-
BioMed Research International 2021Acute respiratory distress syndrome (ARDS) is defined as the acute onset of noncardiogenic edema and subsequent gas-exchange impairment due to a severe inflammatory... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Acute respiratory distress syndrome (ARDS) is defined as the acute onset of noncardiogenic edema and subsequent gas-exchange impairment due to a severe inflammatory process known as cytokine storm. Xuebijing injection (hereinafter referred to as Xuebijing) is a patent drug that was used to treat ARDS or severe pneumonia (SP) in China. However, its efficacy and mechanism of actions remain unclear. In this study, we used meta-analysis and network pharmacology to assess these traits of Xuebijing.
METHODS
We searched PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang databases for randomized controlled trials (RCTs) that evaluated Xuebijing therapy for ARDS or SP. The outcomes were total mortality, intensive care unit (ICU) stay time, and TNF- and IL-6 levels. We performed a meta-analysis using RevMan 5.3 software. The putative targets, top 10 proteins, and possible pathway of Xuebinjing on ARDS were analyzed by network pharmacology. TNF- and IL-6 were further docked with the six main active components of Xuebinjing using AutoDock 4.2.6 and PyMol 1.5.0.3 software.
RESULTS
Fifteen RCTs involving 2778 patients (13 ARDS and 2 SP) were included. Compared with the control, Xuebijing treatment significantly reduced the mortality rate (risk ratio, 0.64 (95% credible interval (CrI), 0.54-0.77)), reduced the ICU stay time (mean difference (MD), -4.51 (95% CrI, -4.97--4.06)), reduced the TNF- ((MD), -1.23 (95% CrI, -1.38--1.08)) and IL-6 ((MD), -1.15 (95% CrI, -1.52--0.78)) levels. The 56 putative targets, top 10 proteins (MAPK1 (mitogen-activated protein kinase 1), MAPK8 (mitogen-activated protein kinase 8), RELA (transcription factor p65), NFKB1 (nuclear factor NF-kappa-B p105 subunit), JUN (transcription factor AP-1), SRC (proto-oncogene tyrosine-protein kinase), TNF (tumor necrosis factor), HRAS (GTPase HRas), IL6 (interleukin-6), and APP (amyloid-beta A4 protein)), and possible pathways (Ret tyrosine kinase, IL2-mediated signaling events, CD4+/CD8+ T cell-related TCR signaling, p75(NTR)-mediated signaling, CXCR4-mediated signaling events, LPA receptor-mediated events, IL12-mediated signaling events, FAS (CD95) signaling pathway, and immune system) of Xuebinjing's action on ARDS were obtained. The molecular docking results showed that all the six components of Xuebinjing docked with TNF-, and two components docked with IL-6 got the binding energies lower than -5.
CONCLUSION
Our results recommended Xuebijing treatment for patients with ARDS. Xuebijing has therapeutic effects on ARDS patients partly by regulating the immune cell/cytokine pathways and thus inhibiting the cytokine storm. TNF- is the cytokine both directly and indirectly inhibited by Xuebijing, and IL-6 is the cytokine mainly indirectly inhibited by Xuebijing.
Topics: Drugs, Chinese Herbal; Gene Expression Regulation; Humans; Intensive Care Units; Proto-Oncogene Mas; Respiratory Distress Syndrome; Signal Transduction
PubMed: 34124260
DOI: 10.1155/2021/8824059 -
Oxidative Medicine and Cellular... 2021This study evaluated the effects of light-emitting diode (LED) on mesenchymal stem cells (MSCs). An electronic search was conducted in PubMed/MEDLINE, Scopus, and Web of...
This study evaluated the effects of light-emitting diode (LED) on mesenchymal stem cells (MSCs). An electronic search was conducted in PubMed/MEDLINE, Scopus, and Web of Science database for articles published from 1980 to February 2020. Ten articles met the search criteria and were included in this review. The risk of bias was evaluated to report quality, safety, and environmental standards. MSCs were derived from adipose tissue, bone marrow, dental pulp, gingiva, and umbilical cord. Protocols for cellular irradiation used red and blue light spectrum with variations of the parameters. The LED has been shown to induce greater cellular viability, proliferation, differentiation, and secretion of growth factors. The set of information available leads to proposing a complex signaling cascade for the action of photobiomodulation, including angiogenic factors, singlet oxygen, mitogen-activated protein kinase/extracellular signal-regulated protein kinase, Janus kinase/signal transducer, and reactive oxygen species. In conclusion, although our results suggest that LED can boost MSCs, a nonuniformity in the experimental protocol, bias, and the limited number of studies reduces the power of systematic review. Further research is essential to find the optimal LED irradiation parameters to boost MSCs function and evaluate its impact in the clinical setting.
Topics: Humans; Light; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Publication Bias; Risk
PubMed: 33623634
DOI: 10.1155/2021/6663539 -
Frontiers in Pediatrics 2021Worldwide neonatal hypoxic-ischemic encephalopathy (HIE) is a common cause of mortality and neurologic disability, despite the implementation of therapeutic hypothermia...
Worldwide neonatal hypoxic-ischemic encephalopathy (HIE) is a common cause of mortality and neurologic disability, despite the implementation of therapeutic hypothermia treatment. Advances toward new neuroprotective interventions have been limited by incomplete knowledge about secondary injurious processes such as cerebral hyperperfusion commonly observed during the first 1-5 days after asphyxia. Cerebral hyperperfusion is correlated with adverse neurodevelopmental outcome and it is a process that remains poorly understood. In order to provide an overview of the existing knowledge on the pathophysiology and highlight the gaps in current understanding of cerebral hyperperfusion in term animals and neonates with HIE, we performed a systematic research. We included papers scoping for study design, population, number of participants, study technique and relevant findings. Methodological quality was assessed using the checklist for cohort studies from The Joanna Briggs Institute. Out of 2,690 results, 34 studies were included in the final review-all prospective cohort studies. There were 14 studies of high, 17 moderate and 3 of low methodological quality. Data from the literature were analyzed in two main subjects: (1) Hemodynamic Changes subdivided into macro- and microscopic hemodynamic changes, and (2) Endogenous Pathways which was subdivided into N-methyl-D-aspartate/Mitogen activated protein kinase (NDMA/MAPK), Nitric Oxide (NO), prostanoids and other endogenous studies. Cerebral hyperperfusion in term neonates with HIE was found to be present 10-30 min after the hypoxic-ischemic event and was still present around day 10 and up to 1 month after birth. Cerebral hyperperfusion was also characterized by angiogenesis and cerebral vasodilation. Additionally, cerebral vasodilation was mediated by endogenous pathways such as MAPK through urokinase Plasminogen Activator (uPA), by neuronal NO synthase following NMDA and by prostanoid synthesis. Future research should elucidate the precise role of NMDA, MAPK and prostanoids in cerebral hyperperfusion. Moreover, research should focus on possible interventions and the effect of hypothermia on hyperperfusion. These findings should be taken into account simultaneously with brain imagining techniques, becoming a valuable asset in assessing the impact in neurodevelopmental outcome.
PubMed: 33604320
DOI: 10.3389/fped.2021.631258 -
ESMO Open Apr 2021Approved first-line treatments for patients with BRAF V600-mutant advanced melanoma include nivolumab (a programmed cell death protein 1 inhibitor) plus ipilimumab (a...
BACKGROUND
Approved first-line treatments for patients with BRAF V600-mutant advanced melanoma include nivolumab (a programmed cell death protein 1 inhibitor) plus ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor; NIVO+IPI) and the BRAF/MEK inhibitors dabrafenib plus trametinib (DAB+TRAM), encorafenib plus binimetinib (ENCO+BINI), and vemurafenib plus cobimetinib (VEM+COBI). Results from prospective randomized clinical trials (RCTs) comparing these treatments have not yet been reported. This analysis evaluated the relative efficacy and safety of NIVO+IPI versus DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma using a matching-adjusted indirect comparison (MAIC).
PATIENTS AND METHODS
A systematic literature review identified RCTs for DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma. Individual patient-level data for NIVO+IPI were derived from the phase III CheckMate 067 trial (BRAF-mutant cohort) and restricted to match the inclusion/exclusion criteria of the comparator trials. Treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using Cox proportional hazards and time-varying hazard ratio (HR) models. Safety outcomes (grade 3 or 4 treatment-related adverse events) with NIVO+IPI and the comparators were compared.
RESULTS
In the Cox proportional hazards analysis, NIVO+IPI showed improved OS compared with DAB+TRAM (HR = 0.53; 95% confidence interval [CI], 0.39-0.73), ENCO+BINI (HR = 0.60; CI, 0.42-0.85), and VEM+COBI (HR = 0.50; CI, 0.36-0.70) for the overall study period. In the time-varying analysis, NIVO+IPI was associated with significant improvements in OS and PFS compared with the BRAF/MEK inhibitors 12 months after treatment initiation. There were no significant differences between NIVO+IPI and BRAF/MEK inhibitor treatment from 0 to 12 months. Safety outcomes favored DAB+TRAM over NIVO+IPI, whereas NIVO+IPI was comparable to VEM+COBI.
CONCLUSION
Results of this MAIC demonstrated durable OS and PFS benefits for patients with BRAF-mutant advanced melanoma treated with NIVO+IPI compared with BRAF/MEK inhibitors, with the greatest benefits noted after 12 months.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Ipilimumab; Melanoma; Mitogen-Activated Protein Kinase Kinases; Nivolumab; Proto-Oncogene Proteins B-raf
PubMed: 33556898
DOI: 10.1016/j.esmoop.2021.100050 -
Cellular and Molecular Neurobiology May 2022Neurodegenerative diseases might be slow but relentless, as we continue to fail in treating or delaying their progression. Given the complexity in the pathogenesis of... (Review)
Review
Neurodegenerative diseases might be slow but relentless, as we continue to fail in treating or delaying their progression. Given the complexity in the pathogenesis of these diseases, a broad-acting approach like photobiomodulation can prove promising. Photobiomodulation (PBM) uses red and infrared light for therapeutic benefits, working by stimulating growth and proliferation. The implications of photobiomodulation have been studied in several neurodegenerative disease models. It has been shown to improve cell survival, decrease apoptosis, alleviate oxidative stress, suppress inflammation, and rescue mitochondrial function. In in vivo models, it has reportedly preserved motor and cognitive skills. Beyond mitochondrial stimulation, the molecular mechanisms by which photobiomodulation protects against neurodegeneration have not been very well studied. This review has systematically been undertaken to study the effects of photobiomodulation at a molecular level and identify the different biochemical pathways and molecular changes in the process. The data showed the involvement of pathways like extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAPK), and protein kinase B (Akt). In addition, the expression of several genes and proteins playing different roles in the disease mechanisms was found to be influenced by PBM, such as neurotrophic factors and secretases. Studying the literature indicated that PBM can be translated to a potential therapeutic tool, acting through a spectrum of mechanisms that work together to decelerate disease progression in the organism, which is difficult to achieve through pharmacological interventions.
Topics: Cell Survival; Humans; Low-Level Light Therapy; Mitochondria; Mitogen-Activated Protein Kinases; Neurodegenerative Diseases
PubMed: 33301129
DOI: 10.1007/s10571-020-01016-9 -
Cancers Sep 2020This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We... (Review)
Review
This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We searched MEDLINE for articles on BRAF inhibitor resistance in patients with melanoma published since January 2010 in the following areas: (1) genetic basis of resistance; (2) epigenetic and transcriptomic mechanisms; (3) influence of the immune system on resistance development; and (4) combination therapy to overcome resistance. Common resistance mutations in melanoma are BRAF splice variants, amplification, neuroblastoma RAS viral oncogene homolog (NRAS) mutations and mitogen-activated protein kinase kinase 1/2 (MEK1/2) mutations. Genetic and epigenetic changes reactivate previously blocked mitogen-activated protein kinase (MAPK) pathways, activate alternative signaling pathways, and cause epithelial-to-mesenchymal transition. Once BRAF inhibitor resistance develops, the tumor microenvironment reverts to a low immunogenic state secondary to the induction of programmed cell death ligand-1. Combining a BRAF inhibitor with a MEK inhibitor delays resistance development and increases duration of response. Multiple other combinations based on known mechanisms of resistance are being investigated. BRAF inhibitor-resistant cells develop a range of 'escape routes', so multiple different treatment targets will probably be required to overcome resistance. In the future, it may be possible to personalize combination therapy towards the specific resistance pathway in individual patients.
PubMed: 33003483
DOI: 10.3390/cancers12102801 -
Translational Cancer Research Oct 2020Lung cancer is the leading cause of cancer-related deaths worldwide and the overall survival of patients with non-small cell lung cancer has not been improved. Let-7...
BACKGROUND
Lung cancer is the leading cause of cancer-related deaths worldwide and the overall survival of patients with non-small cell lung cancer has not been improved. Let-7 family has been shown to act as tumor suppressors by inhibiting oncogenes and key regulators of mitogenic pathways, while far fewer clinical studies addressing the association between let-7 expression and the disease prognosis have been published up to date. Therefore, our meta-analysis aims to determine the prognostic significance of let-7 expression in lung cancer patients.
METHODS
PubMed, EMBASE, the Web of Science and China National Knowledge Infrastructure (CNKI) databases were searched for full-text literature citations. We applied the hazard ratio (HR) with 95% confidence interval (CI) as the appropriate summarized statistics. Q-test and I2 statistic were used to estimate the level of heterogeneity. The publication bias was detected by Begg's test and Egger's test.
RESULTS
Seven eligible studies involving 2,262 patients were selected for this meta-analysis. The combined HR for the seven eligible studies was 0.61 (95% CI: 0.53-0.70, P<0.00001) and heterogeneity of overall prognosis was relatively high (I=76.4%, P=0.000). We conducted a further subgroup analysis, including an evaluation of the relationship between let-7 expression, lung cancer pathology, race, and sample size. All the results revealed that a significantly low let-7 expression in patients was an indicator of poor survival. Neither Begg's test nor Egger's test found publication bias in any analysis.
CONCLUSIONS
The present evidence indicates that the low let-7 expression can be considered as a significant predictor of worse prognosis in patients with lung cancer. The findings of our meta-analysis may be further confirmed in the future by the use of more updated review pooling and more relevant investigations.
PubMed: 35117243
DOI: 10.21037/tcr-20-1240 -
International Journal of Molecular... Jun 2020Acupuncture is clinically used to treat various diseases and exerts positive local and systemic effects in several nervous system diseases. Advanced molecular and... (Review)
Review
Acupuncture is clinically used to treat various diseases and exerts positive local and systemic effects in several nervous system diseases. Advanced molecular and clinical studies have continually attempted to decipher the mechanisms underlying these effects of acupuncture. While a growing understanding of the pathophysiology underlying several nervous system diseases shows it to be related to inflammation and impair cell regeneration after ischemic events, the relationship between the therapeutic mechanism of acupuncture and the p38 MAPK signal pathway has yet to be elucidated. This review discusses the latest advancements in the identification of the effect of acupuncture on the p38 signaling pathway in several nervous system diseases. We electronically searched databases including PubMed, Embase, and the Cochrane Library from their inception to April 2020, using the following keywords alone or in various combinations: "acupuncture", "p38 MAPK pathway", "signaling", "stress response", "inflammation", "immune", "pain", "analgesic", "cerebral ischemic injury", "epilepsy", "Alzheimer's disease", "Parkinson's disease", "dementia", "degenerative", and "homeostasis". Manual acupuncture and electroacupuncture confer positive therapeutic effects by regulating proinflammatory cytokines, ion channels, scaffold proteins, and transcription factors including TRPV1/4, Na, BDNF, and NADMR1; consequently, p38 regulates various phenomena including cell communication, remodeling, regeneration, and gene expression. In this review article, we found the most common acupoints for the relief of nervous system disorders including GV20, GV14, ST36, ST37, and LI4. Acupuncture exhibits dual regulatory functions of activating or inhibiting different p38 MAPK pathways, contributing to an overall improvement of clinical symptoms and function in several nervous system diseases.
Topics: Acupuncture Therapy; Animals; Brain-Derived Neurotrophic Factor; Humans; MAP Kinase Signaling System; Motion Sickness; Nerve Regeneration; Nervous System Diseases; TRPV Cation Channels; p38 Mitogen-Activated Protein Kinases
PubMed: 32630156
DOI: 10.3390/ijms21134693 -
Critical Care (London, England) May 2020Heterogeneity of acute respiratory distress syndrome (ARDS) could be reduced by identification of biomarker-based phenotypes. The set of ARDS biomarkers to prospectively...
BACKGROUND
Heterogeneity of acute respiratory distress syndrome (ARDS) could be reduced by identification of biomarker-based phenotypes. The set of ARDS biomarkers to prospectively define these phenotypes remains to be established.
OBJECTIVE
To provide an overview of the biomarkers that were multivariately associated with ARDS development or mortality.
DATA SOURCES
We performed a systematic search in Embase, MEDLINE, Web of Science, Cochrane CENTRAL, and Google Scholar from inception until 6 March 2020.
STUDY SELECTION
Studies assessing biomarkers for ARDS development in critically ill patients at risk for ARDS and mortality due to ARDS adjusted in multivariate analyses were included.
DATA EXTRACTION AND SYNTHESIS
We included 35 studies for ARDS development (10,667 patients at risk for ARDS) and 53 for ARDS mortality (15,344 patients with ARDS). These studies were too heterogeneous to be used in a meta-analysis, as time until outcome and the variables used in the multivariate analyses varied widely between studies. After qualitative inspection, high plasma levels of angiopoeitin-2 and receptor for advanced glycation end products (RAGE) were associated with an increased risk of ARDS development. None of the biomarkers (plasma angiopoeitin-2, C-reactive protein, interleukin-8, RAGE, surfactant protein D, and Von Willebrand factor) was clearly associated with mortality.
CONCLUSIONS
Biomarker data reporting and variables used in multivariate analyses differed greatly between studies. Angiopoeitin-2 and RAGE in plasma were positively associated with increased risk of ARDS development. None of the biomarkers independently predicted mortality. Therefore, we suggested to structurally investigate a combination of biomarkers and clinical parameters in order to find more homogeneous ARDS phenotypes.
PROSPERO IDENTIFIER
PROSPERO, CRD42017078957.
Topics: Angiopoietin-2; Antigens, Neoplasm; Biomarkers; Humans; Mitogen-Activated Protein Kinases; Multivariate Analysis; Respiratory Distress Syndrome
PubMed: 32448370
DOI: 10.1186/s13054-020-02913-7 -
Frontiers in Immunology 2020Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare combined immunodeficiency (CID) caused by recessive homozygous/compound heterozygous...
Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare combined immunodeficiency (CID) caused by recessive homozygous/compound heterozygous loss-of-function mutations in the gene. Patients with ZAP-70 deficiency present with a variety of clinical manifestations, particularly recurrent respiratory infections and cutaneous involvements. Therefore, a systematic review of ZAP-70 deficiency is helpful to achieve a comprehensive view of this disease. We searched PubMed, Web of Science, and Scopus databases for all reported ZAP-70 deficient patients and screened against the described eligibility criteria. A total of 49 ZAP-70 deficient patients were identified from 33 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. ZAP-70 deficient patients have been reported in the literature with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8%), cutaneous involvement (57.9%), lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%), and increased risk of malignancies (8.1%). The predominant immunologic phenotype was low CD8+ T cell counts (97.9%). Immunologic profiling showed defective antibody production (57%) and decreased lymphocyte responses to mitogenic stimuli such as phytohemagglutinin (PHA) (95%). Mutations of the gene were located throughout the gene, and there was no mutational hotspot. However, most of the mutations were located in the kinase domain. Hematopoietic stem cell transplantation (HSCT) was applied as the major curative treatment in 25 (51%) of the patients, 18 patients survived transplantation, while two patients died and three required a second transplant in order to achieve full remission. Newborns with consanguineous parents, positive family history of CID, and low CD8+ T cell counts should be considered for ZAP-70 deficiency screening, since early diagnosis and treatment with HSCT can lead to a more favorable outcome. Based on the current evidence, there is no genotype-phenotype correlation in ZAP-70 deficient patients.
Topics: Autoimmunity; CD8-Positive T-Lymphocytes; Delayed Diagnosis; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Loss of Function Mutation; Lymphopenia; Male; Phenotype; Severe Combined Immunodeficiency; Treatment Outcome; ZAP-70 Protein-Tyrosine Kinase
PubMed: 32431715
DOI: 10.3389/fimmu.2020.00831