Transcriptional regulation of CYP3A4 by nuclear receptors in human hepatocytes under hypoxia.

The human hepatic cytochrome P-450 3A4 (CYP3A4), recognized as a multifunctional enzyme, has a wide range of substrates including commonly used drugs. Previous investigations demonstrated that the expression of CYP3A4 in human hepatocytes could be regulated by some nuclear receptors (NRs) at transcriptional level under diverse situations. The significance of oxygen on CYP3A4-mediated metabolism seems notable while the regulatory mode of CYP3A4 in the particular case still remains elusive. Recently, striking evidence has emerged that both CYP3A4 and its regulator NR could be inhibited by exposure to hypoxia. Therefore, it is of great importance to elucidate whether and how these NRs act in the transcriptional regulation of CYP3A4 in human hepatocytes under hypoxic conditions. In this review, we mainly summarized transcriptional regulation of the pivotal enzyme CYP3A4 by NRs and explored the possible regulatory pathways of CYP3A4 via these major NRs under hypoxia, expecting to provide favorable evidence for further clinical guidance under such pathological situations.

[Effects of acute hypoxia on expression of pregnane X receptor in liver tissues of rats exposed to high altitude].

OBJECTIVE: To investigate the effects of high-altitude hypoxic environment on the expression of pregnane X receptor (PXR) in rat liver and related mechanism. METHODS: Wistar rats were randomly divided into five groups with 8 rats in each group, the rats were exposed to high-plateau hypoxia for 0 (control group), 12, 24, 36 and 48 h, respectively. Abdominal aortic blood samples were collected for blood gas analysis. HE staining was used to observe the pathological changes of liver tissue. The expression levels of PXR mRNA in liver tissues were determined by RT-PCR. Western blot analysis was performed to determine the protein expression of PXR and protease SUG1 in liver tissues of rats. RESULTS: Compared with the control group, the blood pH of the rats decreased after 12 h of acute hypoxia. After 24 h exposed to hypoxia, SaO2 was lower than 80%, PaO2 was lower than 60 mmHg (1 mmHg=0.133 kPa); and PaCO2 increased after 48 h exposed to hypoxia (P<0.05). There was obvious edema in the central vein of the liver tissue at 12 h and 24 h after exposure to hypoxia. The liver tissue of the rats exposed to hypoxia for 36 h and 48 h showed inflammatory infiltration. The expression of PXR mRNA was significantly decreased by 63%, 96%, 86%, and 85%at 12, 24, 36 h, and 48 h after exposure to hypoxia (all P<0.05), respectively. The protein expression of PXR was significantly up-regulated by 93%and 99%after 36 h and 48 h exposure to hypoxia (all P<0.05), respectively. The protein expression of proteinase SUG1 decreased by 14%, 34%and 46%after 24, 36 and 48 h after hypoxia (all P<0.01). CONCLUSIONS: Acute hypoxia at high altitude can affect the expression of nuclear receptor PXR in rat liver, and protease SUG1 may be a regulatory factor for PXR expression in hypoxia.

Protraction of Mandibular Second Molar for Substitution of Adjacent Missing First Molar With a Mini-Implant-Anchored Albert Loop Appliance.

Protraction of mandibular posterior teeth into edentulous regions is challenging in clinical practice. This case demonstrated a minor tooth movement of a mandibular second molar to substitute its adjacent missing first molar in a 15-year-old female. An efficient bodily movement of the mandibular second molar was achieved through a mini-implant-anchored protraction loop appliance. With this carefully designed biomechanical system, over 10-mm molar protraction was accomplished within 14 months without mesial or lingual tipping. The adjacent third molar erupted spontaneously during the protraction process and drafted mesially. Through brackets and segmented archwire after the protraction, the second and third molars were successfully protracted and good buccal interdigitation was achieved. The combination of the Albert protraction loop and mini-implant allows for more efficient protraction of the mandibular molars, avoiding mesial tipping and lingual rotation of the molars.

Uprighting and protraction of two unilateral mandibular molars using a cantilever arm through a sophisticated biomechanical system with clear aligner: A case report.

Although clear aligner can be efficient and predictable in some tooth movements, mandibular molar protraction is the least predictable owing to biological and biomechanical limitations. This case report presents a 20-year-old female with poor prognosed left mandibular first molar (#36), deviated dental midline and mild crowding. After extraction of #36, clear aligners and an Albert cantilever were used for treatment. Through carefully designed dual mechanical system, we achieved uprighting and protraction of #37 within 27 months, with crown and root movements of 9.9mm and 12.1mm, respectively. The predictability of the crown and root movement was 107.6% and 84.6%. Coincident dental and facial midline, class I molar and canine relationship and good root parallelism were also achieved. Large-distance mandibular molar protraction can be achieved effectively with a combination of Albert cantilever arm and clear aligner.

Evaluation of Optimal Insertion Sites and Angles for Orthodontic Mini-Implants at the Anterior Nasal Spine Region Based on Cone-Beam Computed Tomography.

BACKGROUND: To infer the optimal angulation and height level of mini-implant insertion in the anterior nasal spine (ANS) region from alveolar bone depth (BD) and labial cortical bone thickness (CBT) through cone-beam computed tomography (CBCT), the influences of sex, age, and growth pattern on BD, CBT, and the starting point of the ANS were examined. MATERIAL AND METHODS: BD and CBT were measured on CBCT median sagittal images at specific angles (0, 15, 30, 45, and 60 degrees) to simulate the angulation of insertion. The height level of the first axial image with obvious bone ridge was recorded as the start of ANS. RESULTS: The average height of ANS start was 9.42 mm from the alveolar bone crest between the central incisors. The variations in height level and insertion angle combined, or either of them individually, significantly influenced BD and CBT, demonstrating overall decreasing trends (p < 0.001). BD was not influenced by sex, age, or growth pattern (p > 0.05). However, CBT was found to be correlated with sex and growth pattern, while the height level of ANS start was associated only with growth pattern, particularly in hypodivergent patients (p < 0.05). CONCLUSION: The recommended insertion height level is 14-16 mm from the alveolar bone crest and the recommended angulation is 30-45°. An innovative inequity in the relationship between a certain height level and the insertion angulation is proposed.

A Bibliometric Analysis of Clear Aligner Treatment (CAT) From 2003 to 2023.

Clear aligner treatment (CAT) has been evolving over the past two decades. This study aims to conduct a comprehensive and up-to-date bibliometric analysis of publications related to CAT, presenting the research trends, landscapes, and hot spots in this field. All publications were retrieved from the Web of Science Core Collection from 2003 to 2023. In addition to a general analysis of research landscapes, the following items were analyzed, i.e., countries, institutions, authors, journals, publications, and keywords. A total of 1031 relevant publications were included in this study. From 2003 to the present, the number of publications and citations in this field showed an increasing trend. Italy led in terms of publication counts, and Sichuan University in China had the highest publication counts among institutions. In total, 33 scholars had published a minimum of 10 articles, and the collaborations among them were mostly within each country. The American Journal of Orthodontics and Dentofacial Orthopedics published the most relevant publications. "Predictability of tooth movements," "influencing factors for clinical efficacy," "biomechanics," and "patients' perception and periodontal health" stood out as the core research focus on CAT. Our study identified the most influential countries, institutions and authors, and their cooperative relationships, and detected hot research topics on CAT, calling for more high-quality international collaborative research in the future.

Emerging roles of exosome-derived biomarkers in cancer theranostics: messages from novel protein targets.

Effective biomarkers that guide therapeutics with limited adverse effects, have emerged as attractive research topics in cancer diagnosis and treatment. Cancer-derived exosomes, a type of extracellular vesicles representing molecular signatures of cells of origin, could serve as stable reservoirs for potential biomarkers (i.e., proteins, nucleic acids) in non-invasive cancer diagnosis and prognosis. In this review, the physiological and pathological roles of exosomes and their protein components in facilitating tumorigenesis are highlighted. Exosomes carrying proteins can participate in tumor development and progression through multiple signaling pathways, including EMT, invasion and metastasis. Meanwhile, the practical applications of exosomal proteins in detecting and monitoring several solid-tumor cancers (including lung, breast, pancreatic, colorectal and prostate cancers) were also summarized. More clinically relevant, exosomal proteins play pivotal roles in transmitting oncogenic potential or resistance to therapies in recipient cells, which might further support therapeutic strategy determinations.

Potential Regulation Mechanisms of P-gp in the Blood-Brain Barrier in Hypoxia.

The blood-brain barrier (BBB) is a barrier of the central nervous system (CNS), which can restrict the free exchange of substances, such as toxins and drugs, between cerebral interstitial fluid and blood, keeping the relative physiological stabilization. The brain capillary endothelial cells, one of the structures of the BBB, have a variety of ATP-binding cassette transporters (ABC transporters), among which the most widely investigated is Pglycoprotein (P-gp) that can efflux numerous substances out of the brain. The expression and activity of P-gp are regulated by various signal pathways, including tumor necrosis factor-α (TNF-α)/protein kinase C-ß (PKC- ß)/sphingosine-1-phosphate receptor 1 (S1P), vascular endothelial growth factor (VEGF)/Src kinase, etc. However, it remains unclear how hypoxic signaling pathways regulate the expression and activity of P-gp in brain microvascular endothelial cells. According to previous research, hypoxia affects the expression and activity of the transporter. If the transporter is up-regulated, some drugs enter the brain's endothelial cells and are pumped back into the blood by transporters such as P-gp before they enter the brain tissue, consequently influencing the drug delivery in CNS; if the transporter is down-regulated, the centrally toxic drug would enter the brain tissue and cause serious adverse reactions. Therefore, studying the mechanism of hypoxia-regulating P-gp can provide an important reference for the treatment of CNS diseases with a hypoxia/reoxygenation (H/R) component. This article summarized the mechanism of regulation of P-gp in BBB in normoxia and explored that of hypoxia.