Hypoxia-Inducible Factors and Burn-Associated Acute Kidney Injury-A New Paradigm?

O2 deprivation induces stress in living cells linked to free-radical accumulation and oxidative stress (OS) development. Hypoxia is established when the overall oxygen pressure is less than 40 mmHg in cells or tissues. However, tissues and cells have different degrees of hypoxia. Hypoxia or low O2 tension may be present in both physiological (during embryonic development) and pathological circumstances (ischemia, wound healing, and cancer). Meanwhile, the kidneys are major energy-consuming organs, being second only to the heart, with an increased mitochondrial content and O2 consumption. Furthermore, hypoxia-inducible factors (HIFs) are the key players that orchestrate the mammalian response to hypoxia. HIFs adapt cells to low oxygen concentrations by regulating transcriptional programs involved in erythropoiesis, angiogenesis, and metabolism. On the other hand, one of the life-threatening complications of severe burns is acute kidney injury (AKI). The dreaded functional consequence of AKI is an acute decline in renal function. Taking all these aspects into consideration, the aim of this review is to describe the role and underline the importance of HIFs in the development of AKI in patients with severe burns, because kidney hypoxia is constant in the presence of severe burns, and HIFs are major players in the adaptative response of all tissues to hypoxia.

Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects.

Although pancreatic cancer (PC) was considered in the past an orphan cancer type due to its low incidence, it may become in the future one of the leading causes of cancer death. Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of PC, being a highly aggressive malignancy and having a 5-year survival rate of less than 10%. Non-modifiable (family history, age, genetic susceptibility) and modifiable (smoking, alcohol, acute and chronic pancreatitis, diabetes mellitus, intestinal microbiota) risk factors are involved in PC pathogenesis. Chronic inflammation induced by various factors plays crucial roles in PC development from initiation to metastasis. In multiple malignant conditions such as PC, cytokines, chemokines, and growth factors activate the class I phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) (PI3K/AKT/mTOR) signaling pathway, which plays key roles in cell growth, survival, proliferation, metabolism, and motility. Currently, mTOR, AKT, and PI3K inhibitors are used in clinical studies. Moreover, PI3K/mTOR dual inhibitors are being tested in vitro and in vivo with promising results for PC patients. The main aim of this review is to present PC incidence, risk factors, tumor microenvironment development, and PI3K/AKT/mTOR dysregulation and inhibitors used in clinical, in vivo, and in vitro studies.

Growth Factors, Reactive Oxygen Species, and Metformin-Promoters of the Wound Healing Process in Burns?

Burns can be caused by various factors and have an increased risk of infection that can seriously delay the wound healing process. Chronic wounds caused by burns represent a major health problem. Wound healing is a complex process, orchestrated by cytokines, growth factors, prostaglandins, free radicals, clotting factors, and nitric oxide. Growth factors released during this process are involved in cell growth, proliferation, migration, and differentiation. Reactive oxygen species are released in acute and chronic burn injuries and play key roles in healing and regeneration. The main aim of this review is to present the roles of growth factors, reactive oxygen species, and metformin in the healing process of burn injuries.

Drugs Interfering with Insulin Resistance and Their Influence on the Associated Hypermetabolic State in Severe Burns: A Narrative Review.

It has become widely accepted that insulin resistance and glucose hypermetabolism can be linked to acute pathologies, such as burn injury, severe trauma, or sepsis. Severe burns can determine a significant increase in catabolism, having an important effect on glucose metabolism and on muscle protein metabolism. It is imperative to acknowledge that these alterations can lead to increased mortality through organ failure, even when the patients survive the initial trauma caused by the burn. By limiting the peripheral use of glucose with consequent hyperglycemia, insulin resistance determines compensatory increased levels of insulin in plasma. However, the significant alterations in cellular metabolism lead to a lack of response to insulin's anabolic functions, as well as to a decrease in its cytoprotective role. In the end, via pathological insulin signaling associated with increased liver gluconeogenesis, elevated levels of glucose are detected in the blood. Several cellular mechanisms have been incriminated in the development of insulin resistance in burns. In this context, the main aim of this review article is to summarize some of the drugs that might interfere with insulin resistance in burns, taking into consideration that such an approach can significantly improve the prognosis of the burned patient.

Glucose Metabolism in Burns-What Happens?

Severe burns represent an important challenge for patients and medical teams. They lead to profound metabolic alterations, trigger a systemic inflammatory response, crush the immune defense, impair the function of the heart, lungs, kidneys, liver, etc. The metabolism is shifted towards a hypermetabolic state, and this situation might persist for years after the burn, having deleterious consequences for the patient's health. Severely burned patients lack energy substrates and react in order to produce and maintain augmented levels of glucose, which is the fuel "ready to use" by cells. In this paper, we discuss biological substances that induce a hyperglycemic response, concur to insulin resistance, and determine cell disturbance after a severe burn. We also focus on the most effective agents that provide pharmacological modulations of the changes in glucose metabolism.

Growth Factors, PI3K/AKT/mTOR and MAPK Signaling Pathways in Colorectal Cancer Pathogenesis: Where Are We Now?

Colorectal cancer (CRC) is a predominant malignancy worldwide, being the fourth most common cause of mortality and morbidity. The CRC incidence in adolescents, young adults, and adult populations is increasing every year. In the pathogenesis of CRC, various factors are involved including diet, sedentary life, smoking, excessive alcohol consumption, obesity, gut microbiota, diabetes, and genetic mutations. The CRC tumor microenvironment (TME) involves the complex cooperation between tumoral cells with stroma, immune, and endothelial cells. Cytokines and several growth factors (GFs) will sustain CRC cell proliferation, survival, motility, and invasion. Epidermal growth factor receptor (EGFR), Insulin-like growth factor -1 receptor (IGF-1R), and Vascular Endothelial Growth Factor -A (VEGF-A) are overexpressed in various human cancers including CRC. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and all the three major subfamilies of the mitogen-activated protein kinase (MAPK) signaling pathways may be activated by GFs and will further play key roles in CRC development. The main aim of this review is to present the CRC incidence, risk factors, pathogenesis, and the impact of GFs during its development. Moreover, the article describes the relationship between EGF, IGF, VEGF, GFs inhibitors, PI3K/AKT/mTOR-MAPK signaling pathways, and CRC.

ILs and MMPs Levels in Inflamed Human Dental Pulp: A Systematic Review.

A wide range of mediators are released from the pulp tissue because of bacterial invasion which causes inflammation. Interleukins (ILs) and matrix metalloproteinases (MMPs) have a leading role in initiating and spreading of inflammation because of their synergic action. Biomarkers such as ILs and MMPs can be identified via several methods, establishing the inflammatory response of the dental pulp. The aim of this systematic review is to evaluate the levels of ILs and/or MMPs in human dental pulp. PubMed, OVID, Cochrane, Scopus, Web of Science and Wiley online library databases were searched for original clinical studies. After applying inclusion and exclusion criteria, a quality assessment of studies was performed based on a modified Newcastle-Ottawa scale. In the review were included articles that evaluated the presence of ILs and/or MMPs in pulp tissue using enzyme-linked immunosorbent assay (ELISA) or western blot or multiplex assay. Six articles were included in the present synthesis. Although various diagnostic methods were used, statistically significant higher levels of ILs and/or MMPs were mostly found in the experimental groups compared to healthy pulp samples. The biomarkers studied can be a promising tool to evaluate pulp tissue health or even in pulpitis treatment.

PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects.

Breast cancer is a serious health problem worldwide, representing the second cause of death through malignancies among women in developed countries. Population, endogenous and exogenous hormones, and physiological, genetic and breast-related factors are involved in breast cancer pathogenesis. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is a signaling pathway involved in cell proliferation, survival, invasion, migration, apoptosis, glucose metabolism and DNA repair. In breast tumors, PIK3CA somatic mutations have been reported, located in exon 9 and exon 20. Up to 40% of PIK3CA mutations are estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) -negative in primary and metastatic breast cancer. HER2 is overexpressed in 20-30% of breast cancers. HER1, HER2, HER3 and HER4 are membrane receptor tyrosine kinases involved in HER signaling to which various ligands can be attached, leading to PI3K/AKT activation. Currently, clinical studies evaluate inhibitors of the PI3K/AKT/mTOR axis. The main purpose of this review is to present general aspects of breast cancer, the components of the AKT signaling pathway, the factors that activate this protein kinase B, PI3K/AKT-breast cancer mutations, PI3K/AKT/mTOR-inhibitors, and the relationship between everolimus, temsirolimus and endocrine therapy.

Autophagy, One of the Main Steps in Periodontitis Pathogenesis and Evolution.

Periodontitis represents a complex inflammatory disease that compromises the integrity of the tooth-supporting tissue through the interaction of specific periodontal pathogens and the host's immune system. Experimental data help to outline the idea that the molecular way towards periodontitis initiation and progression presents four key steps: bacterial infection, inflammation, oxidative stress, and autophagy. The aim of this review is to outline the autophagy involvement in the pathogenesis and evolution of periodontitis from at least three points of view: periodontal pathogen invasion control, innate immune signaling pathways regulation and apoptosis inhibition in periodontal cells. The exact roles played by reactive oxygen species (ROS) inside the molecular mechanisms for autophagy initiation in periodontitis still require further investigation. However, clarifying the role and the mechanism of redox regulation of autophagy in the periodontitis context may be particularly beneficial for the elaboration of new therapeutic strategies.

Organic Nanomaterials and Their Applications in the Treatment of Oral Diseases.

There is a growing interest in the development of organic nanomaterials for biomedical applications. An increasing number of studies focus on the uses of nanomaterials with organic structure for regeneration of bone, cartilage, skin or dental tissues. Solid evidence has been found for several advantages of using natural or synthetic organic nanostructures in a wide variety of dental fields, from implantology, endodontics, and periodontics, to regenerative dentistry and wound healing. Most of the research is concentrated on nanoforms of chitosan, silk fibroin, synthetic polymers or their combinations, but new nanocomposites are constantly being developed. The present work reviews in detail current research on organic nanoparticles and their potential applications in the dental field.

Salivary biomarkers: relationship between oxidative stress and alveolar bone loss in chronic periodontitis.

OBJECTIVES: Oxidative stress is implicated in the pathogenesis of many systemic and oral diseases such as periodontal disease. The main aim of this study is to explore a possible association between salivary markers of OS and alveolar bone loss. MATERIALS AND METHODS: The study included 20 patients with chronic periodontitis and 20 controls. Salivary OS biomarkers 8-hidroxy-desoxguanosine (8-HOdG), malondialdehyde (MDA), uric acid, total antioxidant capacity (TAC) and glutathione peroxidase (GPx) were evaluated. Bone loss markers such as C-terminal telopeptide of type I collagen (CTX I), matrix metalloproteinases-8 (MMP-8), osteocalcin and 25-hydroxy vitamin D3 (25- OH D) were detected in this study. The methods included general biochemical tests and ELISA. RESULTS: Salivary 8-OHdG, MDA levels were significantly higher in the chronic periodontitis group compared with controls (p < 0.05). Salivary activities for uric acid, TAC and GPx were significantly decreased in patients with chronic periodontitis vs controls (p < 0.05). Salivary levels for CTX I, MMP-8, 25-OH D and Osteocalcin were significantly higher in the chronic periodontitis group compared to the controls (p < 0.05). A significant positive correlation was observed between salivary levels of MDA and CTX I. Significant negative correlations between uric acid and CTX I and between MMP-8 and uric acid have been found. Significant positive correlations were observed between CTX I, MMP-8, 25-OH D, osteocalcin and clinical parameters of periodontal disease. CONCLUSIONS: Important oxidative stress associated with alveolar bone loss biomarkers can be detected in saliva of patients with periodontal disease.

A STEPwise Approach for Oral Hygiene Behavior of Schoolchildren in Romania.

This research analyzes the dental hygiene habits of schoolchildren from parents' perspectives, using the STEPS approach recommended by the World Health Organization. The key points of oral health care in children include the role of the family in encouraging and maintaining proper oral hygiene practices. This study aimed to assess the oral hygiene practices of schoolchildren with on-site dentists in Romania. Additionally, it sought to establish correlations between these behaviors and the educational levels of the adults with whom they live with. The participants were selected from the zero grade to the eighth grade, totaling 3843students. Statistical analysis involved the application of Fisher's Exact Test and Z-tests with Bonferroni correction. Multinominal and binominal logistic regression models were employed to predict the impact of parents' education on children's oral health status and behavior. The oral health status of children evaluated by parents as poor was more frequent in children whose parents had a primary or gymnasium education (p < 0.001). Female adults with a university education evaluated the gum health of their children as very good to a much greater extent (41.7%, p < 0.001). Regarding the use of auxiliary means, the majority of parents with a university education mentioned that their children use dental floss (26.4% females/27.4% males) (p < 0.001), compared to those with primary education, where the percentage was only (1.2% males/3.5% females) (p < 0.001). The results of this study highlight that the education level of the adults with whom the children live with influences the perception of the teeth and gums health status, the frequency of oral hygiene, the use of fluoride toothpaste, and auxiliary brushing aids.

Analysis of Gingival Fibroblasts Behaviour in the Presence of 3D-Printed versus Milled Methacrylate-Based Dental Resins-Do We Have a Winner?

Computer-aided design and computer-aided manufacturing (CAD/CAM) techniques are based on either subtractive (milling prefabricated blocks) or additive (3D printing) methods, and both are used for obtaining dentistry materials. Our in vitro study aimed to investigate the behavior of human gingival fibroblasts exposed to methacrylate (MA)-based CAD/CAM milled samples in comparison with that of MA-based 3D-printed samples to better elucidate the mechanisms of cell adaptability and survival. The proliferation of human gingival fibroblasts was measured after 2 and 24 h of incubation in the presence of these samples using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and the membrane integrity was assessed through the lactate dehydrogenase release. The level of reactive oxygen species, expression of autophagy-related protein LC3B-I, and detection of GSH and caspase 3/7 were evaluated by fluorescence staining. The MMP-2 levels were measured using a Milliplex MAP kit. The incubation with MA-based 3D-printed samples significantly reduced the viability, by 16% and 28% from control after 2 and 24 h, respectively. There was a 25% and 55% decrease in the GSH level from control after 24 h of incubation with the CAD/CAM milled and 3D-printed samples, respectively. In addition, higher levels of LC3B-I and MMP-2 were obtained after 24 h of incubation with the MA-based 3D samples compared to the CAD/CAM milled ones. Therefore, our results outline that the MA-CAD/CAM milled samples displayed good biocompatibility during 24-h exposure, while MA-3D resins are proper for short-term utilization (less than 24 h).

The Evaluation of the Trueness of Dental Mastercasts Obtained through Different 3D Printing Technologies.

In contemporary dentistry, several 3D printing techniques, including a stereolithography apparatus (SLA), digital light processing (DLP), liquid crystal display (LCD), and PolyJet 3D inkjet printing technology (PolyJet), are employed for model production. Despite their widespread use, there remains a paucity of the literature regarding the trueness and precision of these devices in dental applications. Existing studies comparing the accuracy of dental models manufactured by different printing technologies yield disparate conclusions regarding dental prosthesis manufacturing. This study aimed to test two null hypotheses: first, that the trueness of various new-generation 3D printers is equivalent, and second, that the trueness of printing by these printers is sufficient for achieving high-precision mastercasts in dental prosthodontics manufacturing. The research focuses on evaluating the trueness of five contemporary dental 3D printers: Anycubic Mono X 6Ks (Hongkong Anycubic Technology Co., Hongkong, China), Asiga Max (Asiga, Sydney, Australia), Creo C5 (Planmeca Oy, Helsinki, Finland), Form 3B (Formlabs, Boston, MA, USA), and J5 Dentajet (Stratasys Ltd., Eden Prairie, MN, USA). The methodology employed involved the creation of a digital test object using Blender software, adhering meticulously to the dimensions outlined in ISO standard 20896-1. These dimensions were chosen to be both relevant for this study and representative of clinical scenarios. Subsequently, the test object was printed and precise measurements were conducted utilizing a metrology-type Nikon XTH225 ST Reflection target in conjunction with VGStudio MAX analysis software. The results of our investigation revealed clinically negligible deviations in ball dimensions across all printers, with the maximum observed deviations ranging between 1.17% and 2.03% (notably observed in the Creo C5 printer). Transversal distortion exhibited variance based on the linear accuracy of each printer, with Stratasys21 and Formlabs 3B demonstrating superior accuracy among the evaluated printers. Distortions in the analyzed dimensions (specifically, anterior b-c, posterior a-d, and oblique a-c) were found to be uniform. In conclusion, while the first null hypothesis was rejected, indicating variations in trueness among the 3D printers assessed, our findings affirm the suitability of all five analyzed 3D printers for clinical applications. Consequently, these printers can be utilized for the fabrication of high-precision mastercasts in dental prosthodontics manufacturing.

Exploring the Threefold Viewpoint on Children's Oral Health in a Cross-Sectional Study.

Oral health is situated within the framework of the global health agenda, addressing facets pertaining to well-being and quality of life. The research is based on the need to address variables at the community level to improve schoolchildren's oral health and promote healthy behaviors and aims to carry out an in-depth analysis from the perspective of the factors that influence children's oral health. Step 1, designed by the World Health Organization, was utilized. An easy-to-use web interface was created for data collection. The statistical analysis consisted of using multinomial and binominal logistic regression models. The level of education of the adult has a high probability of influencing the consumption of unhealthy or healthy foods, it has a significant probability of exerting influence on social or medical problems and a correlation was found between the level of academic education and the pattern of dental visits. The development of health-promoting behaviors begins in childhood and involves parents, who have an essential role in the education of their children. Oral health promotion programs in schools need to target the child-adult-teacher-dentist relationships. Taking into consideration the aforementioned, a threefold viewpoint is necessary for the development of a national program aimed at promoting the oral health of schoolchildren in Romania.

Volatility, Uncertainty, Complexity, and Ambiguity (VUCA) in Healthcare.

Our professional activity is constantly under pressure from a multitude of elements and factors that can be classified into the four components of the VUCA phenomenon-volatility, uncertainty, complexity, and ambiguity-components that define the turbulence and challenges of the external environment. Considering the general elements of this phenomenon, we designed a new VUCA dimension specific to the healthcare field within which we have identified and analyzed all the factors that can influence the main actors of the doctor-patient relationship and the effects that can occur within the healthcare system in which this relationship is born. In this context, we generated the VUCA treatment in healthcare capable of mitigating the impact of this phenomenon; this treatment involves essential elements in overcoming possible crises and vulnerabilities of the medical profession. The VUCA treatment in healthcare requires combating volatility, uncertainty, complexity, and ambiguity through vision, understanding, clarity, and agility, which are grounded in the doctor's need to acquire cross-functional competencies (soft skills). These competencies are applicable by using functional mechanisms and techniques that support the doctor in developing adaptability and anticipation skills, understanding the patient's needs and addressing them, and ensuring the functionality and efficiency of the healthcare system by transferring these elements from micro-management to macro-management levels.

Application of Common Culinary Herbs for the Development of Bioactive Materials.

Hyssop (Hyssopus officinalis L.) and oregano (Origanum vulgare L.), traditionally used for their antimicrobial properties, can be considered viable candidates for nanotechnology applications, in particular for the phytosynthesis of metal nanoparticles. The present work aims to evaluate the potential application of hyssop and oregano for the phytosynthesis of silver nanoparticles, as well as to evaluate the biological activities of their extracts and obtained nanoparticles (antioxidant potential, as well as cell viability, inflammation level and cytotoxicity in human fibroblasts HFIB-G cell line studies). In order to obtain natural extracts, two extraction methods were applied (classical temperature extraction and microwave-assisted extraction), with the extraction method having a major influence on their composition, as demonstrated by both the total phenolic compounds (significantly higher for the microwave-assisted extraction; the oregano extracts had consistently higher TPC values, compared with the hyssop extracts) and in terms of individual components identified via HPLC. The obtained nanoparticles ware characterized via X-ray diffraction (XRD) and transmission electron microscopy (TEM), with the lowest dimension nanoparticles being recorded for the nanoparticles obtained using the oregano microwave extract (crystallite size 2.94 nm through XRD, average diameter 10 nm via TEM). The extract composition and particle size also influenced the antioxidant properties (over 60% DPPH inhibition being recorded for the NPs obtained using the oregano microwave extract). Cell viability was not affected at the lowest tested concentrations, which can be correlated with the nitric oxide level. Cell membrane integrity was not affected after exposure to classic temperature hyssop extract-NPs, while the other samples led to a significant LDH increase.

Collateral Victims of Defensive Medical Practice.

This paper analyzes the phenomenon of defensive medical practice, starting from the doctor-patient relationship, and the behavioral and professional factors that can influence the proper functioning of this relationship and the healthcare system. We analyze medical malpractice, given the increase in the number of accusations, as an essential factor in triggering the defensive behavior of doctors, together with other complementary factors that emphasize the need for protection and safety of doctors. The possible consequences for the doctor-patient relationship that defensive practice can generate are presented and identified by analyzing the determining role of the type of health system (fault and no-fault). At the same time, we investigate the context in which overspecialization of medical personnel can generate a form of defensive practice as a result of the limiting effect on the performance of a certain category of operations and procedures. The increase in the number of malpractice accusations impacts the medical community-"the stress syndrome induced by medical malpractice"-turning doctors into collateral victims who, under the pressure of diminishing their reputational safety, practice defensively to protect themselves from future accusations. This type of defensive behavior puts pressure on the entire healthcare system by continuously increasing costs and unresolved cases, which impact patients by limiting access to medical services in the public and private sectors.

Salivary antioxidant biomarkers in non-ferrous metals mine workers--a pilot study.

OBJECTIVE: The purpose of the present study is to evaluate the relationships between occupational exposure to mine dust, salivary antioxidants and their possible implications in the pathogenicity of different exposure diseases. MATERIAL AND METHODS: We studied 30 individuals with long-term occupational exposure to non-ferrous metal mine conditions and a control group consisted of 30 healthy volunteers. Salivary uric acid, gammaglutamyltransferase (GGT), albumin and the total antioxidant capacity (TAC) were measured. RESULTS: Statistically significant differences in salivary GGT (P = 0.004), TAC (P < 0.001) and uric acid (P = 0.02) were noted between the two groups. A strong positive correlation between TAC and uric acid was recorded in controls (r = 0.76, P = 0.0002). CONCLUSIONS: Saliva may provide an important line of antioxidant defense in humans exposed to oxidant threats. These components may also serve as convenient biomarkers to monitor oxidant exposure.

Autophagy Plays Multiple Roles in the Soft-Tissue Healing and Osseointegration in Dental Implant Surgery-A Narrative Review.

Dental endo-osseous implants have become a widely used treatment for replacing missing teeth. Dental implants are placed into a surgically created osteotomy in alveolar bone, the healing of the soft tissue lesion and the osseointegration of the implant being key elements to long-term success. Autophagy is considered the major intracellular degradation system, playing important roles in various cellular processes involved in dental implant integration. The aim of this review is an exploration of autophagy roles in the main cell types involved in the healing and remodeling of soft tissue lesions and implant osseointegration, post-implant surgery. We have focused on the autophagy pathway in macrophages, endothelial cells; osteoclasts, osteoblasts; fibroblasts, myofibroblasts and keratinocytes. In macrophages, autophagy modulates innate and adaptive immune responses playing a key role in osteo-immunity. Autophagy induction in endothelial cells promotes apoptosis resistance, cell survival, and protection against oxidative stress damage. The autophagic machinery is also involved in transporting stromal vesicles containing mineralization-related factors to the extracellular matrix and regulating osteoblasts' functions. Alveolar bone remodeling is achieved by immune cells differentiation into osteoclasts; autophagy plays an important and active role in this process. Autophagy downregulation in fibroblasts induces apoptosis, leading to better wound healing by improving excessive deposition of extracellular matrix and inhibiting fibrosis progression. Autophagy seems to be a dual actor on the scene of dental implant surgery, imposing further research in order to completely reveal its positive features which may be essential for clinical efficacy.