-
Cell Death & Disease Feb 2023Sepsis is a life-threatening disorder disease defined as infection-induced dysregulated immune responses and multiple organ dysfunction. The imbalance between... (Review)
Review
Sepsis is a life-threatening disorder disease defined as infection-induced dysregulated immune responses and multiple organ dysfunction. The imbalance between hyperinflammation and immunosuppression is a crucial feature of sepsis immunity. Epigenetic modifications, including histone modifications, DNA methylation, chromatin remodeling, and non-coding RNA, play essential roles in regulating sepsis immunity through epi-information independent of the DNA sequence. In recent years, the mechanisms of histone modification in sepsis have received increasing attention, with ongoing discoveries of novel types of histone modifications. Due to the capacity for prolonged effects on immune cells, histone modifications can induce immune cell reprogramming and participate in the long-term immunosuppressed state of sepsis. Herein, we systematically review current mechanisms of histone modifications involved in the regulation of sepsis, summarize their role in sepsis from an immune perspective and provide potential therapeutic opportunities targeting histone modifications in sepsis treatment.
Topics: Humans; Histones; Histone Code; Epigenesis, Genetic; Sepsis; DNA Methylation
PubMed: 36774341
DOI: 10.1038/s41419-023-05656-9 -
The Cochrane Database of Systematic... Jan 2023There is strong evidence that our current consumption of salt is a major factor in the development of increased blood pressure (BP) and that a reduction in our salt... (Review)
Review
BACKGROUND
There is strong evidence that our current consumption of salt is a major factor in the development of increased blood pressure (BP) and that a reduction in our salt intake lowers BP, whether BP levels are normal or raised initially. Effective control of BP in people with diabetes lowers the risk of strokes, heart attacks and heart failure and slows the progression of chronic kidney disease (CKD) in people with diabetes. This is an update of a review first published in 2010.
OBJECTIVES
To evaluate the effect of altered salt intake on BP and markers of cardiovascular disease and of CKD in people with diabetes.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies up to 31 March 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of altered salt intake in individuals with type 1 and type 2 diabetes. Studies were included when there was a difference between low and high sodium intakes of at least 34 mmol/day.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed studies and resolved differences by discussion. We calculated mean effect sizes as mean difference (MD) and 95% confidence intervals (CI) using the random-effects model. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
MAIN RESULTS
Thirteen RCTs (313 participants), including 21 comparisons (studies), met our inclusion criteria. One RCT (two studies) was added to this review update. Participants included 99 individuals with type 1 diabetes and 214 individuals with type 2 diabetes. Two RCTs (four studies) included some participants with reduced overall kidney function. The remaining studies either reported that participants with reduced glomerular filtration rate (GFR) were excluded from the study or only included participants with microalbuminuria and normal GFR. Five studies used a parallel study design, and 16 used a cross-over design. Studies were at high risk of bias for most criteria. Random sequence generation and allocation concealment were adequate in only three and two studies, respectively. One study was at low risk of bias for blinding of participants and outcome assessment, but no studies were at low risk for selective reporting. Twelve studies reported non-commercial funding sources, three reported conflicts of interest, and eight reported adequate washout between interventions in cross-over studies. The median net reduction in 24-hour urine sodium excretion (24-hour UNa) in seven long-term studies (treatment duration four to 12 weeks) was 76 mmol (range 51 to 124 mmol), and in 10 short-term studies (treatment duration five to seven days) was 187 mmol (range 86 to 337 mmol). Data were only available graphically in four studies. In long-term studies, reduced sodium intake may lower systolic BP (SBP) by 6.15 mm Hg (7 studies: 95% CI -9.27 to -3.03; I² = 12%), diastolic BP (DBP) by 3.41 mm Hg (7 studies: 95% CI -5.56 to -1.27; I² = 41%) and mean arterial pressure (MAP) by 4.60 mm Hg (4 studies: 95% CI -7.26 to -1.94; I² = 28%). In short-term studies, low sodium intake may reduce SBP by 8.43 mm Hg (5 studies: 95% CI -14.37 to -2.48; I² = 88%), DBP by 2.95 mm Hg (5 studies: 95% CI -4.96 to -0.94; I² = 70%) and MAP by 2.37 mm Hg (9 studies: 95% CI -4.75 to -0.01; I² = 65%). There was considerable heterogeneity in most analyses but particularly among short-term studies. All analyses were considered to be of low certainty evidence. SBP, DBP and MAP reductions may not differ between hypertensive and normotensive participants or between individuals with type 1 or type 2 diabetes. In hypertensive participants, SBP, DBP and MAP may be reduced by 6.45, 3.15 and 4.88 mm Hg, respectively, while in normotensive participants, they may be reduced by 8.43, 2.95 and 2.15 mm Hg, respectively (all low certainty evidence). SBP, DBP and MAP may be reduced by 7.35, 3.04 and 4.30 mm Hg, respectively, in participants with type 2 diabetes and by 7.35, 3.20, and 0.08 mm Hg, respectively, in participants with type 1 diabetes (all low certainty evidence). Eight studies provided measures of urinary protein excretion before and after salt restriction; four reported a reduction in urinary albumin excretion with salt restriction. Pooled analyses showed no changes in GFR (12 studies: MD -1.87 mL/min/1.73 m², 95% CI -5.05 to 1.31; I² = 32%) or HbA1c (6 studies: MD -0.62, 95% CI -1.49 to 0.26; I² = 95%) with salt restriction (low certainty evidence). Body weight was reduced in studies lasting one to two weeks but not in studies lasting for longer periods (low certainty evidence). Adverse effects were reported in only one study; 11% and 21% developed postural hypotension on the low-salt diet and the low-salt diet combined with hydrochlorothiazide, respectively.
AUTHORS' CONCLUSIONS
This systematic review shows an important reduction in SBP and DBP in people with diabetes with normal GFR during short periods of salt restriction, similar to that obtained with single drug therapy for hypertension. These data support the international recommendations that people with diabetes with or without hypertension or evidence of kidney disease should reduce salt intake to less than 5 g/day (2 g sodium).
Topics: Humans; Diabetic Nephropathies; Sodium Chloride, Dietary; Diabetes Mellitus, Type 1; Hypertension; Renal Insufficiency, Chronic; Sodium; Diabetes Mellitus, Type 2
PubMed: 36645291
DOI: 10.1002/14651858.CD006763.pub3 -
Frontiers in Cardiovascular Medicine 2022Heart failure is the end stage of all cardiovascular diseases, which brings a heavy burden to the global health network. Arotinolol, as a new type of β Receptor...
BACKGROUND
Heart failure is the end stage of all cardiovascular diseases, which brings a heavy burden to the global health network. Arotinolol, as a new type of β Receptor blocker, has a good antihypertensive effect. Many clinical trials have observed the clinical efficacy of arotinolol in the treatment of essential hypertension. However, so far, there has been no systematic evaluation on the efficacy and safety of arotinolol in the treatment of chronic heart failure.
OBJECTIVE
The purpose of this review was to systematically evaluate the clinical efficacy of arotinolol in patients with chronic heart failure.
METHODS
Randomized controlled trials (RCTs) of arotinolol in the treatment of chronic heart failure were retrieved from seven databases according to the Cochrane manual, including CNKI (China National Knowledge Infrastructure), Wan fang database, VIP database, PubMed, Sinomed, EMBASE, and the Cochrane Library databases. The main outcomes were the effective rate, left ventricular ejection fraction (LVEF), blood pressure, heart rate, cardiac index, stroke volume (SV), brain natriuretic peptide (BNP), hypersensitive C-reactive protein (Hs-CRP), left ventricular end diastolic volume (LVEDV), left ventricular end diastolic diameter (LVEDD), and adverse events (AEs).
RESULTS
A total of 17 trials met the qualification criteria, which included 1,717 patients with heart failure. Most trials had uncertain risks in terms of random sequence generation, allocation hiding, patient loss, and result evaluation. Meta analysis showed that arotinolol significantly improved the treatment efficiency of patients with heart failure (standardized mean difference (SMD) = 4.07, 95% confidence interval (CI) [2.89, 5.72], = 0.00, = 0), LVEF (SMD = 1.59, 95% CI [0.99, 2.19], = 0.000 0, = 95.8%), cardiac index (SMD = 0.32, 95% CI [0.11, 0.53], = 0.03), = 0), SV (SMD = 2.00, 95% CI [1.57, 2.34], = 0.000, = 64.2%), lower BNP (SMD = -0.804, 95% CI [-0.97, -0.64], = 0.000, = 94.4%), and LVEDV (SMD = -0.25, 95% CI [-0.45, -0.05], = 0.015, = 0). There was no statistical significance for blood pressure (SMD = -0.09, 95% CI [-0.69, 0.51], = 0.775, = 90.2%; SMD = -0.16, 95% CI [-0.79, 0.48], = 0.632, = 91.2%), heart rate (SMD = -0.12, 95% CI [-1.00, 0.75], = 0.787, = 96.1%), Hs-CRP (SMD = -1.52, 95% CI [-3.43, 0.40], = 0.121, = 98.3%), and LVEDD (SMD = -0.07, 95% CI [-0.90, 0.76], = 0.870, = 96.5%).
CONCLUSION
Arotinolol can safely and effectively improve the effective rate of patients with chronic heart failure, increase LVEF, increase CI and SV, and reduce BNP and LVEDV. However, because of the low overall quality of the included randomized controlled trials, these findings need to be considered carefully. More high-quality randomized controlled trials are needed for further verification, to provide a more scientific basis for the safety and effectiveness of arotinolol in the clinical treatment of heart failure.
SYSTEMATIC REVIEW REGISTRATION
[https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=371214], identifier [CRD:420223371214].
PubMed: 36588575
DOI: 10.3389/fcvm.2022.1071387 -
Frontiers in Immunology 2022The diversity of three hypervariable loops in antibody heavy chain and light chain, termed the complementarity-determining regions (CDRs), defines antibody's binding...
The diversity of three hypervariable loops in antibody heavy chain and light chain, termed the complementarity-determining regions (CDRs), defines antibody's binding affinity and specificity owing to the direct contact between the CDRs and antigens. These CDR regions typically contain tyrosine (Tyr) residues that are known to engage in both nonpolar and pi stacking interaction with antigens through their complementary aromatic ring side chains. Nearly two decades ago, sulfotyrosine residue (sTyr), a negatively charged Tyr formed by Golgi-localized membrane-bound tyrosylprotein sulfotransferases during protein trafficking, were also found in the CDR regions and shown to play an important role in modulating antibody-antigen interaction. This breakthrough finding demonstrated that antibody repertoire could be further diversified through post-translational modifications, in addition to the conventional genetic recombination. This review article summarizes the current advances in the understanding of the Tyr-sulfation modification mechanism and its application in potentiating protein-protein interaction for antibody engineering and production. Challenges and opportunities are also discussed.
Topics: Complementarity Determining Regions; Immunoglobulin Heavy Chains; Antigens; Golgi Apparatus; Tyrosine
PubMed: 36569848
DOI: 10.3389/fimmu.2022.1072702 -
BMC Genomics Dec 2022Modern human brains and skull shapes differ from other hominids. Brain growth disorders as micro- (ASPM, MCPH1) and macrocephaly (NFIX, GLI3) have been highlighted as...
BACKGROUND
Modern human brains and skull shapes differ from other hominids. Brain growth disorders as micro- (ASPM, MCPH1) and macrocephaly (NFIX, GLI3) have been highlighted as relevant for the evolution in humans due to the impact in early brain development. Genes associated with macrocephaly have been reported to cause this change, for example NSD1 which causes Sotos syndrome.
RESULTS
In this study we performed a systematic literature review, located the reported variants associated to Sotos syndrome along the gene domains, compared the sequences with close primates, calculated their similarity, Ka/Ks ratios, nucleotide diversity and selection, and analyzed the sequence and structural conservation with distant primates. We aimed to understand if NSD1 in humans differs from other primates since the evolution of NSD1 has not been analyzed in primates, nor if the localization of the mutations is limited to humans. Our study found that most variations causing Sotos syndrome are in exon 19, 22 and 10. In the primate comparison we did not detect Ka/Ks ratios > 1, but a high nucleotide diversity with non-synonymous variations in exons 10, 5, 9, 11 and 23, and sites under episodic selection in exon 5 and 23, and human, macaque/colobus/tarsier/galago and tarsier/lemur/colobus. Most of the domains are conserved in distant primates with a particular progressive development from a simple PWWP1 in O. garnetti to a complex structure in Human.
CONCLUSION
NSD1 is a chromatin modifier that suggests that the selection could influence brain development during modern human evolution and is not present in other primates; however, nowadays the nucleotide diversity is associated with Sotos syndrome.
Topics: Humans; Animals; Sotos Syndrome; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Tarsiidae; Colobus; Nuclear Proteins; Mutation; Exons; Hominidae; Megalencephaly; Nucleotides; Cytoskeletal Proteins; Cell Cycle Proteins
PubMed: 36550402
DOI: 10.1186/s12864-022-09071-w -
BMC Medical Genomics Dec 2022The incidence of hereditary spherocytosis (HS) is approximately 1:2000 in the western population, while it is much lower in the Chinese population. It is difficult to...
BACKGROUND
The incidence of hereditary spherocytosis (HS) is approximately 1:2000 in the western population, while it is much lower in the Chinese population. It is difficult to make a definite diagnosis due to the variable genotypic features and the lack of well-documented evidence for HS patients. Gene sequence examination is helpful for clear diagnosis.
CASE PRESENTATION
We presented the case of a 29-year-old male HS patient with skin yellowness, anorexia, and cholecystolithiasis as the first manifestations. Laboratory examination of the patient and his parents showed a mild reduction in hemoglobin and mean corpuscular hemoglobin concentration, increased reticulocytes, and promotion of indirect bilirubin in the patient and his father. Furthermore, small globular red blood cells with increased osmotic fragility were observed. In particular, the eosin-5'-maleimide binding test provided the strong evidence that band 3 protein was deleted in the erythrocyte membrane. Next-generation sequencing (NGS) and Sanger sequencing further demonstrated a heterozygous nonsense variant (exon16, c.G1985A: p.W662X) in SLC4A1, inherited from his father. Thus, the patient was diagnosed with HS, and then was effectively treated. After splenectomy, the anemia was relieved without any obvious unpleasant side effects.
CONCLUSION
We report an extremely rare case of HS in China that presented with hereditary hemolytic anemia with band 3 deletion resulting from a novel variant of SLC4A1, and systematically review a large number of related literatures. This study, therefore, significantly contributes to the literature on HS.
Topics: Adult; Humans; Male; Anion Exchange Protein 1, Erythrocyte; Asian People; Erythrocytes; Genotype; Heterozygote; Spherocytosis, Hereditary
PubMed: 36463227
DOI: 10.1186/s12920-022-01399-2 -
International Journal of Molecular... Oct 2022Adult skeletal muscle fibres are classified as type 1, 2A, 2X, and 2B. These classifications are based on the expression of the dominant myosin heavy chain isoform.... (Review)
Review
Adult skeletal muscle fibres are classified as type 1, 2A, 2X, and 2B. These classifications are based on the expression of the dominant myosin heavy chain isoform. Muscle fibre-specific gene expression and proportions of muscle fibre types change during development and in response to exercise, chronic electrical stimulation, or inactivity. To identify genes whose gain or loss-of-function alters type 1, 2A, 2X, or 2B muscle fibre proportions in mice, we conducted a systematic review of transgenic mouse studies. The systematic review was conducted in accordance with the 2009 PRISMA guidelines and the PICO framework. We identified 25 "muscle fibre genes" (, , , , , , , , , , , , , , , , , , , , , , , and ) whose gain or loss-of-function significantly changes type 1, 2A, 2X or 2B muscle fibre proportions in mice. The fact that 15 of the 25 muscle fibre genes are transcriptional regulators suggests that muscle fibre-specific gene expression is primarily regulated transcriptionally. A reanalysis of existing datasets revealed that the expression of and increases and decreases after exercise, respectively. This suggests that these genes help to regulate the muscle fibre adaptation to exercise. Finally, there are many known DNA sequence variants of muscle fibre genes. It seems likely that such DNA sequence variants contribute to the large variation of muscle fibre type proportions in the human population.
Topics: Adult; Mice; Animals; Humans; Muscle Fibers, Skeletal; Myosin Heavy Chains; Protein Isoforms; Electric Stimulation; Muscle, Skeletal; RNA-Binding Proteins; Forkhead Transcription Factors; Nuclear Receptor Co-Repressor 1
PubMed: 36361732
DOI: 10.3390/ijms232112933 -
International Journal of Molecular... Oct 2022Dapsone (DDS), Rifampicin (RIF) and Ofloxacin (OFL) are drugs recommended by the World Health Organization (WHO) for the treatment of leprosy. In the context of leprosy,... (Meta-Analysis)
Meta-Analysis Review
Dapsone (DDS), Rifampicin (RIF) and Ofloxacin (OFL) are drugs recommended by the World Health Organization (WHO) for the treatment of leprosy. In the context of leprosy, resistance to these drugs occurs mainly due to mutations in the target genes (Folp1, RpoB and GyrA). It is important to monitor antimicrobial resistance in patients with leprosy. Therefore, we performed a meta-analysis of drug resistance in Mycobacterium leprae and the mutational profile of the target genes. In this paper, we limited the study period to May 2022 and searched PubMed, Web of Science (WOS), Scopus, and Embase databases for identified studies. Two independent reviewers extracted the study data. Mutation and drug-resistance rates were estimated in Stata 16.0. The results demonstrated that the drug-resistance rate was 10.18% (95% CI: 7.85-12.51). Subgroup analysis showed the highest resistance rate was in the Western Pacific region (17.05%, 95% CI:1.80 to 13.78), and it was higher after 2009 than before [(11.39%, 7.46-15.33) vs. 6.59% (3.66-9.53)]. We can conclude that the rate among new cases (7.25%, 95% CI: 4.65-9.84) was lower than the relapsed (14.26%, 95 CI%: 9.82-18.71). Mutation rates of Folp1, RpoB and GyrA were 4.40% (95% CI: 3.02-5.77), 3.66% (95% CI: 2.41-4.90) and 1.28% (95% CI: 0.87-1.71) respectively, while the rate for polygenes mutation was 1.73% (0.83-2.63). For further analysis, we used 368 drug-resistant strains as research subjects and found that codons (Ser, Pro, Ala) on RpoB, Folp1 and GyrA are the most common mutation sites in the determining region (DRDR). In addition, the most common substitution patterns of Folp1, RpoB, and GyrA are Pro→Leu, Ser→Leu, and Ala→Val. This study found that a higher proportion of patients has developed resistance to these drugs, and the rate has increased since 2009, which continue to pose a challenge to clinicians. In addition, the amino acid alterations in the sequence of the DRDR regions and the substitution patterns mentioned in the study also provide new ideas for clinical treatment options.
Topics: Humans; Rifampin; Dapsone; Leprostatic Agents; Ofloxacin; Drug Resistance, Bacterial; Mycobacterium leprae; Leprosy; Mutation; Amino Acids; Microbial Sensitivity Tests
PubMed: 36293307
DOI: 10.3390/ijms232012443 -
European Journal of Cancer (Oxford,... Nov 2022Grading and classification of IDH-mutant astrocytomas has shifted from solely histology towards histology combined with molecular diagnostics. In this systematic review,... (Review)
Review
BACKGROUND
Grading and classification of IDH-mutant astrocytomas has shifted from solely histology towards histology combined with molecular diagnostics. In this systematic review, we give an overview of all currently known clinically relevant molecular markers within IDH-mutant astrocytomas grade 2 to 4.
METHODS
A literature search was performed in five electronic databases for English original papers on patient outcome with respect to a molecular marker as determined by DNA/RNA sequencing, micro-arrays, or DNA methylation profiling in IDH-mutant astrocytomas grade 2 to 4. Papers were included if molecular diagnostics were performed on tumour tissue of at least 15 IDH-mutant astrocytoma patients, and if the investigated molecular markers were not limited to the diagnostic markers MGMT, ATRX, TERT, and/or TP53.
RESULTS
The literature search identified 4508 unique articles, published between August 2012 and December 2021, of which ultimately 44 articles were included. Numerous molecular markers from these papers were significantly correlated to patient outcome. The associations between patient outcome and non-canonical IDH mutations, PI3K mutations, high expression of MSH2, high expression of RAD18, homozygous deletion of CDKN2A/B, amplification of PDGFRA, copy number neutral loss of chromosomal arm 17p, loss of chromosomal arm 19q, the G-CIMP-low DNA methylation cluster, high total CNV, and high tumour mutation burden were confirmed in multiple studies.
CONCLUSIONS
Multiple genetic and epigenetic markers are associated with survival in IDH-mutant astrocytoma patients. Commonly affected are the RB signalling pathway, the RTK-PI3K-mTOR signalling pathway, genomic stability markers, and (epigenetic) gene regulation.
Topics: Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; DNA; DNA-Binding Proteins; Homozygote; Humans; Isocitrate Dehydrogenase; Lymphoma, Follicular; MutS Homolog 2 Protein; Mutation; Phosphatidylinositol 3-Kinases; Sequence Deletion; TOR Serine-Threonine Kinases; Ubiquitin-Protein Ligases
PubMed: 36152406
DOI: 10.1016/j.ejca.2022.08.016 -
Cancers Sep 2022Deregulation of conventional protein kinases is associated with the growth and development of cancer cells. Alpha-kinase 1 (ALPK1) belongs to a newly discovered family... (Review)
Review
BACKGROUND
Deregulation of conventional protein kinases is associated with the growth and development of cancer cells. Alpha-kinase 1 (ALPK1) belongs to a newly discovered family of serine/threonine protein kinases with no sequence homology to conventional protein kinases, and its function in cancer is poorly understood.
METHODS
In this systematic review, we searched for and analyzed studies linking ALPK1 to cancer development and progression.
RESULTS
Based on the current evidence obtained using human, animal, cellular, and tissue models, ALPK1 is located upstream and triggers cancer cell development and metastasis by regulating the inflammatory response through phosphorylation. Its mRNA and protein levels were found to correlate with advanced tumor size and lymph node metastasis, which occur from the cellular cytoplasm into the nucleus. ALPK1 is also strongly associated with gout, chronic kidney disease, and diabetes, which are considered as inflammatory diseases and associated with cancer.
CONCLUSION
ALPK1 is an oncogene involved in carcinogenesis. Chronic inflammation is the common regulatory mechanism between cancer and these diseases. Future research should focus on identifying inhibitors of serine/threonine and ALPK1 at their phosphorylation sites, which would block various signal transductions and potentially offer kinase-targeted therapeutic agents for patients with cancer and inflammatory diseases.
PubMed: 36139553
DOI: 10.3390/cancers14184390