-label design. CONCLUSION: When given six ketamine infusions, patients with high insomnia were more likely to respond and remit than those with low insomnia. Patients with high insomnia showed not only a shorter latency to respond and remit, but also greater improvement than those with low insomnia.

Neurocognitive effects of six ketamine infusions and the association with antidepressant response in patients with unipolar and bipolar depression.

BACKGROUND: Ketamine has proven to have rapid, robust antidepressant effects on treatment-resistant depression. However, whether repeated ketamine infusions would cause short-and long-term neurocognitive impairments was not clear. Our aims were to investigate the neurocognitive effects of six ketamine infusions and to examine the association between these infusions and the antidepressant response in patients with unipolar and bipolar depression. METHODS: Six intravenous infusions of ketamine (0.5 mg/kg) over a 12-day period were administered to 84 patients with unipolar and bipolar depression. Severity of depressive symptoms and four domains of neurocognition, including speed of processing, working memory, visual learning and verbal learning, were assessed at baseline, one day following the last infusion and again two weeks post-infusion. RESULTS: Significant improvements were found on speed of processing ( F=9.344, p<0.001) and verbal learning ( F=5.647, p=0.004) in a linear mixed model. The Sobel test showed significant indirect effects between time and improvement in speed of processing (Sobel test=3.573, p<0.001) as well as improvement in verbal learning (Sobel test=6.649, p<0.001), which were both significantly mediated by change in depressive symptoms. Logistic regression analysis showed ketamine responders had better visual learning at baseline than non-responders (B=0.118, p<0.001). CONCLUSIONS: Our findings suggest that neurocognitive function would not deteriorate after six ketamine infusions, while verbal learning and speed of processing improved over 13 days and 26 days of observation, respectively. However, this change was mainly accounted for by improvements in severity of depressive symptoms over time. Greater baseline visual learning predicted an antidepressant response over six ketamine infusions.

Effects of DISC1 Polymorphisms on Resting-State Spontaneous Neuronal Activity in the Early-Stage of Schizophrenia.

Background: Localized abnormalities in the synchrony of spontaneous neuronal activity, measured with regional homogeneity (ReHo), has been consistently reported in patients with schizophrenia (SCZ) and their unaffected siblings. To date, little is known about the genetic influences affecting the spontaneous neuronal activity in SCZ. DISC1, a strong susceptible gene for SCZ, has been implicated in neuronal excitability and synaptic function possibly associated with regional spontaneous neuronal activity. This study aimed to examine the effects of DISC1 variations on the regional spontaneous neuronal activity in SCZ. Methods: Resting-state fMRI data were obtained from 28 SCZ patients and 21 healthy controls (HC) for ReHo analysis. Six single nucleotide polymorphisms (SNPs) of DISC1 gene were genotyped using the PCR and direct sequencing. Results: Significant diagnosis × genotype interactions were noted for three SNPs (rs821616, rs821617, and rs2738880). For rs821617, the interactions were localized to the precuneus, basal ganglia and pre-/post-central regions. Significant interactive effects were identified at the temporal and post-central gyri for rs821616 (Ser704Cys) and the inferior temporal gyrus for rs2738880. Furthermore, post-hoc analysis revealed that the DISC1 variations on these SNPs exerted different influences on ReHo between SCZ patients and HC. Conclusion: To our knowledge this is the first study to unpick the influence of DISC1 variations on spontaneous neuronal activity in SCZ; Given the emerging evidence that ReHo is a stable inheritable phenotype for schizophrenia, our findings suggest the DISC1 variations are possibly an inheritable source for the altered ReHo in this disorder.