Cardiovascular mortality risk in patients with ovarian cancer: a population-based study.

OBJECTIVES: Ovarian cancer (OC) can occur at different ages and is affected by a variety of factors. In order to evaluate the risk of cardiovascular mortality in patients with ovarian cancer, we included influencing factors including age, histological type, surgical method, chemotherapy, whether distant metastasis, race and developed a nomogram to evaluate the ability to predict occurrence. At present, we have not found any correlation studies on cardiovascular death events in patients with ovarian cancer. This study was designed to provide targeted measures for effective prevention of cardiovascular death in patients with ovarian cancer. METHODS: Kaplan-Meier analysis and multivariable Cox proportional model were performed to evaluate the effectiveness of cardiovascular diseases on overall survival (OS) and ovarian cancer-specific survival (OCSS). We compared multiple groups including clinical, demographic, therapeutic characteristics and histological types. Cox risk regression analysis, Kaplan-Meier survival curves, and propensity score matching were employed for analyzing the data. RESULTS: A total of 88,653 ovarian cancer patients were collected, of which 2,282 (2.57%) patients died due to cardiovascular-related diseases. Age, chemotherapy and whether satisfactory cytoreduction surgery is still the most important factors affecting the prognosis of ovarian cancer patients, while different histological types, diagnosis time, and race also have a certain impact on the prognosis. The newly developed nomogram model showed excellent predictive performance, with a C-index of 0.759 (95%CI: 0.757-0.761) for the group. Elderly patients with ovarian cancer are still a high-risk group for cardiovascular death [HR: 21.07 (95%CI: 5.21-85.30), p < 0.001]. The calibration curve showed good agreement from predicted survival probabilities to actual observations. CONCLUSION: This study found that age, histology, surgery, race, chemotherapy, and tumor metastasis are independent prognostic factors for cardiovascular death in patients with ovarian cancer. The nomogram-based model can accurately predict the OS of ovarian cancer patients. It is expected to inform clinical decision-making and help develop targeted treatment strategies for this population.

Lactate/Hydroxycarboxylic Acid Receptor 1 in Alzheimer's Disease: Mechanisms and Therapeutic Implications-Exercise Perspective.

Lactate has a novel function different from previously known functions despite its traditional association with hypoxia in skeletal muscle. It plays various direct and indirect physiological functions. It is a vital energy source within the central nervous system (CNS) and a signal transmitter regulating crucial processes, such as angiogenesis and inflammation. Activating lactate and its associated receptors elicits effects like synaptic plasticity and angiogenesis alterations. These effects can significantly influence the astrocyte-neuron lactate shuttle, potentially impacting cognitive performance. Decreased cognitive function relates to different neurodegenerative conditions, including Alzheimer's disease (AD), ischemic brain injury, and frontotemporal dementia. Therefore, lactic acid has significant potential for treating neurodegenerative disorders. Exercise is a method that induces the production of lactic acid, which is similar to the effect of lactate injections. It is a harmless and natural way to achieve comparable results. Animal experiments demonstrate that high-intensity intermittent exercise can increase vascular endothelial growth factor (VEGF) levels, thus promoting angiogenesis. In vivo, lactate receptor-hydroxycarboxylic acid receptor 1 (HCAR1) activation can occur by various stimuli, including variations in ion concentrations, cyclic adenosine monophosphate (cAMP) level elevations, and fluctuations in the availability of energy substrates. While several articles have been published on the benefits of physical activity on developing Alzheimer's disease in the CNS, could lactic acid act as a bridge? Understanding how HCAR1 responds to these signals and initiates associated pathways remains incomplete. This review comprehensively analyzes lactate-induced signaling pathways, investigating their influence on neuroinflammation, neurodegeneration, and cognitive decline. Consequently, this study describes the unique role of lactate in the progression of Alzheimer's disease.

Optimization of small molecule degraders and antagonists for targeting estrogen receptor based on breast cancer: current status and future.

The estrogen receptor (ER) is a classical receptor protein that plays a crucial role in mediating multiple signaling pathways in various target organs. It has been shown that ER-targeting therapies inhibit breast cancer cell proliferation, enhance neuronal protection, and promote osteoclast formation. Several drugs have been designed to specifically target ER in ER-positive (ER+) breast cancer, including selective estrogen receptor modulators (SERM) such as Tamoxifen. However, the emergence of drug resistance in ER+ breast cancer and the potential side effects on the endometrium which has high ER expression has posed significant challenges in clinical practice. Recently, novel ER-targeted drugs, namely, selective estrogen receptor degrader (SERD) and selective estrogen receptor covalent antagonist (SERCA) have shown promise in addressing these concerns. This paper provides a comprehensive review of the structural functions of ER and highlights recent advancements in SERD and SERCA-related small molecule drugs, especially focusing on their structural optimization strategies and future optimization directions. Additionally, the therapeutic potential and challenges of novel SERDs and SERCAs in breast cancer and other ER-related diseases have been discussed.

Aerobic Exercise Facilitates the Nuclear Translocation of SREBP2 by Activating AKT/SEC24D to Contribute Cholesterol Homeostasis for Improving Cognition in APP/PS1 Mice.

Impaired cholesterol synthesizing ability is considered a risk factor for the development of Alzheimer's disease (AD), as evidenced by reduced levels of key proteases in the brain that mediate cholesterol synthesis; however, cholesterol deposition has been found in neurons in tangles in the brains of AD patients. Although it has been shown that statins, which inhibit cholesterol synthesis, reduce the incidence of AD, this seems paradoxical for AD patients whose cholesterol synthesizing capacity is already impaired. In this study, we aimed to investigate the effects of aerobic exercise on cholesterol metabolism in the brains of APP/PS1 mice and to reveal the mechanisms by which aerobic exercise improves cognitive function in APP/PS1 mice. Our study demonstrates that the reduction of SEC24D protein, a component of coat protein complex II (COPII), is a key factor in the reduction of cholesterol synthesis in the brain of APP/PS1 mice. 12 weeks of aerobic exercise was able to promote the recovery of SEC24D protein levels in the brain through activation of protein kinase B (AKT), which in turn promoted the expression of mem-brane-bound sterol regulatory element-binding protein 2 (SREBP2) nuclear translocation and the expression of key proteases mediating cholesterol synthesis. Simultaneous aerobic exercise restored cholesterol transport capacity in the brain of APP/PS1 mice with the ability to efflux excess cholesterol from neurons and reduced neuronal lipid rafts, thereby reducing cleavage of the APP amyloid pathway. Our study emphasizes the potential of restoring intracerebral cholesterol homeostasis as a therapeutic strategy to alleviate cognitive impairment in AD patients.

Aerobic exercise regulates GPR81 signal pathway and mediates complement- microglia axis homeostasis on synaptic protection in the early stage of Alzheimer's disease.

AIMS: Memory impairment is a major clinical manifestation in Alzheimer's disease (AD) patients, while regular exercise may prevent and delay degenerative changes in memory functions, and our aim is to explore the influence and molecular mechanisms of aerobic exercise on the early stages of Alzheimer's disease. MAIN METHODS: 3-month-old male APP/PS1 transgenic AD mice and C57BL/6J wild-type mice were randomly divided into four groups: wild-type and APP/PS1 mice with sedentary (WT-SED, AD-SED), and running (WT-RUN, AD-RUN) for 12-weeks. The spatial learning and memory function, RNA-sequencing, spine density, synaptic associated protein, mRNA and protein expression involved in G protein-coupled receptor 81 (GPR81) signaling pathway, and complement factors in brain were measured. KEY FINDINGS: Aerobic exercise improved spatial learning and memory in APP/PS1 mice, potentially attributed to increased dendritic spine density. Subsequently, potential underlying mechanisms were identified through RNA sequencing: regular aerobic exercise could activate the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) cAMP/PKA signaling pathway and upregulate synaptic function-related proteins to promote synaptic growth, possibly by modulating GPR81. Notably, regular aerobic exercise inhibited microglial activation, reversed the microglial phenotype, reduced the production of initiation factor C1q and central factor C3 in the complement cascade in the brain, prevented the colocalization of microglia and PSD-95, and thus prevented synaptic loss. SIGNIFICANCE: Physical exercise could play a critical role in improving cognitive function in AD by promoting synaptic growth and preventing synaptic loss, which may be related to the regulation of the GPR81/cAMP/PKA signaling pathway and inhibition of complement-mediated microglial phagocytosis of synapses.

Effect of Exercise and Oral Niacinamide Mononucleotide on Improving Mitochondrial Autophagy in Alzheimer's Disease.

Oral niacinamide mononucleotide (NMN) and aerobic exercise have been shown to enhance niacinamide adenine dinucleotide (NAD+) in the body. NAD+ plays a critical role in the body and can directly and indirectly affect many key cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cell aging, and immune cell function. It is noteworthy that the level of NAD+ decreases gradually with increasing age. Decreased levels of NAD+ have been causally associated with a number of diseases associated with aging, including cognitive decline, cancer, metabolic diseases, sarcopenia, and frailty. Many diseases related to aging can be slowed down or even reversed by restoring NAD+ levels. For example, oral NMN or exercise to increase NAD+ levels in APP/PS1 mice have been proven to improve mitochondrial autophagy, but currently, there is no regimen combining oral NMN with exercise. This review summarizes recent studies on the effect of oral NMN on the enhancement of NAD+ in vivo and the improvements in mitochondrial autophagy abnormalities in AD through aerobic exercise, focusing on (1) how oral NMN improves the internal NAD+ level; (2) how exercise regulates the content of NAD+ in the body; (3) the relationship between exercise activation of NAD+ and AMPK; (4) how SIRT1 is regulated by NAD+ and AMPK and activates PGC-1α to mediate mitochondrial autophagy through changes in mitochondrial dynamics. By summarizing the results of the above four aspects, and combined with the synthesis of NAD+ in vivo, we can infer how exercise elevates the level of NAD+ in vivo to mediate mitochondrial autophagy, so as to propose a new hypothesis that exercise interferes with Alzheimer's disease (AD).

Reexamining the Causes and Effects of Cholesterol Deposition in the Brains of Patients with Alzheimer's Disease.

Alzheimer's disease (AD) is a degenerative disease of the central nervous system. Numerous studies have shown that imbalances in cholesterol homeostasis in the brains of AD patients precede the onset of clinical symptoms. In addition, cholesterol deposition has been observed in the brains of AD patients even though peripheral cholesterol does not enter the brain through the blood‒brain barrier (BBB). Studies have demonstrated that cholesterol metabolism in the brain is associated with many pathological conditions, such as amyloid beta (Aß) production, Tau protein phosphorylation, oxidative stress, and inflammation. In 2022, some scholars put forward a new hypothesis of AD: the disease involves lipid invasion and its exacerbation of the abnormal metabolism of cholesterol in the brain. In this review, by discussing the latest research progress, the causes and effects of cholesterol retention in the brains of AD patients are analyzed and discussed. Additionally, the possible mechanism through which AD may be improved by targeting cholesterol is described. Finally, we propose that improving the impairments in cholesterol removal observed in the brains of AD patients, instead of further reducing the already impaired cholesterol synthesis in the brain, may be the key to preventing cholesterol deposition and improving the corresponding pathological symptoms.

Transient receptor potential ankyrin 1 (TRPA1) modulators: Recent update and future perspective.

The transient receptor potential ankyrin 1 (TRPA1) channel is a non-selective cation channel that senses irritant chemicals. Its activation is closely associated with pain, inflammation, and pruritus. TRPA1 antagonists are promising treatments for these diseases, and there has been a recent upsurge in their application to new areas such as cancer, asthma, and Alzheimer's disease. However, due to the generally disappointing performance of TRPA1 antagonists in clinical studies, scientists must pursue the development of antagonists with higher selectivity, metabolic stability, and solubility. Moreover, TRPA1 agonists provide a deeper understanding of activation mechanisms and aid in antagonist screening. Therefore, we summarize the TRPA1 antagonists and agonists developed in recent years, with a particular focus on structure-activity relationships (SARs) and pharmacological activity. In this perspective, we endeavor to keep abreast of cutting-edge ideas and provide inspiration for the development of more effective TRPA1-modulating drugs.

Effects of Sitagliptin on Metabolic Indices and Hormone Levels in Polycystic Ovary Syndrome: a Meta-analysis of Randomized Controlled Trials.

To evaluate the effects of sitagliptin on the metabolic indices and hormone levels in patients with polycystic ovary syndrome (PCOS). PubMed, EMBASE, Web of Science, Cochrane Library, WanFang Data, and China National Knowledge Infrastructure (CNKI) were searched for randomized controlled trials (RCTs) published up to March 2022. Eligible studies were identified based on the inclusion criteria. The primary outcomes included the homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), and total testosterone level (TT). Other outcomes included levels of sex hormones, glucose, and lipid metabolism. Forty-five studies were initially identified, and 6 RCTs with 394 patients were finally included in this study. The meta-analysis results suggest that sitagliptin improved HOMA-IR (WMD = - 0.35; 95% CI (- 0.62, - 0.08); P = 0.01), BMI (WMD = - 1.27; 95% CI (- 1.76, - 0.77); P < 0.00001), TT (SMD = - 0.66; 95% CI (- 1.25, - 0.07); P = 0.03), and HDL-C (SMD = 0.11; 95% CI (0.03, 0.18); P = 0.005). No significant differences were observed between the sitagliptin and control groups in other outcomes and in terms of adverse events. Evidence from meta-analyses suggests that sitagliptin was superior in improving insulin sensitivity, total serum testosterone, high-density lipoprotein, and body mass index. However, due to the limitations of published studies, it is difficult to draw a definite conclusion. Larger, higher-quality studies are needed to evaluate the efficacy of sitagliptin in women with PCOS.

Treadmill Exercise Modulates Intestinal Microbes and Suppresses LPS Displacement to Alleviate Neuroinflammation in the Brains of APP/PS1 Mice.

Neuroinflammation occurs throughout the pathogenesis of Alzheimer's disease (AD). Here, we investigated the effects of treadmill exercise on neuroinflammation in APP/PS1 transgenic AD mice and the potential involvement of microbe-gut-brain axis (MGB) mechanisms based on growing evidence that AD's pathogenesis is correlated with a deterioration in the function of gut microbiota. APP/PS1 transgenic AD mice were subjected to 12 weeks of treadmill exercise, followed by spatial memory tests. After the behavioral study, the amyloid (Aß) pathology, gut microbes and metabolites, bacterial lipopolysaccharide (LPS) displacement, and degree of neuroinflammation were analyzed. We found that this strategy of exercise enriched gut microbial diversity and alleviated neuroinflammation in the brain. Notably, exercise led to reductions in pathogenic bacteria such as intestinal Allobaculum, increases in probiotic bacteria such as Akkermansia, increased levels of intestine-brain barrier proteins, and attenuated LPS displacement. These results suggest that prolonged exercise can effectively modulate gut microbes and the intestinal barrier and thereby reduce LPS displacement and ultimately alleviate AD-related neuroinflammation.

Dual-target inhibitors of indoleamine 2, 3 dioxygenase 1 (Ido1): A promising direction in cancer immunotherapy.

Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that catalyzes the kynurenine (Kyn) pathway of tryptophan metabolism in the first step, and the kynurenine pathway plays a fundamental role in immunosuppression in the tumor microenvironment. Therefore, researchers are vigorously developing IDO1 inhibitors, hoping to apply them to cancer immunotherapy. Nowadays, there have been 11 kinds of IDO1 inhibitors entering clinical trials, among which many inhibitors have shown good tumor inhibitory effect in phase I/II clinical trials. But the phase III study of the most promising IDO1 inhibitor compound 29 (Epacadostat) failed in 2018, which may be caused by the compensation effect offered by tryptophan 2,3-dioxygenase (TDO), the mismatched drug combination strategies, or other reasons. Luckily, dual-target inhibitors show great potential and advantages in solving these problems. In recent years, many studies have linked IDO1 to popular targets and selected many IDO1 dual-target inhibitors through pharmacophore fusion strategy and library construction, which enhance the tumor inhibitory effect and reduce side effects. Currently, three kinds of IDO1/TDO dual-target inhibitors have entered clinical trials, and extensive studies have been developing on IDO1 dual-target inhibitors. In this review, we summarize the IDO1 dual-target inhibitors developed in recent years and focus on the structure optimization process, structure-activity relationship, and the efficacy of in vitro and in vivo experiments, shedding a light on the pivotal significance of IDO1 dual-target inhibitors in the treatment of cancer, providing inspiration for the development of new IDO1 dual-target inhibitors.

Pixel crosstalk in naked-eye micro-LED 3D display.

Micro-LED display is considered to be the most promising display technology, and naked-eye 3D display represents the most advanced frontier of display. Naked-eye 3D micro-LED display has both the advantages of micro-LED display and the characteristics of naked-eye 3D display. Only conceptual solutions for 3D micro-LED display have been reported so far. The effect of luminescence distribution and the direction of micro-LED devices on crosstalk in the naked-eye 3D display is not clear. In this paper, we first investigated the chip-shaping effect on the emission characteristics, mainly the luminescence distribution and direction of the micro-LED, and then we investigated the influence of luminescence distribution and direction of micro-LED on the pixel crosstalk in naked-eye micro-LEDs 3D display. Our work should advance the micro-LED display, especially the micro-LED 3D display.

Unidirectional-emitting GaN-based micro-LED for 3D display.

Naked-eye 3D micro-LED display combines the 3D characteristics and advantages of micro-LED simultaneously. A conventional micro-LED device emission exhibits Lambertian distribution, and it requires stacking of multiple optical components into a 3D display, resulting in bulky systems, low efficiency, and a limited viewing zone and points. We propose and investigate a single-chip micro-LED with unidirectional emission through an in-situ integrated resonant cavity and metasurface, which has great potential to be used for an efficient naked-eye 3D display with a wide viewing angle and multiple viewpoints. This Letter promotes the application of GaN-based micro-LEDs in a display, especially a 3D display.

Circularly polarized light emission from a GaN micro-LED integrated with functional metasurfaces for 3D display.

This Letter proposes a circularly polarized (CP) light GaN micro-LED which is integrated with functional metasurfaces. The one-dimensional metallic nanograting can achieve a high transverse electric (TE) reflectivity (${{\rm{R}}_{\rm{TE}}}$) and extinction ratio (ER) of TE and transverse magnetic (TM) waves, which is highly polarized output for micro-LEDs. Besides, the nanograting, which is integrated on the bottom of the GaN layer, can also support a resonant cavity, together with the top distributed Bragg reflector, which can shape the radiation pattern. By optimizing the structure parameters of nanograting, the ${{\rm{R}}_{\rm{TE}}}$ achieves over 80%, and the ER reaches higher than 38 dB at 450 nm for the GaN micro-LED. Additionally, the metasurface, which acts as a quarter-wave plate, was investigated to control the phase delay between the polarization state of the electric wave in two orthogonal components. Finally, the circular shape of the transmitted pattern denotes the high performance of the metasurface which is integrated in the micro-LED for CP light emission. The work reported in this Letter might provide potential application in a 3D polarized light display.

Multiplexing multifoci optical metasurfaces for information encoding in the ultraviolet spectrum.

Recently, optical metasurfaces have attracted much attention due to their versatile features in manipulating phase, polarization, and amplitude of both reflected and transmitted light. Because it controls over four degrees of freedom: phase, polarization, amplitude, and wavelength of light wavefronts, optical cryptography is a promising technology in information security. So far, information encoding can be implemented by the metasurface in one-dimensional (1D) mode (either wavelength or polarization) and in a two-dimensional (2D) mode of both wavelength and polarization. Here, we demonstrate multiplexing multifoci optical metasurfaces for information encoding in the ultraviolet spectrum both in the 1D and 2D modes in the spatial zone, composed of high-aspect-ratio aluminum nitride nanorods, which introduce discontinuous phases through the Pancharatnam-Berry phase to realize multifoci in the spatial zone. Since the multiplexed multifocal optical metasurfaces are sensitive to the helicity of the incident light and the wavelength is within the ultraviolet spectrum, the security of the information encrypted by it would be guaranteed.

Erratum: Yang, X. et al. Optimization of Culture Conditions for Amoxicillin Degrading Bacteria Screened from Pig Manure. Int. J. Environ. Res. Public Health 2020, 17, 1973.

The second affiliation of the paper should have been included in our original article [...].

Erratum: Yang, X., et al. Isolation, Screening, and Characterization of Antibiotic-Degrading Bacteria for Penicillin V Potassium (PVK) from Soil on a Pig Farm. Int. J. Environ. Res. Public Health 2019, 16, 2166.

The second affiliation of the paper should have been included in our original article [...].

Sputtering AlN/InxAl1-xN distributed Bragg reflector across the full visible range on Si and SiO2 substrates.

III-nitride-based distributed Bragg reflectors (DBRs) are advantageous in being in-situ integrated in III-nitride devices, and the bandgaps and their other corresponding optical parameters are tunable. However, a growing nitride DBR with low strain and high reflectivity remains a challenge. Here we demonstrate an AlN/InxAl1-xN DBR grown on Si and SiO2 substrates by reactive radio-frequency magnetron sputtering. Reflectance wavelengths covering the whole visible regions of the visible spectrum were achieved by rationally tuning the indium composition in InxAl1-xN and each layer's thickness of an AlN/InxAl1-xN DBR. This Letter should advance the design and fabrication of nitride optical and optoelectrical devices by incorporating an AlN/InxAl1-xN DBR, such as vertical-cavity surface-emitting laser (VCSEL) and RC LEDs.

Ultrawide bandgap AlN metasurfaces for ultraviolet focusing and routing.

All-dielectric metasurfaces offer a promising way to control amplitude, polarization, and phase of light. However, ultraviolet (UV) component metasurfaces are rarely reported due to significant absorption loss for most dielectric materials and the required smaller footprint or feature size. Here, we demonstrate broadband UV focusing and routing in both transmission and reflection modes in simulations by adopting aluminum nitride (AlN) with ultrawide bandgap and a waveplate metasurface structure. As for experiments, the on-axis, off-axis focusing characteristics in transmission mode have been investigated at representative UVA (375 nm) wavelength for the first time, to the best of our knowledge. Furthermore, we fabricated a UV transmission router for monowavelength, guiding UV light to the designated different spatial positions of the same or different focal planes. Our work is meaningful for the development of UV photonics components and devices and would facilitate the integration and miniaturization of UV nanophotonics.

Three-dimensional metal-semiconductor-metal AlN deep-ultraviolet detector.

Conventional metal-semiconductor-metal (MSM) ultraviolet (UV) detectors have the disadvantage of limited adjustable structural parameters, finite electrical field, and long carrier path. In this Letter, we demonstrate a three-dimensional (3D) MSM structural AlN-based deep-UV (DUV) detector, fabricated through simple trench etching and metal deposition, while flip bonding to the silicon substrate forms a flip-chip 3D-MSM (FC-3DMSM) device. 3D-MSM devices exhibit improved responsiveness and response speed, compared with conventional MSM devices. Time-dependent photoresponse of all devices is also investigated here. The enhanced performance of the 3D-MSM device is to be attributed to the intensified electrical field from the 3D metal electrode configuration and the inhibition of the carrier vertical transport, which unambiguously increases the carrier collection efficiency and migration speed, and thus the responsivity and speed as well. This work should advance the design and fabrication of AlN-based DUV detectors.