The Relationship between Different Delivery Timing and the Outcome of Premature Rupture of Membranes in Primiparous Women.

Objective: To investigate the relationship between different delivery timing and the outcome of premature rupture of membranes (PROM) in primiparous women. Methods: Within the context of exploring optimal delivery strategies for managing PROM, we conducted a retrospective study at Shijiazhuang Fourth Hospital. From May 2019 to May 2022, a total of 400 single pregnant women with premature rupture of membranes (PROM) at different gestational weeks (28-36 weeks) were enrolled. This study aims to understand the impact of delivery timing on pregnancy outcomes more clearly. Pregnant women were divided into two distinct groups based on gestational weeks: Group A (28 to 33 weeks, n=192) and Group B (34 to 36 weeks, n=208). The clinical data of pregnant women were analyzed retrospectively, and the methods of delivery, maternal and infant pregnancy outcomes, and factors affecting delivery outcomes were compared in different groups. Results: Compared with the delivery methods of the two groups, the proportion of vaginal delivery in group A (69.27%) was significantly higher than that in group B (49.04%). The proportion of assisted vaginal delivery and cesarean section (13.54% and 17.19%) was significantly lower than that in group B (18.75% and 32.21%) (P < .001). There was no difference in neonatal death outcomes between the two groups (P > .297). The incidence of chorioamnionitis, postpartum hemorrhage, and puerperal infection in group A (25.00%), (19.27%) and (11.46%) was significantly higher than that in group B (6.25%), (5.29%) and (2.40%), respectively. The incidence rates of neonatal asphyxia, neonatal respiratory distress syndrome (NRDS), and hypoxic-ischemic encephalopathy (HIE) in group A were 9.38%, 7.29%, and 6.77%, which were significantly higher than those in group B (1.92%, 0.48% and 0.48%) (P = .001). There was no difference in neonatal death outcomes at different delivery times (P = .259). The incidence rates of amniotic infection, postpartum hemorrhage, and puerperal infection were (3.98%), (7.39%) and (3.41%), which were significantly lower than those of pregnant women from PROM to delivery time ≥48 h (24.11%), (15.63%) and (9.38%). The incidence rates of neonatal asphyxia, NRDS, and HIE were (1.14%), (1.14%) and (2.27%) in neonates from PROM to delivery time < 48 h, significantly lower than those in neonates from PROM to delivery time ≥48 h (8.93%), (5.80%), and (4.46%) (P < .001). Logistic regression analysis showed that the older the gestational week was the protective factor for amniotic space infection, postpartum hemorrhage, puerperal infection, neonatal asphyxia, NRDS, and HIE. Late delivery time was an independent risk factor for amniotic cavity infection(P < .001), postpartum hemorrhage(P = .014), puerperal infection(P = .023), neonatal asphyxia(P = .004), and NRDS (P = .028). Conclusion: In pregnant women with PROM who are not at full term, a greater gestational week is associated with a lower rate of adverse delivery outcomes. In contrast, a longer time interval between membrane rupture and delivery is associated with a higher rate of adverse delivery outcomes.

Polyphenol Compound 18a Modulates UCP1-Dependent Thermogenesis to Counteract Obesity.

Recent studies increasingly suggest that targeting brown/beige adipose tissues to enhance energy expenditure offers a novel therapeutic approach for treating metabolic diseases. Brown/beige adipocytes exhibit elevated expression of uncoupling protein 1 (UCP1), which is a thermogenic protein that efficiently converts energy into heat, particularly in response to cold stimulation. Polyphenols possess potential anti-obesity properties, but their pharmacological effects are limited by their bioavailability and distribution within tissue. This study discovered 18a, a polyphenol compound with a favorable distribution within adipose tissues, which transcriptionally activates UCP1, thereby promoting thermogenesis and enhancing mitochondrial respiration in brown adipocytes. Furthermore, in vivo studies demonstrated that 18a prevents high-fat-diet-induced weight gain and improves insulin sensitivity. Our research provides strong mechanistic evidence that UCP1 is a complex mediator of 18a-induced thermogenesis, which is a critical process in obesity mitigation. Brown adipose thermogenesis is triggered by 18a via the AMPK-PGC-1α pathway. As a result, our research highlights a thermogenic controlled polyphenol compound 18a and clarifies its underlying mechanisms, thus offering a potential strategy for the thermogenic targeting of adipose tissue to reduce the incidence of obesity and its related metabolic problems.

Discovery of Oral AMP-Activated Protein Kinase Activators for Treating Hyperlipidemia.

Activation of AMP-activated protein kinase (AMPK) is proposed to alleviate hyperlipidemia. With cordycepin and N6-(2-hydroxyethyl) adenosine (HEA) as lead compounds, a series of adenosine-based derivatives were designed, synthesized, and evaluated on activation of AMPK. Finally, compound V1 was identified as a potent AMPK activator with the lipid-lowering effect. Molecular docking and circular dichroism indicated that V1 exerted its activity by binding to the γ subunit of AMPK. V1 markedly decreased the serum low-density lipoprotein cholesterol levels in C57BL/6 mice, golden hamsters, and rhesus monkeys. V1 was selected as the clinical compound and concluded Phase 1 clinical trials. A single dose of V1 (2000 mg) increased AMPK activation in human erythrocytes after 5 and 12 h of treatment. RNA sequencing data suggested that V1 downregulated expression of genes involved in regulation of apoptotic process, lipid metabolism, endoplasmic reticulum stress, and inflammatory response in liver by activating AMPK.

Spatial distribution characteristics and influencing factors of traditional villages based on geodetector: Jiarong Tibetan in Western Sichuan, China.

Jiarong Tibetan is a regional group with distinctive regional characteristics and possess precious traditional village resources. Studying the spatial distribution and influencing factors of traditional villages is of vital significance for the protection and renewal of villages and the revitalization of cultural heritage. Nevertheless, due to the fact that the Jiarong Tibetan inhabited area has not been clearly defined for a long time, there is a lack of holistic discussion on the distribution features and driving mechanisms of traditional villages in this region. In order to fill this research gap, the paper is the first to break away from the existing county administrative divisions to define the study area. Moreover, the analysis is carried out by using the nearest neighbor index, kernel density, GoeDa and Geodetector, etc. for traditional villages at national-level and provincial-level. The results show that the spatial distribution of the traditional villages of Jiarong Tibetan is characterized by typical aggregation, with the core intensive area in Danba County and the sub-core intensive area in the central and northern parts. The results of factor detection show that the spatial distribution pattern of the traditional villages is the consequence of the synergistic effect of multiple factors, and the interaction effect is significantly enhanced. The economic level and climatic conditions play a controlling role, and population, elevation, intangible cultural heritage and rivers also have notable effects. The findings of study can offer scientific guidance and suggestions for the inheritance and development of traditional villages in Jiarong Tibetan settlement area.

Antiphospholipid antibody-related hepatic vasculitis in a juvenile after non-severe COVID-19: a case report and literature review.

Antiphospholipid antibodies (aPL) are both laboratory evidence and causative factors for a broad spectrum of clinical manifestations of antiphospholipid syndrome (APS), with thrombotic and obstetric events being the most prevalent. Despite the aPL-triggered vasculopathy nature of APS, vasculitic-like manifestations rarely exist in APS and mainly appear associated with other concurrent connective tissue diseases like systemic lupus erythematous. Several studies have characterized pulmonary capillaritis related to pathogenic aPL, suggesting vasculitis as a potential associated non-thrombotic manifestation. Here, we describe a 15-year-old girl who develops hepatic infarction in the presence of highly positive aPL, temporally related to prior non-severe COVID-19 infection. aPL-related hepatic vasculitis, which has not been reported before, contributes to liver ischemic necrosis. Immunosuppression therapy brings about favorable outcomes. Our case together with retrieved literature provides supportive evidence for aPL-related vasculitis, extending the spectrum of vascular changes raised by pathogenic aPL. Differentiation between thrombotic and vasculitic forms of vascular lesions is essential for appropriate therapeutic decision to include additional immunosuppression therapy. We also perform a systematic review to characterize the prevalence and clinical features of new-onset APS and APS relapses after COVID-19 for the first time, indicating the pathogenicity of aPL in a subset of COVID-19 patients.

Transcutaneous auricular vagus nerve stimulation for epilepsy.

BACKGROUND: Several studies have suggested that transcutaneous vagus nerve stimulation (tVNS) may be effective for the treatment of epilepsy. However, auricular acupoint therapy (including auricular acupuncture and auricular point-sticking therapy), a method of stimulating the vagus nerve, has been poorly reviewed. This systematic review is the first to categorize auricular acupoint therapy as transcutaneous auricular vagus nerve stimulation (taVNS), aiming to assess the efficacy of taVNS in patients with epilepsy (PWE), and to analyse the results of animal experiments on the antiepileptic effects of taVNS. METHODS: We searched MEDLINE, EMBASE, Web of Science, Scopus, and various Chinese databases from their inception to June 10, 2023 and found nine clinical studies (including a total of 788 PWE) and eight preclinical studies. We performed a meta-analysis and systematic review of these articles to assess the efficacy of taVNS in PWE and the association between taVNS and electroencephalogram (EEG) changes. We also analysed the effects on epileptic behaviour, latency of the first seizure, and seizure frequency in epileptic animals. The PRISMA 2020 checklist provided by the EQUATOR Network was used in this study. RESULTS: taVNS had a higher response rate in PWE than the control treatment (OR = 2.94, 95 % CI = 1.94 - 4.46, P < 0.05). The analysis showed that the taVNS group showed wider EEG changes than the control group (OR = 2.17, 95 % CI 1.03 to 4.58, P < 0.05). The preclinical studies analysis revealed significant differences in epileptic behaviour (SMD = -4.78, 95 % CI -5.86 to -3.71, P < 0.05) and seizure frequency (SMD = -5.06, 95 % CI -5.96 to -4.15, P < 0.05) between the taVNS and control groups. No statistical difference was found in the latency of the first seizure between the two groups (SMD =13.54; 95 % CI 7.76 to 19.33, P < 0.05). CONCLUSION: Based on the available data, PWE may benefit from the use of taVNS. taVNS is an effective procedure for improving epileptic behaviour in animal models.

Clinical remission of moderate generalized myasthenia gravis through exclusive use of Buzhong Yiqi decoction: A case report.

BACKGROUND: Myasthenia gravis (MG) is a rare autoimmune neuromuscular disorder with significant morbidity and mortality. Traditional Chinese medicine (TCM) offers an alternative approach to standard pharmacological and surgical interventions, which are often associated with adverse side effects. This case report details the clinical remission of a 50-year-old male with moderate generalized MG following exclusive treatment with a modified Buzhong Yiqi decoction (BYD), a TCM formula, without the use of immunosuppressive agents. CASE SUMMARY: The patient presented with diplopia, bilateral ptosis, weakness in chewing, limb weakness, and other symptoms indicative of spleen and stomach qi deficiency. Modified BYD was prescribed, focusing on strengthening the spleen, nourishing qi and blood, and enhancing immune response. The treatment included ingredients such as Radix Astragali, Angelica sinensis, Atractylodes macrocephala, and others, aiming to restore balance and improve the patient's condition. After two weeks of TCM treatment, the patient showed significant improvement in symptoms of myasthenia. By the second month, all clinical symptoms had disappeared. The patient continued to receive the TCM regimen until the thirtieth month of treatment. At the time of writing this report, the patient has no clinical symptoms and has experienced no relapse. Notably, no obvious adverse effects were reported throughout the treatment. CONCLUSION: The success of this case suggests that TCM may serve as an independent treatment option for moderate MG, offering a steroid-free alternative, which would be particularly valuable for patients who are intolerant of or refuse steroid therapy, potentially with significant clinical implications. However it needs a randomized clinical trial comparing TCM to conventional Western medicine treatment to validate it.

Organophosphorus Flame Retardant TPP-Induced Human Corneal Epithelial Cell Apoptosis through Caspase-Dependent Mitochondrial Pathway.

A widely used organophosphate flame retardant (OPFR), triphenyl phosphate (TPP), is frequently detected in various environmental media and humans. However, there is little known on the human corneal epithelium of health risk when exposed to TPP. In this study, human normal corneal epithelial cells (HCECs) were used to investigate the cell viability, morphology, apoptosis, and mitochondrial membrane potential after they were exposed to TPP, as well as their underlying molecular mechanisms. We found that TPP decreased cell viability in a concentration-dependent manner, with a half maximal inhibitory concentration (IC50) of 220 µM. Furthermore, TPP significantly induced HCEC apoptosis, decreased mitochondrial membrane potential in a dose-dependent manner, and changed the mRNA levels of the apoptosis biomarker genes (Cyt c, Caspase-9, Caspase-3, Bcl-2, and Bax). The results showed that TPP induced cytotoxicity in HCECs, eventually leading to apoptosis and changes in mitochondrial membrane potential. In addition, the caspase-dependent mitochondrial pathways may be involved in TPP-induced HCEC apoptosis. This study provides a reference for the human corneal toxicity of TPP, indicating that the risks of OPFR to human health cannot be ignored.

Recognizing Functional Groups of MES/APG Mixed Surfactants for Enhanced Solubilization toward Benzo[a]pyrene.

Benzo[a]pyrene is difficult to remove from soil due to its high octanol/water partition coefficient. The use of mixed surfactants can increase solubility but with the risk of secondary soil contamination, and the compounding mechanism is still unclear. This study introduced a new approach using environmentally friendly fatty acid methyl ester sulfonate (MES) and alkyl polyglucoside (APG) to solubilize benzo[a]pyrene. The best result was obtained when the ratio of MES/APG was 7:1 under 6 g/L total concentration, with an apparent solubility (Sw) of 8.58 mg/L and a molar solubilization ratio (MSR) of 1.31 for benzo[a]pyrene, which is comparable to that of Tween 80 (MSR, 0.95). The mechanism indicates that the hydroxyl groups (-OH) in APG form "O-H···OSO2-" hydrogen bonding with the sulfonic acid group (-SO3-) of MES, which reduces the electrostatic repulsion between MES molecules, thus facilitating the formation of large and stable micelles. Moreover, the strong solubilizing effect on benzo[a]pyrene should be ascribed to the low polarity of ester groups (-COOCH3) in MES. Functional groups capable of forming hydrogen bonds and having low polarity are responsible for the enhanced solubilization of benzo[a]pyrene. This understanding helps choose suitable surfactants for the remediation of PAH-contaminated soils.

Health risk assessment of heavy metal(loid)s in road dust via dermal exposure pathway from a low latitude plateau provincial capital city: The importance of toxicological verification.

The human health risk assessment through the dermal exposure of metal (loid)s in dust from low latitude and high geological background plateau cities was largely unknown. In this study, the road dust samples were harvested from a typical low-latitude plateau provincial capital city Kunming, Southwest China. The total concentration and dermal bioaccessibility of heavy metal (loid)s in road dust were determined, and their health risks as well as cytotoxicity on human skin keratinocytes were also assessed. The average concentrations of As (28.5 mg/kg), Cd (2.65 mg/kg), Mn (671 mg/kg), and Zn (511 mg/kg) exceeded the soil background values. Arsenic had the highest bioaccessibility after 2 h (3.79%), 8 h (4.24%), and 24 h (16.6%) extraction. The dermal pathway when bioaccessibility is considered has a higher hazard quotient than the conventional method using total metal(loid)s in the dust. In addition, toxicological verification suggested that the dust extracts suppressed the cell viability, increased the reactive oxygen species (ROS) level and DNA damage, and eventually activated the mitochondria-mediated apoptosis pathway, evidenced by the upregulation of Caspase-3/9, Bax, and Bak-1. Cadmium was positively correlated with the mRNA expression of Bax. Taken together, our data indicated that both dermal bioaccessibility and cytotoxicity should be considered for accurate human skin health risk assessment of heavy metal(loid)s in road dust, which may provide new insight for accurate human health risk assessment and environmental management.

The establishment of diseased human whole organ model by normothermic machine perfusion technique: Principle of concept.

BACKGROUND: The global incidence of liver diseases is rising, yet there remains a dearth of precise research models to mimic these diseases. The use of normothermic machine perfusion (NMP) to study diseased livers recovered from liver transplantation (LT) recipients presents a promising avenue. Accordingly, we have developed a machine perfusion system tailored specifically for the human whole diseased livers and present our experience from the NMP of diseased livers. METHODS: Six diseased livers recovered from LT recipients with different diagnoses were collected. The diseased livers were connected to the machine perfusion system that circulated tailored perfusate, providing oxygen and nutrients. The pressure and flow of the system were recorded, and blood gas analysis and laboratory tests of perfusate and bile were examined to analyze the function of the diseased livers. Liver tissues before and after NMP were collected for histological analysis. RESULTS: Experiments showed that the system maintained the diseased livers in a physiological state, ensuring stable hemodynamics and a suitable partial pressure of oxygen and carbon dioxide. The results of blood gas analysis and laboratory tests demonstrated a restoration and sustenance of metabolism with minimal damage. Notably, a majority of the diseased livers exhibited bile production continuously, signifying their vivid functional integrity. The pathological characteristics remained stable before and after NMP. CONCLUSION: We successfully established the machine perfusion system tailored specifically for diseased human whole livers. Through the application of this system, we have developed a novel in vitro model that faithfully recapitulates the main features of human liver disease. This model holds immense promise as an advanced disease modeling platform, offering profound insights into liver diseases and potential implications for research and therapeutic development.

Simultaneous determination of BGT-002 and its acyl glucuronide metabolite ZM326E-M2 in human plasma by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study.

BGT-002, a new type of ATP-citrate lyase inhibitor, is a promising therapeutic for treatment of hypercholesterolemia. After an oral administration of BGT-002 to subjects, it underwent extensive metabolism and an acyl monoglucuronide (ZM326E-M2) on 1- carboxylic acid group was the major circulating metabolite. In this study, an LC-MS/MS method was developed and validated for the simultaneous determination of BGT-002 and ZM326E-M2 in plasma and the evaluation of their pharmacokinetic characteristics in humans. After extraction from the plasma by acetonitrile-induced protein precipitation, the analytes were separated on a Waters ACQUITY UPLC® BEH C18 column using acetonitrile and 2 mM ammonium acetate containing 0.1% formic acid as the mobile phase for gradient elution. Negative electrospray ionization was performed using multiple reaction monitoring (MRM) of m/z 501.3→325.4 for ZM326E-M2 and m/z 507.3→331.2 for D6-ZM326E-M2, and pseudo-MRM of m/z 325.3→325.3 for BGT-002 and m/z 331.3→331.3 for D6-ZM326E, respectively. The method was validated with respect to accuracy, precision, linearity, stability, selectivity, matrix effect, and recovery. The analytical range in human plasma was linear over a concentration range of 0.0500-50.0 µg/mL for BGT-002 and 0.0100-10.0 µg/mL for ZM326E-M2. The pharmacokinetic results showed that after a single oral administration of 100 mg BGT-002, the parent drug was rapidly absorbed with a mean time to peak concentration (tmax) of 1.13 h, compared with BGT-002, the tmax (4.00 h) of ZM326E-M2 was significantly delayed. The peak concentration and plasma exposure of ZM326E-M2 were about 14.1% and 19.5% of the parent drug, suggesting that attention should be paid to the safety and efficacy of ZM326E-M2 in clinical research.

The Potential Role and Therapeutic Relevance of Cellular Senescence in Skeletal Pathophysiology.

Biological aging profoundly impairs the homeostasis of the skeletal system. Cellular senescence, a hallmark of biological aging, plays an instrumental role in bone disease. The underlying mechanisms of cellular senescence, triggered by both intracellular and extracellular stimuli, are multifaceted and yet to be uncovered. Recent research indicates that acute cellular senescence often serves beneficial roles, such as contributing to growth, development, and tissue regeneration. By contrast, chronic cellular senescence, primarily driven by the accumulation of senescent cells (SnCs) and the release of senescence-associated secretory phenotypes (SASP), has detrimental effects on the skeletal system by irreversibly disrupting bone homeostasis and promoting age-related disorders. Furthermore, the bone marrow is rich in immune cells and their exposure to SASP often leads to immune dysfunction, resulting in unresolved chronic inflammation and compromised adaptive immunity. Until now, the impact of SnCs and SASP on the skeleton has remained elusive. Meanwhile, extensive efforts are being made to combat age-related diseases through various strategies. Among them, SnCs and SASP are the primary targets for antiaging therapeutic clearance, resulting in the development of "senolytics" and "senomorphics," respectively. In this review, we summarize and highlight the role of SnCs and SASP in skeletal pathophysiology, the mechanism of cellular senescence in affecting bone metabolism, and potential therapeutic approaches, particularly senolytics and senomorphics, in treating cellular senescence-related bone diseases.

Emerging roles of nerve-bone axis in modulating skeletal system.

Over the past decades, emerging evidence in the literature has demonstrated that the innervation of bone is a crucial modulator for skeletal physiology and pathophysiology. The nerve-bone axis sparked extensive preclinical and clinical investigations aimed at elucidating the contribution of nerve-bone crosstalks to skeleton metabolism, homeostasis, and injury repair through the perspective of skeletal neurobiology. To date, peripheral nerves have been widely reported to mediate bone growth and development and fracture healing via the secretion of neurotransmitters, neuropeptides, axon guidance factors, and neurotrophins. Relevant studies have further identified several critical neural pathways that stimulate profound alterations in bone cell biology, revealing a complex interplay between the skeleton and nerve systems. In addition, inspired by nerve-bone crosstalk, novel drug delivery systems and bioactive materials have been developed to emulate and facilitate the process of natural bone repair through neuromodulation, eventually boosting osteogenesis for ideal skeletal tissue regeneration. Overall, this work aims to review the novel research findings that contribute to deepening the current understanding of the nerve-bone axis, bringing forth some schemas that can be translated into the clinical scenario to highlight the critical roles of neuromodulation in the skeletal system.

AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.

Exercise-induced activation of adenosine monophosphate-activated protein kinase (AMPK) and substrate phosphorylation modulate the metabolic capacity of mitochondria in skeletal muscle. However, the key effector(s) of AMPK and the regulatory mechanisms remain unclear. Here, we showed that AMPK phosphorylation of the folliculin interacting protein 1 (FNIP1) serine-220 (S220) controls mitochondrial function and muscle fuel utilization during exercise. Loss of FNIP1 in skeletal muscle resulted in increased mitochondrial content and augmented metabolic capacity, leading to enhanced exercise endurance in mice. Using skeletal muscle-specific nonphosphorylatable FNIP1 (S220A) and phosphomimic (S220D) transgenic mouse models as well as biochemical analysis in primary skeletal muscle cells, we demonstrated that exercise-induced FNIP1 (S220) phosphorylation by AMPK in muscle regulates mitochondrial electron transfer chain complex assembly, fuel utilization, and exercise performance without affecting mechanistic target of rapamycin complex 1-transcription factor EB signaling. Therefore, FNIP1 is a multifunctional AMPK effector for mitochondrial adaptation to exercise, implicating a mechanism for exercise tolerance in health and disease.

Necklace-like Te-Au reticula platform with three dimensional hotspots Surface-Enhanced Raman Scattering (SERS) sensor for food hazards analysis.

In this work, we combined three-dimensional (3D) necklace-like Te-Au reticula as novel surface-enhanced Raman scattering (SERS) active substrates with oxidation-reduction displacement reactions to construct a molecular machine for SERS detection. The structurally tunable 3D necklace-like spatial structures generated more active 'hot spots' and thus enhanced the sensitivity of SERS signals. Besides, layers of ultrathin nanowires showed high sequence dependence that ensure the repeatability and abundant hotspots at interparticle gaps and guarantee the high SERS performance of the substrate. A better-localized surface plasmon resonance (LSPR) effect of the sensor was verified by finite-difference time-domain (FDTD) analysis in both Raman intensities and electromagnetic field distributions compared to the citrate-stabilized AuNPs and CTAB-protected AuNRs. The proposed strategy can also serve as a universally amplified and sensitive detection platform for monitoring different molecules, thus achieving an amplification detection of 3,3'-diethylthiatricarbocyanine iodide (DTTCI) are 1 nM and R6G with a low limit of detection of 1 pM. Especially, the intensity of the main vibration of R6G from 30 spots of SERS data with excellent reproducibility (relative standard deviation of 6.25 %). High selectivity and accuracy of the SERS sensor were proved by practical analysis melamine (MM) in milk with a linear calibration curve (R2 = 0.9962) and a limit of detection of 0.75 mg/kg. Our research provides a new perspective to construct 3D SERS sensor from integrated structural design.

DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser56 to diminish pancreatic ß cell function upon overnutrition.

Impeded autophagy can impair pancreatic ß cell function by causing apoptosis, of which DAP-related apoptosis-inducing kinase-2 (DRAK2) is a critical regulator. Here, we identified a marked up-regulation of DRAK2 in pancreatic tissue across humans, macaques, and mice with type 2 diabetes (T2D). Further studies in mice showed that conditional knockout (cKO) of DRAK2 in pancreatic ß cells protected ß cell function against high-fat diet feeding along with sustained autophagy and mitochondrial function. Phosphoproteome analysis in isolated mouse primary islets revealed that DRAK2 directly phosphorylated unc-51-like autophagy activating kinase 1 (ULK1) at Ser56, which was subsequently found to induce ULK1 ubiquitylation and suppress autophagy. ULK1-S56A mutation or pharmacological inhibition of DRAK2 preserved mitochondrial function and insulin secretion against lipotoxicity in mouse primary islets, Min6 cells, or INS-1E cells. In conclusion, these findings together indicate an indispensable role of the DRAK2-ULK1 axis in pancreatic ß cells upon metabolic challenge, which offers a potential target to protect ß cell function in T2D.

Formyl phloroglucinol meroterpenoids from the leaves of Eucalyptus globulus subsp. maidenii and their ATP-citrate lyase inhibitory activities.

Three new formyl phloroglucinol meroterpenoids, eumaidials A-C (1-3), were isolated from the leaves of Eucalyptus globulus subsp. maidenii, along with ten known analogues (4-13). Their chemical structures were determined by various spectral data and electronic circular dichroism calculations. Eumaidial A (1) is the first ß-caryophyllene-based formyl phloroglucinol meroterpenoids from the genus Eucalyptus. Compounds 1-4 and 10 exhibited ATP-citrate lyase inhibitory activities, and compounds 2 and 3 suppressed the hepatocyte lipogenesis.

Road dust exposure and human corneal damage in a plateau high geological background provincial capital city: Spatial distribution, sources, bioaccessibility, and cytotoxicity of dust heavy metals.

Ocular surface diseases are common in the plateau city, Kunming China, the continued daily exposure to heavy metals in dust may be an important inducement. In this study, the 150 road dust samples from five functional areas in Kunming were collected. The concentrations, distribution, possible sources, and bioaccessibility of heavy metals were analyzed. The adverse effects of dust extracts on human corneal epithelial cells and the underlying mechanisms were also assessed. The concentrations (mg·kg-1) of As (19.1), Cd (2.67), Cr (90.5), Cu (123), Pb (78.4), and Zn (389) in road dust were higher than the soil background, with commercial and residential areas showing the highest pollution. Their bioaccessibility in artificial tears was As (6.59 %) > Cu (5.11 %) > Ni (1.47 %) > Cr (1.17 %) > Mn (0.84 %) > Cd (0.76 %) > Zn (0.50 %) > Pb (0.31 %). The two main sources of heavy metals included tire and mechanical abrasion (24.5 %) and traffic exhaust (21.6 %). All dust extracts induced cytotoxicity, evidenced by stronger inhibition of cell viability, higher production of ROS, and altered mRNA expression of antioxidant enzymes and cell cycle-related genes, with commercial- areas-2 (CA2)-dust extract showing the greatest oxidative damage and cell cycle arrest. Our data may provide new evidence that dust exposure in high geological background cities could trigger human cornea damage.

Impact of poor medication adherence on clinical outcomes and health resource utilization in patients with hypertension and/or dyslipidemia: systematic review.

INTRODUCTION: We aimed to summarize evidence on the effect of poor medication adherence on clinical outcomes and health resource utilization (HRU) among patients with hypertension and/or dyslipidemia. AREAS COVERED: A systematic review of studies reporting clinical outcomes and HRU for patients by status of adherence to antihypertensives and/or lipid-lowering medications was searched using Embase, MEDLINE, and MEDLINE In-Process and supplemented by manual searches of conference abstracts. In total, 45 studies were included, with most being retrospective observational studies (n = 36). Patients with poor adherence to antihypertensives and lipid-lowering medications compared with those with good adherence showed less reduction of blood pressure (BP) and low-density lipoprotein cholesterol (LDL-c) after 6-12 months follow-up (∆ systolic BP: 1.2 vs. -4.5 mmHg; ∆LDL-c: -14.0 to -18.9 vs. -34.1 to -42.0 mg/dL). Poor adherence was also significantly associated with a higher risk of cardiovascular events (HR: 1.1-1.9) and mortality (HR: 1.4-1.8) in patients with hypertension and dyslipidemia and increased HRU (i.e. outpatient visits, risk of cardiovascular-related and all-cause hospitalization, annual inpatient days, total health-care costs). EXPERT OPINION: Poor adherence is associated with poor clinical outcomes and increased HRU, highlighting the need to enhance medication adherence in patients with hypertension and/or dyslipidemia.

High blood pressure is a leading cause of death and disease burden followed by high lipid levels in blood. Due to the silent nature of the diseases, patients can fall short of optimal medicinal treatment adherence and persistence, leading to poor outcomes and disease complications. The effectiveness of medicinal interventions depends on the appropriate medication-taking behavior of patients as lower adherence can lead to poor treatment benefits. Research was conducted to look for published studies that assessed the effect of lower medication adherence on clinical outcomes and health resource use among patients with high blood pressure, high lipid levels in blood, or both. Researchers were able to find 45 already published studies, from which 32 evaluated the use of blood pressure lowering medications and 7 evaluated the use of lipid-lowering medications, while 6 included patients treated with both types of medications. Refill of pharmacy prescription records was the most common method of assessing treatment adherence. Researchers found that patients with lower adherence to these medications compared with those with good adherence showed less decrease in blood pressure levels and less improvement in blood lipid levels after 6­12 months of follow-up. Patients who had lower adherence also had higher rates of cardiovascular events and deaths and increased usage of health services including visits to outpatient clinics, getting admitted to hospitals, and a longer stay of hospitalizations, leading to a higher overall healthcare cost. These findings suggest lower adherence is associated with poor clinical outcomes and increased health-care resource usage, highlighting the need to improve medication adherence in patients with high blood pressure and high lipid levels in blood.