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Pharmacogenomics and Personalized... 2022In neonates, pharmacogenetics has an additional layer of complexity. This is because in addition to genetic variability in genes that code for proteins relevant to... (Review)
Review
In neonates, pharmacogenetics has an additional layer of complexity. This is because in addition to genetic variability in genes that code for proteins relevant to clinical pharmacology, there are rapidly maturational changes in these proteins. Consequently, pharmacotherapy in neonates has unique challenges. To provide a contemporary overview on pharmacogenetics in neonates, we conducted a systematic review to identify, describe and quantify the impact of pharmacogenetics on pharmacokinetics and -dynamics in neonates and infants (PROSPERO, CRD42022302029). The search was performed in Medline, Embase, Web of Science and Cochrane, and was extended by a PubMed search on the 'top 100 Medicines' (medicine + newborn/infant + pharmacogen*) prescribed to neonates. Following study selection (including data in infants, PGx related) and quality assessment (Newcastle-Ottawa scale, Joanna Briggs Institute tool), 55/789 records were retained. Retained records relate to metabolizing enzymes involved in phase I [cytochrome P450 (CYP1A2, CYP2A6, CYP2B6, CYP2C8/C9/C18, CYP2C19, CYP2D6, CYP3A5, CYP2E1)], phase II [glutathione-S-transferases, N-acetyl transferases, UDP-glucuronosyl-transferase], transporters [ATP-binding cassette transporters, organic cation transporters], or receptor/post-receptor mechanisms [opioid related receptor and post-receptor mechanisms, tumor necrosis factor, mitogen-activated protein kinase 8, vitamin binding protein diplotypes, corticotrophin-releasing hormone receptor-1, nuclear receptor subfamily-1, vitamin K epoxide reductase complex-1, and angiotensin converting enzyme variants]. Based on the available overview, we conclude that the majority of reported pharmacogenetic studies explore and extrapolate observations already described in older populations. Researchers commonly try to quantify the impact of these polymorphisms in small datasets of neonates or infants. In a next step, pharmacogenetic studies in neonatal life should go beyond confirmation of these associations and explore the impact of pharmacogenetics as a covariate limited to maturation of neonatal life (ie, fetal malformations, breastfeeding or clinical syndromes). The challenge is to identify the specific factors, genetic and non-genetic, that contribute to the best benefit/risk balance.
PubMed: 35795337
DOI: 10.2147/PGPM.S350205 -
Frontiers in Pharmacology 2022Cellular differentiation is pivotal in health and disease. Interfering with the process of differentiation, such as inhibiting the differentiation of adipocytes and...
Cellular differentiation is pivotal in health and disease. Interfering with the process of differentiation, such as inhibiting the differentiation of adipocytes and inducing the differentiation of cancer cells, is considered a therapeutic approach. Sesquiterpene lactones, primarily found in plants, have been attracted attention as differentiating/dedifferentiating agents tested on various human or animal cells. However, a consensus on sesquiterpene lactones' effects and their mechanism of action is required. In this sense, through a systematic review, we have investigated the differentiating/dedifferentiating effects of sesquiterpene lactones on human or animal cells. 13 different cell lines originated from humans, mice, and rats, in addition to the effects of a total of 21 sesquiterpene lactones, were evaluated in the included studies. These components had either inducing, inhibiting, or no effect on the cells, mediating their effects through JAK-STAT, PI3K-Akt, mitogen-activated protein kinases, NFκB, PPARγ pathways. Although nearly all inducing and inhibiting effects were attributed to cancerous and normal cells, respectively, this is likely a result of a biased study design. Few studies reported negative results along with others, and no study was found reporting only negative results. As a result, not only are the effects and mechanism of action of sesquiterpene lactones not vivid but our knowledge and decisions are also misconducted. Moreover, there is a significant knowledge gap regarding the type of evaluated cells, other sesquiterpene lactones, and the involved signaling pathways. In conclusion, sesquiterpene lactones possess significant effects on differentiation status, leading to potentially efficient therapy of obesity, osteoporosis, and cancer. However, reporting negative results and further investigations on other cells, sesquiterpene lactones, and signaling pathways are highly suggested to pave the path of sesquiterpene lactones to the clinic more consciously.
PubMed: 35444549
DOI: 10.3389/fphar.2022.862446 -
PeerJ 2022Titanium dioxide dental implants have a controversial effect on reactive oxygen species (ROS) production. ROS is necessary for cellular signal transmission and proper... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Titanium dioxide dental implants have a controversial effect on reactive oxygen species (ROS) production. ROS is necessary for cellular signal transmission and proper metabolism, but also has the ability to cause cell death as well as DNA, RNA, and proteins damage by excessive oxidative stress. This study aimed to systematically review the effect of titanium dioxide dental implant-induced oxidative stress and its role on the osteogenesis-angiogenesis coupling in bone remodeling.
METHODS
This systematic review was performed conforming to preferred reporting items for systematic review and meta-analysis (PRISMA) model. Four different databases (PubMed, Science Direct, Scopus and Medline databases) as well as manual searching were adopted. Relevant studies from January 2000 till September 2021 were retrieved. Critical Appraisal Skills Programme (CASP) was used to assess the quality of the selected studies.
RESULTS
Out of 755 articles, only 14 which met the eligibility criteria were included. Six studies found that titanium dioxide nanotube (TNT) reduced oxidative stress and promoted osteoblastic activity through its effect on Wnt, mitogen-activated protein kinase (MAPK) and forkhead box protein O1 (FoxO1) signaling pathways. On the other hand, three studies confirmed that titanium dioxide nanoparticles (TiONPs) induce oxidative stress, reduce ostegenesis and impair antioxidant defense system as a significant negative correlation was found between decreased SIR3 protein level and increased superoxide (O ). Moreover, five studies proved that titanium implant alloy enhances the generation of ROS and induces cytotoxicity of osteoblast cells via its effect on NOX pathway.
CONCLUSION
TiONPs stimulate a wide array of oxidative stress related pathways. Scientific evidence are in favor to support the use of TiO nanotube-coated titanium implants to reduce oxidative stress and promote osteogenesis in bone remodeling. To validate the cellular and molecular cross talk in bone remodeling of the present review, well-controlled clinical trials with a large sample size are required.
Topics: Reactive Oxygen Species; Titanium; Dental Implants; Oxidative Stress; Bone Remodeling
PubMed: 35261818
DOI: 10.7717/peerj.12951 -
Oncology Letters Apr 2022Currently, standard treatment of patients with metastatic colorectal cancer (mCRC) comprises chemotherapy (CT) and/or biological therapy (BT) and/or best supportive care...
Currently, standard treatment of patients with metastatic colorectal cancer (mCRC) comprises chemotherapy (CT) and/or biological therapy (BT) and/or best supportive care (BSC). The present study performed a meta-analysis on five phase II-III randomized clinical trials, which compared CT/BT/BSC as the control arm with the immune checkpoint inhibitors (ICIs) anti-programmed cell death protein 1 (PD-1) or its ligand (PD-L1) alone or in combination with cytotoxic T lymphocyte antigen 4 or mitogen activated protein kinase kinase inhibitors as the experimental arm, to evaluate whether a standard approach could be overcome using the novel target therapy strategy. Pooled hazard ratio (HR) for progression-free survival was 0.95 in favor of the experimental arm [95% confidence interval (CI), 0.74-1.22; P=0.68]. Heterogeneity was significant: Cochran's Q, 21.0; P=0.0082; I index, 76%. Pooled HR for overall survival was 0.88 in favor of the experimental arm (95% CI, 0.75-1.02; P=0.08). Heterogeneity was not significant (Cochran's Q, 6.0; P=0.31; I index, 16%). The present meta-analysis demonstrated a trend toward the improvement of survival by PD-1/PD-L1 blockade in mCRC. Further homogeneous studies are necessary to strengthen these results, beyond the known benefits of ICIs in deficient mismatch repair/high microsatellite instability tumors.
PubMed: 35251353
DOI: 10.3892/ol.2022.13254 -
Molecular Syndromology Feb 2022Noonan syndrome spectrum disorders are a group of phenotypically related conditions, resembling Noonan syndrome, caused by germline pathogenic variants in genes within... (Review)
Review
Noonan syndrome spectrum disorders are a group of phenotypically related conditions, resembling Noonan syndrome, caused by germline pathogenic variants in genes within the Ras/mitogen-activated protein kinase (Ras/MAPK) signalling pathway. Lymphatic dysplasia with a clinical lymphatic abnormality is one of the major features. We performed a systematic review to get more insight in (1) the prevalence of clinically lymphatic abnormalities in patients with a genetically proven Noonan syndrome spectrum disorder, (2) if a genotype-lymphatic phenotype relation can be found and describe the clinical presentation and course of the lymphatic abnormality. Most studies report patients with Noonan syndrome. Prenatally, the prevalence of increased nuchal translucency differs from 7% in patients with pathogenic variant to 38% in patients with pathogenic variants, and the prevalence of pleural effusions differed from 7% in patients with pathogenic to 29% in patients with pathogenic variants. Postnatally, the prevalence of lymphedema differs from 16% in patients with pathogenic variants to 44% in patients with pathogenic variants, and the prevalence of acquired chylothorax is 4% in patients with pathogenic variants. Lymphatic abnormalities do occur in patients with cardiofaciocutaneous syndrome and Costello syndrome. In conclusion, Noonan syndrome spectrum disorders, Noonan syndrome in particular, are associated with lymphatic abnormalities. Combining the available published literature about genetically proven Noonan syndrome spectrum disorders, it appears likely that the lifetime prevalence of these abnormalities in Noonan syndrome is higher than the 20% that were generally accepted so far. This is increasingly important, because the activation of the RAS/MAPK pathway can be inhibited by RAS/MAPK inhibitors, and clinically severe lymphatic abnormalities may improve.
PubMed: 35221870
DOI: 10.1159/000517605 -
Frontiers in Bioscience (Landmark... Jan 2022p38 MAPK (mitogen-activated protein kinases) family proteins (α, β, γ and δ) are key inflammatory kinases and play an important role in relaying and processing...
p38 MAPK (mitogen-activated protein kinases) family proteins (α, β, γ and δ) are key inflammatory kinases and play an important role in relaying and processing intrinsic and extrinsic signals in response to inflammation, stress, and oncogene to regulate cell growth, cell death and cell transformation. Recent studies in genetic mouse models revealed that p38α in epithelial cells mostly suppresses whereas in immune cells it promotes inflammation and inflammation-associated oncogenesis. On the contrary, p38γ and p38δ signaling in immune and epithelial cells is both pro-inflammatory and oncogenic. This review summarizes recent discoveries in this field, discusses possible associated mechanisms, and highlights potentials of systemically targeting isoform-specific p38 MAPKs. Understanding of p38 MAPK isoform-specific and cell/tissue- and perhaps stage-dependent effects and their integrated regulated activity in inflammation and in inflammation-associated oncogenesis is essential for effectively targeting this group of kinases for therapeutic intervention.
Topics: Animals; Carcinogenesis; Inflammation; Mice; Mitogen-Activated Protein Kinases; Protein Isoforms; p38 Mitogen-Activated Protein Kinases
PubMed: 35090336
DOI: 10.31083/j.fbl2701031 -
Journal of Diabetes Investigation Mar 2022Type 2 diabetes is known as a risk factor for pancreatic cancer (PC). Various genetic and environmental factors cause both these global chronic diseases. The mechanisms... (Review)
Review
Type 2 diabetes is known as a risk factor for pancreatic cancer (PC). Various genetic and environmental factors cause both these global chronic diseases. The mechanisms that define their relationships are complex and poorly understood. Recent studies have implicated that metabolic abnormalities, including hyperglycemia and hyperinsulinemia, could lead to cell damage responses, cell transformation, and increased cancer risk. Hence, these kinds of abnormalities following molecular events could be essential to develop our understanding of this complicated link. Among different molecular events, focusing on shared signaling pathways including metabolic (PI3K/Akt/mTOR) and mitogenic (MAPK) pathways in addition to regulatory mechanisms of gene expression such as those involved in non-coding RNAs (miRNAs, circRNAs, and lncRNAs) could be considered as powerful tools to describe this association. A better understanding of the molecular mechanisms involved in the development of type 2 diabetes and pancreatic cancer would help us to find a new research area for developing therapeutic and preventive strategies. For this purpose, in this review, we focused on the shared molecular events resulting in type 2 diabetes and pancreatic cancer. First, a comprehensive literature review was performed to determine similar molecular pathways and non-coding RNAs; then, the final results were discussed in more detail.
Topics: Animals; Diabetes Mellitus, Type 2; Humans; MAP Kinase Signaling System; MicroRNAs; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; RNA, Long Noncoding; TOR Serine-Threonine Kinases
PubMed: 34859606
DOI: 10.1111/jdi.13727 -
European Psychiatry : the Journal of... Nov 2021Mental disorders in comorbidity with chronic skin diseases may worsen disease outcome and patients' quality of life. We hypothesized the comorbidity of depression,...
BACKGROUND
Mental disorders in comorbidity with chronic skin diseases may worsen disease outcome and patients' quality of life. We hypothesized the comorbidity of depression, anxiety syndromes, or symptoms as attributable to biological mechanisms that the combined diseases share.
METHODS
We conducted a systematic review based on the Preferred Reporting Items for Systematic Review and Meta-Analysis statement searching into PubMed, PsycInfo, and Scopus databases. We examined the literature regarding the comorbidity of psoriasis (Ps), atopic dermatitis (AD), or hidradenitis suppurativa with depression and/or anxiety in adults ≥18 years and the hypothetical shared underlying biological mechanisms.
RESULTS
Sixteen studies were analyzed, mostly regarding Ps and AD. Brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling and nuclear factor kappa-light-chain-enhancer of activated B cells/p38 mitogen-activated protein kinase pathways arose as shared mechanisms in Ps animal models with depression- and/or anxiety-like behaviors. Activated microglia and neuroinflammatory responses emerged in AD depressive models. As to genetic studies, atopic-dermatitis patients with comorbid anxiety traits carried the short variant of serotonin transporter and a polymorphism of the human translocator protein gene. A GA genotype of catechol-O-methyltransferase gene was instead associated with Ps. Reduced natural killer cell activity, IL-4, serotonin serum levels, and increased plasma cortisol and IgE levels were hypothesized in comorbid depressive AD patients. In Ps patients with comorbid depression, high serum concentrations of IL-6 and IL-18, as well as IL-17A, were presumed to act as shared inflammatory mechanisms.
CONCLUSIONS
Further studies should investigate mental disorders and chronic skin diseases concurrently across patients' life course and identify their temporal relation and biological correlates. Future research should also identify biological characteristics of individuals at high risk of the comorbid disorders and associated complications.
Topics: Animals; Anxiety; Catechol O-Methyltransferase; Comorbidity; Depression; Dermatitis, Atopic; Hidradenitis Suppurativa; Humans; Psoriasis; Quality of Life
PubMed: 34819201
DOI: 10.1192/j.eurpsy.2021.2249 -
Journal of Cutaneous and Aesthetic... 2021Epidermal Growth Factor (rhEGF) is a promising skin antiaging agent that successfully promotes skin wound repair, and it has been investigated in the past decade for... (Review)
Review
INTRODUCTION
Epidermal Growth Factor (rhEGF) is a promising skin antiaging agent that successfully promotes skin wound repair, and it has been investigated in the past decade for these purposes. However, there are no updated systematic reviews, in English or English, that support the efficacy of rhEGF as a regenerative skin treatment or systematic reviews that compile the uses of rhEGF as facial aesthetic therapy and regenerative medicine.
AIM
To describe the current state of facial aesthetic and regenerative medicine treatments in which rhEGF has been effectively used.
MATERIALS AND METHODS
An exhaustive search was carried out in "Medline" (via "PubMed"), "Cochrane," "Bireme" through the Virtual Health Library (VHL), "Elsevier" via "Science Direct," "Springer," "SciELo," "ResearchGate," and Google Scholar. Studies related to the use of rhEGF in addressing skin disorders or skin aging are included.
RESULTS
Overall, 49 articles were found, which described the use of rhEGF for skin regeneration and restructuring. Efficacy in the regeneration of skin wounds was verified through the intradermal and topical application of formulations with rhEGF. Most clinical trials in aesthetics point to an effective inversion of skin aging. However, uncontrolled or randomized trials abound, so that does not represent enough evidence to establish its efficiency. There are transient adverse effects for both cases.
CONCLUSION
The rhEGF considers an effective therapeutic alternative for patients with recalcitrant skin wounds and skin aging, as it is a potent and specific mitogenic factor for the skin.
PubMed: 34566354
DOI: 10.4103/JCAS.JCAS_25_20 -
Journal of Carcinogenesis 2021Preclinical studies and clinical trials have emphasized the decisive role of lipid metabolism in tumor proliferation and metastasis. This systematic review aimed to... (Review)
Review
Preclinical studies and clinical trials have emphasized the decisive role of lipid metabolism in tumor proliferation and metastasis. This systematic review aimed to explore the existing literature to evaluate the role and significance of the genes and pathways most commonly involved in the regulation of lipid metabolism in cancer. The literature search was performed as per Preferred Reporting Items for Systematic Reviews and Meta-analyses. Approximately 2396 research articles were initially selected, of which 215 were identified as potentially relevant for abstract review. Upon further scrutiny, 62 of the 215 studies were reviews, seminars, or presentations, and 44 were original study articles and were thus included in the systematic review. The predominant gene involved in lipid metabolism in cancer was stearoyl-coenzyme A desaturase 1 (SCD1), followed by fatty acid synthase (FASN). The pathway most commonly involved in lipid metabolism in cancer was the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, followed by the mitogen activated protein kinase (MAPK) pathway. SCD1 and FASN play significant roles in the initiation and progression of cancer and represent attractive targets for potentially effective anti-cancer treatment strategies. The regulation of cancer metabolism by the Akt kinases will be an interesting topic of future study.
PubMed: 34321955
DOI: 10.4103/jcar.JCar_15_20