Impact of tocilizumab on anti-CD19 chimeric antigen receptor T-cell therapy in B-cell acute lymphoblastic leukemia.

BACKGROUND: Tocilizumab is commonly used for the management of chimeric antigen receptor (CAR) T-cell therapy-associated cytokine release syndrome (CRS). However, it remains unknown whether tocilizumab or its dosage affects the efficacy and safety of CAR T-cell therapy. The objective of this multicenter retrospective study was to explore the impact of tocilizumab on CAR T-cell therapy. METHODS: In total, 93 patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving humanized anti-CD19 CAR T cells were recruited from May 2016 to November 2022. Forty-five patients received tocilizumab (tocilizumab group), whereas 48 patients did not (nontocilizumab group). Thirteen patients received >1 dose of tocilizumab. The primary end point was the effect of tocilizumab on the efficacy and safety of CAR T cells. Additionally, proliferation, killing, and cytokine assays of CAR T cells were performed in vitro in the presence of tocilizumab. RESULTS: The median age of the patients was 33 years, with 47 males and 46 females. Patients in the tocilizumab group showed similar complete response (CR) rate, overall survival (OS), and event-free survival (EFS) compared with the nontocilizumab group. Compared with patients who received ≤1 dose of tocilizumab, receiving >1 dose of tocilizumab did not affect their CR rate, OS, or EFS. In the tocilizumab group, all patients experienced CRS and 26.7% experienced immune effector cell-associated neurotoxicity syndrome (ICANS). In the nontocilizumab group, 64.6% of patients experienced CRS and 8.3% experienced ICANS. Up to 75% of ICANS and 87.5% of grade ≥3 ICANS occurred in the tocilizumab group. In vitro, tocilizumab did not impair the proliferation and killing effects of CAR T cells. CONCLUSIONS: Tocilizumab does not affect the efficacy of CAR T cells but may increase the likelihood of ICANS.

CARD11 regulates the thymic Treg development in an NF-κB-independent manner.

Introduction: CARD11 is a lymphoid lineage-specific scaffold protein regulating the NF-κB activation downstream of the antigen receptor signal pathway. Defective CARD11 function results in abnormal development and differentiation of lymphocytes, especially thymic regulatory T cells (Treg). Method: In this study, we used patients' samples together with transgenic mouse models carrying pathogenic CARD11 mutations from patients to explore their effects on Treg development. Immunoblotting and a GFP receptor assay were used to evaluate the activation effect of CARD11 mutants on NF-κB signaling. Then the suppressive function of Tregs carrying distinct CARD11 mutations was measured by in vitro suppression assay. Finally, we applied the retroviral transduced bone marrow chimeras to rescue the Treg development in an NF-κB independent manner. Results and discuss: We found CARD11 mutations causing hyper-activated NF-κB signals also gave rise to compromised Treg development in the thymus, similar to the phenotype in Card11 deficient mice. This observation challenges the previous view that CARD11 regulates Treg lineage dependent on the NF-kB activation. Mechanistic investigations reveal that the noncanonical function CARD11, which negatively regulates the AKT/ FOXO1 signal pathway, is responsible for regulating Treg generation. Moreover, primary immunodeficiency patients carrying CARD11 mutation, which autonomously activates NF-κB, also represented the reduced Treg population in their peripheral blood. Our results propose a new regulatory function of CARD11 and illuminate an NF-κB independent pathway for thymic Treg lineage commitment.

Demulsification of Emulsion Using Heptanoic Acid during Aqueous Enzymatic Extraction and the Characterization of Peanut Oil and Proteins Extracted.

Peanut oil body emulsion occurs during the process of aqueous enzymatic extraction (AEE). The free oil is difficult to release and extract because its structure is stable and not easily destroyed. Demulsification can release free oil in an oil body emulsion, so various fatty acids were selected for the demulsification. Changes in the amount of heptanoic acid added, solid-liquid ratio, reaction temperature, and reaction time were adopted to investigate demulsification, and the technological conditions of demulsification were optimized. While the optimal conditions were the addition of 1.26% of heptanoic acid, solid-liquid ratio of 1:3.25, reaction temperature of 72.7 °C, and reaction time of 55 min, the maximum free oil yield was (95.84 ± 0.19)%. The analysis of the fatty acid composition and physicochemical characterization of peanut oils extracted using four methods were studied during the AEE process. Compared with the amount of oil extracted via other methods, the unsaturated fatty acids of oils extracted from demulsification with heptanoic acid contained 78.81%, which was significantly higher than the other three methods. The results of physicochemical characterization indicated that the oil obtained by demulsification with heptanoic acid had a higher quality. According to the analysis of the amino acid composition, the protein obtained using AEE was similar to that of commercial peanut protein powder (CPPP). However, the essential amino acid content of proteins extracted via AEE was significantly higher than that of CPPP. The capacity of water (oil) holding, emulsifying activity, and foaming properties of protein obtained via AEE were better than those for CPPP. Overall, heptanoic acid demulsification is a potential demulsification method, thus, this work provides a new idea for the industrial application of simultaneous separation of oil and proteins via AEE.

Stretchable and recyclable gelatin Ionogel based ionic skin with extensive temperature tolerant, self-healing, UV-shielding, and sensing capabilities.

Fabricating sustainable ionic skin with multi-functional outstanding performances using biocompatible natural polymer-based ionogel is highly desired but remains a great challenge up to now. Herein, a green and recyclable ionogel has been fabricated by in-situ cross-linking of gelatin with a green bio-based multifunctional cross-linker of Triglycidyl Naringenin in ionic liquid. Benefiting from the unique multifunctional chemical crosslinking networks along with multiple reversible non-covalent interactions, the as-prepared ionogels exhibit high stretchability (>1000 %), excellent elasticity, fast room-temperature self-healability (>98 % healing efficiency at 6 min), and good recyclability. These ionogels are also highly conductive (up to 30.7 mS/cm at 150 °C), and exhibit extensive temperature tolerance (-23 to 252 °C) and outstanding UV-shielding ability. As a result, the as-prepared ionogel can easily be applied as stretchable ionic skin for wearable sensors, which exhibits high sensitivity, fast response time (102 ms), excellent temperature tolerance, and stability over 5000 stretching-relaxing cycles. More importantly, the gelatin-based sensor can be used in signal monitor system for various human motion real-time detection. This sustainable and multifunctional ionogel provides a new idea for easy and green preparation of advanced ionic skins.

Highly Tough, Stretchable, and Recyclable Ionogels with Crosslink-Enhanced Emission Characteristics for Anti-Counterfeiting and Motion Detection.

Traditional luminescent ionogels often suffer from poor mechanical properties and a lack of recyclability and regeneration, which limits their further application and sustainable development. Herein, a luminescent ionogel with strong mechanical properties and good recyclability has been designed and fabricated by introducing dynamic coordination bonds via in situ one-step crosslinking of acrylic acid in ionic liquid of 1-ethyl-3-methylimidazolium diethylphosphate by zinc dimethacrylate. Due to the special crosslinking of dynamic coordination bonds along with the hydrogen bond interaction, the as-prepared ionogel displays excellent stretchability and toughness, good self-adhesiveness, fast self-healability, and recyclability. Interestingly, the obtained ionogels exhibit tunable photoluminescence caused by the crosslink-enhanced emission (CEE) effect from the coordination bonds. Importantly, ionogels can be applied in information storage, information encryption, anti-counterfeiting due to their simple and in situ preparation method, and their special fluorescence performances. Moreover, an ionogel-based wearable sensor has rapid response time and a high gauge factor of 3.22 within a wide strain range from 1 to 700%, which can monitor various human movements accurately from subtle to large-scale motions. This paper offers a promising way to fabricate sustainable functional ionic liquid-based composites with CEE characteristics via an in situ one-step polymerization method.

CaMKIV mediates spine growth deficiency of hippocampal neurons by regulation of EGR3/BDNF signal axis in congenital hypothyroidism.

Congenital hypothyroidism (CH) will cause cognitive impairment in the condition of delayed treatment. The hippocampus is one of the most affected tissues by CH, in which the functional structures of hippocampal neurons manifest deficiency due to aberrant expression of effector molecules. The Ca2+/Calmodulin-dependent protein kinase, CaMKIV, is downregulated in the hippocampal neurons, influencing the growth of dendritic spines in response to CH. However, the underlying mechanism is not fully elucidated. In the present study, the early growth response factor 3 (EGR3) was regulated by CaMKIV in the hippocampal neurons of CH rat pups, as was analyzed by transcriptome sequencing and in vitro cell experiments. EGR3 localized within hippocampal neurons in CA1, CA3, and dentate gyrus regions. Deficient EGR3 in the primary hippocampal neurons significantly reduced the density of dendritic spines by downregulating the expression of BDNF, and such effects could be rescued by supplementing recombinant BDNF protein. Taken together, CH mediates cognitive impairment of pups through the inactivation of CaMKIV in the hippocampal neurons, which decreases the expression of EGR3 and further reduces the production of BDNF, thereby impairing the growth of dendritic spines. Identifying CaMKIV/EGR3/BDNF pathway in the hippocampal neurons in the context of CH will benefit the drug development of intellectual disability caused by CH.

Visible-light-mediated aerobic Ritter-type C-H amination of diarylmethanes using DDQ/tert-butyl nitrite.

A metal-free photocatalytic Ritter-type C-H amination of unactivated sp3 carbons using molecular oxygen as a terminal oxidant has been developed. By employing a co-catalytic system of 3-dichloro-4,5-dicyano-1,4-benzoquinone (DDQ) and tert-butyl nitrite (TBN), this novel strategy provides a low cost, sustainable and scalable way to synthesise a broad range of secondary amides in moderate to excellent yields under mild conditions.

Value of the prognostic nutritional index (PNI) in patients with newly diagnosed, CD5-positive diffuse large B-cell lymphoma: A multicenter retrospective study of the Huaihai Lymphoma Working Group.

BACKGROUND: CD5-positive diffuse large B-cell lymphoma (DLBCL) is a clinically rare subtype of DLBCL with aggressive clinical manifestations and a poor prognosis. It has been demonstrated that the prognostic nutritional index (PNI), an indicator of nutritional status and systemic inflammation, is a significant prognostic factor for several types of lymphoma. The objective of this multicenter retrospective study was to explore the prognostic value of the PNI in patients with CD5-positive DLBCL. METHODS: In total, 207 patients with CD5-positive DLBCL were recruited from 11 centers of the Huaihai Lymphoma Working Group. Maximally selected rank statistics analysis was used to identify optimal cutoff points for the PNI. A Cox proportional hazards model was used for univariable and multivariable analyses. Kaplan-Meier curves were used to calculate survival rates and draw survival curves, and the log-rank test was used to compare differences between groups. RESULTS: The median age at diagnosis was 61 years, and the 5-year overall survival rate was 47.5%. According to the maximally selected rank statistics analysis, a score of 49.7 was the optimal cutoff point for the PNI. Subgroup analysis showed that the PNI could re-stratify patients in BCL-2-negative, MYC-negative, high-intermediate-risk and high-risk International Prognostic Index, BCL-6-positive and BCL-6-negative, high Ki-67 score (≥0.9), Ann Arbor stage III/IV, Eastern Cooperative Oncology Group performance status ≥2, and germinal center B subgroups. Multivariable analysis revealed that PNI, age, Eastern Cooperative Oncology Group performance status, albumin level, and red blood cell count were independent prognostic factors for CD5-positive DLBCL. CONCLUSIONS: The PNI was a significant prognostic indicator for CD5-positive DLBCL and was able to re-stratify the prognosis for clinicopathologic subgroups of patients with CD5-positive DLBCL.

Muscle-Mimetic Highly Tough, Conductive, and Stretchable Poly(ionic liquid) Liquid Crystalline Ionogels with Ultrafast Self-Healing, Super Adhesive, and Remarkable Shape Memory Properties.

Here, we report a simple method for preparing muscle-mimetic highly tough, conductive, and stretchable liquid crystalline ionogels which contains only one poly(ionic liquid) (PIL) in an ionic liquid via in situ free radical photohomopolymerization by using nitrogen gas instead of air atmosphere. Due to eliminating the inhibition caused by dissolved oxygen, the polymerization under nitrogen gas has much higher molecular weight, lower critical sol-gel concentration, and stronger mechanical properties. More importantly, benefiting from the unique loofah-like microstructures along with the strong internal ionic interactions, entanglements of long PIL chains and liquid crystalline domains, the ionogels show special optical anisotropic, superstretchability (>8000%), high fracture strength (up to 16.52 MPa), high toughness (up to 39.22 MJ/m3), and have ultrafast self-healing, ultrastrong adhesive, and excellent shape memory properties. Due to its excellent stretchability and good conductive-strain responsiveness, the as-prepared ionogel can be easily applied for high-performance flexible and wearable sensors for motion detecting. Therefore, this paper provides an effective route and developed method to generate highly stretchable conductive liquid crystalline ionogels/elastomers that can be used in widespread flexible and wearable electronics.

Experimental investigations and the modeling approach for CO2 solubility in aqueous blended amine systems of monoethanolamine, 2-amino-2-methyl-1-propanol, and 2-(butylamino)ethanol.

In this work, new CO2 solubility data on three types of aqueous amine blends were reported to complement existing databases. The experiments were conducted at temperatures of 313 K (absorption condition) and 363 K (desorption condition). The effect of the MEA concentration on the CO2 solubility in several amine blends at low CO2 partial pressure (8 to 50.65 kPa) were studied in this work, including 0.1, 0.3, 0.5 mol/L MEA + 2 mol/L AMP; 0.1, 0.3, 0.5 mol/L MEA + 2 mol/L BEA; and 0.1, 0.3, 0.5 mol/L MEA + 1, 2 mol/L AMP + 1, 2 mol/L BEA. Besides, an additional group of equilibrium CO2 solubility data were conducted at 298 K in order to estimate the heat of CO2 absorption of the blended solvents at a temperature range from 298 to 313 K. A new simplified Kent-Eisenberg model was developed for the predictions of blended solvents, and a multilayer neural network model with Levenberg-Marquardt backpropagation algorithm was developed upon five hundred reliable published experimental data. The predictions from two methods are both in good agreement with the experimental CO2 solubility data.

Cold Atmospheric Plasma Boosts Virus Multiplication via EGFR(Tyr1068) Phosphorylation-Mediated Control on Cell Mitophagy.

Objectives: Vaccination still remains as the most effective approach for preventing infectious diseases such as those caused by virus infection, with cell-based vaccine manufacturing being one flexible solution regarding the spectrum of infectious disorders it can prevent. Rapid cell-based virus propagation can enable high yield of vaccines against viral diseases that may offer critical values in the industry when handling emergent situations such as the ongoing viral disease pandemic. Methods: Through investigating the phenomenon and biological mechanism underlying redox-triggered cell survival towards enhanced viral particle production, this study explores novel strategies for improved yield of viral particles at a reduced cost to meet the increasing demand on cell-based vaccine manufacturing against viral diseases. Results: We found in this study that cold atmospheric plasma (CAP), composed of multiple reactive oxygen and nitrogen species including H2O2, could effectively enhance virus replication via triggering cell mitophagy that was dynamically modulated by the p-EGFR(Tyr1068)/p-Drp1(Ser616) axis using IBRV and MDBK as the virus and cell models, respectively; and removing H2O2 can further enhance virus yield via releasing cells from excessive G0/G1 cell cycle arrest. The observed efficacy of CAP was extended to other viruses such as CDV and CPV. Conclusion: This study provides experimental evidences supporting the use of CAP as a modulator of cell survival including mitophagy and mitochondria dynamics, and makes CAP an interesting and promising tool for enhancing the yield of viral vaccines if translated into the industry.

Anti-PD-1 Therapy Enhances the Efficacy of CD30-Directed Chimeric Antigen Receptor T Cell Therapy in Patients With Relapsed/Refractory CD30+ Lymphoma.

Anti-CD30 CAR-T is a potent candidate therapy for relapsed/refractory (r/r) CD30+ lymphomas with therapy limitations, and the efficacy needed to be further improved. Herein a multi-center phase II clinical trial (NCT03196830) of anti-CD30 CAR-T treatment combined with PD-1 inhibitor in r/r CD30+ lymphoma was conducted. After a lymphocyte-depleting chemotherapy with fludarabine and cyclophosphamide, 4 patients in cohort 1 and 3 patients in cohort 2 received 106/kg and 107/kg CAR-T cells, respectively, and 5 patients in cohort 3 received 107/kg CAR-T cells combined with anti-PD-1 antibody. The safety and the efficacy of CAR-T cell therapy were analyzed. Cytokine release syndrome (CRS) was observed in 4 of 12 patients, and only 1 patient (patient 9) experienced grade 3 CRS and was treated with glucocorticoid and tocilizumab. No CAR-T-related encephalopathy syndrome was observed. Only two patients in cohorts 2 and 3 experienced obviously high plasma levels of IL-6 and ferritin after CD30 CAR-T cell infusion. The overall response rate (ORR) was 91.7% (11/12), with 6 patients achieving complete remission (CR) (50%). In cohorts 1 and 2, 6 patients got a response (85.7%), with 2 patients achieving CR (28.6%). In cohort 3, 100% ORR and 80% CR were obtained in 5 patients without ≥3 grade CRS. With a median follow-up of 21.5 months (range: 3-50 months), the progression-free survival and the overall survival rates were 45 and 70%, respectively. Of the 11 patients who got a response after CAR-T therapy, 7 patients (63.6%) maintained their response until the end of follow-up. Three patients died last because of disease progression. Taken together, the combination of anti-PD-1 antibody showed an enhancement effect on CD30 CAR-T therapy in r/r CD30+ lymphoma patients with minimal toxicities.

Dual Thermo-Responsive and Strain-Responsive Ionogels for Smart Windows and Temperature/Motion Monitoring.

In this work, a stretchable, dual thermo-responsive and strain-responsive ionogel has been synthesized by one-step photopolymerization. The obtained ionogel shows an ultrahigh stretchability (∼3000%), a high ionic conductivity (up to 3.1 mS/cm), and a good temperature tolerance (-40 to 300 °C). Importantly, these ionogels show an upper critical solution temperature-type phase transition with a wide tunable phase-transition temperature (17.5-42.5 °C) and reversible color/transparency switching. In particular, the as-prepared ionogel-based flexible/wearable temperature monitors and smart windows show an excellent designability and programmability, temperature modulation ability, and thermal responsiveness. Moreover, the ionogels-based strain sensors have temperature- and strain-dual responsibility and a broad strain-sensing range (1-700%), which can effectively monitor various motions. This strategy of fabricating dual thermo- and strain-responsive ionogels by using a one-step method and only one polymer holds great promise for the next generation of multifunctional stimuli-responsive materials.

Ultrastretchable, Adhesive, Fast Self-Healable, and Three-Dimensional Printable Photoluminescent Ionic Skin Based on Hybrid Network Ionogels.

Developing multifunctional stretchable ionic skin (I-Skin) to mimic the sensations of the human skin is of great interest and shows promising potential in wearable sensors and human-machine interfaces (HMIs). However, common ionogels prepared with small-molecule cross-linkers and single networks can hardly satisfy the requirements of adjustable mechanical properties, strong adhesion, fast self-healability, and good stability in extreme environments. Herein, an ultrastretchable (>10,000%), ultrastrong adhesive (>6.8 MPa), ultrafast self-healable (10 s), high thermally stable (-60 to 250 °C), and three-dimensional (3D)-printable photoluminescent ionogel with shape memory properties has been designed. The ionogel consists of hyperbranched polymer covalent-cross-linked poly(zwitterionic ionic liquid)-co-poly(acrylic acid) and multiple dynamic bonding cross-linked networks. The excellent performance of the ionogel-based high-stretchable strain sensor and the triboelectric nanogenerator (TENG)-based self-powered touch sensor is further demonstrated over a wide temperature range (-40 to 150 °C). More importantly, ionogel-based I-Skin can work as an HMI for human gesture recognition and real-time wireless control of robots under extreme vacuum conditions and can also self-heal immediately along with function recovery after mechanical damage.

Development and Validation of a Novel Prognostic Nomogram for CD5-Positive Diffuse Large B-Cell Lymphoma: A Retrospective Multicenter Study in China.

BACKGROUND: CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is a rare subtype of DLBCL with invasive clinical features and poor prognosis. Current clinical variables based on prognostic systems for DLBCL are inadequate to accurately stratify the prognosis of CD5+ DLBCL. METHODS: A total of 195 CD5+ DLBCL patients were retrospectively recruited from nine centers in Huaihai Lymphoma Working Group. MaxStat analysis was used to identify optimal cutoff points for continuous variables; univariable and multivariable Cox analyses were used for variable selection; Kaplan-Meier curve was used to analyze the value of variables on prognosis; and C-index, Brier score, and decision curve analysis were measured for predicting model performance. RESULTS: The derivation and validation cohorts consisted of 131 and 64 patients. Of the whole cohort, median age at diagnosis was 61 years, of whom 100 (51.28%) were males and the 5-year overall survival rate was 42.1%. MYC, BCL-2, and the coexpression of MYC/BCL-2 could distinguish the survival of CD5+ DLBCL. Multivariable analysis showed that age, IPI, red blood cell count, neutrophil count, MYC expression, and hepatosplenomegaly were independent predictors, and the prognostic nomogram was developed. The C-index of the nomogram was 0.809 in the derivation and 0.770 in the validation cohort. Decision curve analysis proved that compared with IPI, the specific nomogram showed a better identification in CD5+ DLBCL. CONCLUSION: The proposed nomogram provided a valuable tool for prognosis prediction in patients with CD5+ DLBCL.

Design and Evaluation of a Prescription Drug Monitoring Program for Chinese Patent Medicine based on Knowledge Graph.

BACKGROUND: Chinese patent medicines are increasingly used clinically, and the prescription drug monitoring program is an effective tool to promote drug safety and maintain health. METHODS: We constructed a prescription drug monitoring program for Chinese patent medicines based on knowledge graphs. First, we extracted the key information of Chinese patent medicines, diseases, and symptoms from the domain-specific corpus by the information extraction. Second, based on the extracted entities and relationships, a knowledge graph was constructed to form a rule base for the monitoring of data. Then, the named entity recognition model extracted the key information from the electronic medical record to be monitored and matched the knowledge graph to realize the monitoring of the Chinese patent medicines in the prescription. RESULTS: Named entity recognition based on the pretrained model achieved an F1 value of 83.3% on the Chinese patent medicines dataset. On the basis of entity recognition technology and knowledge graph, we implemented a prescription drug monitoring program for Chinese patent medicines. The accuracy rate of combined medication monitoring of three or more drugs of the program increased from 68% to 86.4%. The accuracy rate of drug control monitoring increased from 70% to 97%. The response time for conflicting prescriptions with two drugs was shortened from 1.3S to 0.8S. The response time for conflicting prescriptions with three or more drugs was shortened from 5.2S to 1.4S. CONCLUSIONS: The program constructed in this study can respond quickly and improve the efficiency of monitoring prescriptions. It is of great significance to ensure the safety of patients' medication.

Zi Qi Decoction Alleviates Liver Fibrosis by Inhibiting the Toll-Like Receptor 4 (TLR4)-Related Nuclear Factor kappa b (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) Signaling Pathways.

BACKGROUND Hepatic stellate cells (HSCs) play a vital role in hepatic fibrogenesis. Our recent clinical study indicated that the Zi Qi decoction, a Traditional Chinese Medicine formula, exhibited good efficacy in alleviating liver fibrosis, but the underlying mechanism remains elusive. MATERIAL AND METHODS Rats repeatedly injected with CCl4 and cells stimulated with lipopolysaccharide were used as in vivo and in vitro models for liver fibrosis, respectively. The viability of LX-2 cells was evaluated with MTT assay. Relative messenger RNA (mRNA) expression of representative extracellular matrix (ECM) components was detected with real-time quantitative polymerase chain reaction (RT-qPCR). Moreover, total and phosphorylation levels of ECM proteins and pathway-related proteins were detected with western blotting. Immunofluorescent staining was used to show the nuclear translocation of nuclear factor kappa b (NF-kappaB) p65. Hematoxylin & eosin (H&E) and Masson trichrome staining and immunohistochemistry were performed to evaluate the extent of liver fibrosis. The levels of alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transpeptidase (GGT), Hyp, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were tested with an enzyme-linked immunosorbent assay. In addition, 7.0T micro-magnetic resonance imaging (micro-MRI) was used to evaluate the severity of hepatic damage. RESULTS The Zi Qi decoction inhibited lipopolysaccharide-mediated upregulation of mRNA and protein levels of representative ECM proteins both in vivo and in vitro. The Zi Qi decoction also suppressed activation of the Toll-like receptor 4 (TLR4)-related NF-kappaB signaling pathway and subsequently inhibited the nuclear translocation of activated NF-kappaB. Moreover, another TLR4 downstream pathway, mitogen-activated protein kinase (MAPK), was simultaneously restrained. The results of liver pathology and MRI in rat models also suggested the efficacy of the Zi Qi decoction in attenuating liver damage. CONCLUSIONS The Zi Qi decoction inhibited liver fibrosis by inhibiting the TLR4-related NF-kB and MAPK signaling pathways and preventing activation of HSCs.

The efficacy of novel metabolic targeted agents and natural plant drugs for nonalcoholic fatty liver disease treatment: A PRISMA-compliant network meta-analysis of randomized controlled trials.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease characterized by excess accumulation of fat in hepatocytes. Because no drug has been approved for NAFLD treatment, this work analyzed the effects of agents resulting from 2 research hotspots, metabolic target agents, and natural plant drugs, on NAFLD with network meta-analysis. METHODS: Public databases were searched through August 14, 2020. Randomized controlled trials that compared obeticholic acid, elafibranor, cenicriviroc, selonsertib, curcumin, silymarin, and resveratrol to placebo were included. Liver pathology improvement, hepatic biochemical indicators, and lipid metabolism indicators were analyzed. RESULTS: Thirty-five studies were included in the meta-analysis. Obeticholic acid was found to significantly increase the frequency of liver biopsy improvement compared to placebo (OR: 2.10; 95% CI: 1.60, 2.77). The ranking results among the hepatic biochemical indicators showed that obeticholic acid (94.9%) and elafibranor (86.3%) have a relative advantage in reducing alanine aminotransferase (ALT) levels, and obeticholic acid also had an advantage (95.4%) in reducing aspartate aminotransferase (AST) levels. Considering lipid metabolic indicators, elafibranor (expSMD: 0.01; 95% CI: 0.00, 0.05; SUCRA: 100%), and obeticholic acid (expSMD: 0.48; 95% CI: 0.28,0.84; SUCRA: 75.6%) significantly reduced triglyceride (TG) levels compared with placebo; moreover, obeticholic acid, but not elafibranor, caused a serious increase in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels and a decrease in high-density lipoprotein cholesterol (HDL-C) levels. CONCLUSIONS: Novel metabolic targeted agents generally have better effects than natural plant drugs, especially obeticholic acid, and elafibranor. However, obeticholic acid showed serious adverse effects such as increasing LDL-C levels and decreasing HDL-C levels. Curcumin showed potential advantages for NAFLD but lacked statistical significance.

TRPV1 feed-forward sensitisation depends on COX2 upregulation in primary sensory neurons.

Increased activity and excitability (sensitisation) of a series of molecules including the transient receptor potential ion channel, vanilloid subfamily, member 1 (TRPV1) in pain-sensing (nociceptive) primary sensory neurons are pivotal for developing pathological pain experiences in tissue injuries. TRPV1 sensitisation is induced and maintained by two major mechanisms; post-translational and transcriptional changes in TRPV1 induced by inflammatory mediators produced and accumulated in injured tissues, and TRPV1 activation-induced feed-forward signalling. The latter mechanism includes synthesis of TRPV1 agonists within minutes, and upregulation of various receptors functionally linked to TRPV1 within a few hours, in nociceptive primary sensory neurons. Here, we report that a novel mechanism, which contributes to TRPV1 activation-induced TRPV1-sensitisation within ~ 30 min in at least ~ 30% of TRPV1-expressing cultured murine primary sensory neurons, is mediated through upregulation in cyclooxygenase 2 (COX2) expression and increased synthesis of a series of COX2 products. These findings highlight the importance of feed-forward signalling in sensitisation, and the value of inhibiting COX2 activity to control pain, in nociceptive primary sensory neurons in tissue injuries.

Both Bupivacaine and Levobupivacaine inhibit colon cancer cell growth but not melanoma cells in vitro.

BACKGROUND: Retrospective studies indicate that the use of regional anaesthesia causes a reduction in cancer recurrence after oncological surgery, which could be due to anaesthetic's negating effect on immunosuppression related to the surgical stress response. Local anaesthetics may also exert direct suppressive effects on malignant cells, an area where further investigation is urgently needed. METHODS: Human colon cancer cells and human melanoma cells were cultured and then treated with 1 mM bupivacaine or levobupivacaine for up to 24 or 48 h. Their migratory ability was measured by scratch assay, proliferation determined with Ki67 immunofluorescence staining, and apoptosis accessed with annexin V and PI staining on flow cytometry. The effects of bupivacaine and levobupivacaine on cellular signaling and molecular response, specifically, on endoplasmic reticulum stress (ERS), were studied with immunostaining and western blot. RESULTS: In colon cancer cells, treatment with bupivacaine and levobupivacaine significantly inhibited cell migration (**p < 0.01, ***p < 0.001; n = 4) and proliferation (**p < 0.01; n = 4), while increasing the expression of CHOP (***p < 0.001; n = 4) and decreased the expression of Grp78 (*p < 0.05; n = 4). These effects were not mirrored by melanoma cells, such that no significant increase in apoptosis was seen in either melanoma cell lines following treatment. CONCLUSION: These in vitro data suggested that both bupivacaine and levobupivacaine suppress colorectal adenocarcinoma cell proliferation and migration, which are concurrent with increased endoplasmic reticulum stress. Conversely, melanoma cells are more resilient to these two commonly used local anaesthetics. Further in vivo studies or clinical trials are needed.