Infant and adult human intestinal enteroids are morphologically and functionally distinct.

Human intestinal enteroids (HIEs) are gaining recognition as physiologically relevant models of the intestinal epithelium. While HIEs from adults are used extensively in biomedical research, few studies have used HIEs from infants. Considering the dramatic developmental changes that occur during infancy, it is important to establish models that represent infant intestinal characteristics and physiological responses. We established jejunal HIEs from infant surgical samples and performed comparisons to jejunal HIEs from adults using RNA sequencing (RNA-Seq) and morphologic analyses. We then validated differences in key pathways through functional studies and determined whether these cultures recapitulate known features of the infant intestinal epithelium. RNA-Seq analysis showed significant differences in the transcriptome of infant and adult HIEs, including differences in genes and pathways associated with cell differentiation and proliferation, tissue development, lipid metabolism, innate immunity, and biological adhesion. Validating these results, we observed a higher abundance of cells expressing specific enterocyte, goblet cell, and enteroendocrine cell markers in differentiated infant HIE monolayers, and greater numbers of proliferative cells in undifferentiated 3D cultures. Compared to adult HIEs, infant HIEs portray characteristics of an immature gastrointestinal epithelium including significantly shorter cell height, lower epithelial barrier integrity, and lower innate immune responses to infection with an oral poliovirus vaccine. HIEs established from infant intestinal tissues reflect characteristics of the infant gut and are distinct from adult cultures. Our data support the use of infant HIEs as an ex vivo model to advance studies of infant-specific diseases and drug discovery for this population. IMPORTANCE: Tissue or biopsy stem cell-derived human intestinal enteroids are increasingly recognized as physiologically relevant models of the human gastrointestinal epithelium. While enteroids from adults and fetal tissues have been extensively used for studying many infectious and non-infectious diseases, there are few reports on enteroids from infants. We show that infant enteroids exhibit both transcriptomic and morphological differences compared to adult cultures. They also differ in functional responses to barrier disruption and innate immune responses to infection, suggesting that infant and adult enteroids are distinct model systems. Considering the dramatic changes in body composition and physiology that begin during infancy, tools that appropriately reflect intestinal development and diseases are critical. Infant enteroids exhibit key features of the infant gastrointestinal epithelium. This study is significant in establishing infant enteroids as age-appropriate models for infant intestinal physiology, infant-specific diseases, and responses to pathogens.

Silencing of ZNF610 suppresses cell proliferation and migration in lung adenocarcinoma.

Zinc finger proteins (ZNFs) play a significant role in the initiation and progression of tumors. Nevertheless, the specific contribution of ZNF610 to lung adenocarcinoma (LUAD) remains poorly understood. This study sought is to elucidate the role of ZNF610 in LUAD. Transcript data of LUAD were obtained from The Cancer Genome Atlas Program (TCGA) database and processed via R program. The expression of ZNF610 was assessed in various cell lines. To compare the proliferative capacity of cells with or without ZNF610 silencing, CCK8, cell colony formation assay, and Celigo label-free cell counting assay were employed. Furthermore, transwell migration and invasion assays were conducted to evaluate the migratory and invasive abilities of the cells. The expression levels of genes and proteins were assessed using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot techniques. In different LUAD cells, the expression level of ZNF610 was found to be significantly higher in LUAD cells compared to MRC-5 and BASE-2B cells. Moreover, the silencing of ZNF610 resulted in a decrease in cell proliferation and migration abilities. Additionally, the apoptosis rate of cells increased upon silencing ZNF610. Notably, the proportion of cells in the G0/G1 phase increased, while the proportion of cells in the S phase decreased following ZNF610 silencing. Finally, ß-catenin and snail were identified as downstream targets of ZNF610 in cells. Our findings suggest that silencing ZNF610 could inhibit LUAD cell proliferation and migration, possibly through the downregulation of ß-catenin and snail.

High spatiotemporal mapping of cortical blood flow velocity with an enhanced accuracy.

Cerebral blood flow velocity is one of the most essential parameters related to brain functions and diseases. However, most existing mapping methods suffer from either inaccuracy or lengthy sampling time. In this study, we propose a particle-size-related calibration method to improve the measurement accuracy and a random-access strategy to suppress the sampling time. Based on the proposed methods, we study the long-term progress of cortical vasculopathy and abnormal blood flow caused by glioma, short-term variations of blood flow velocity under different anesthetic depths, and cortex-wide connectivity of the rapid fluctuation of blood flow velocities during seizure onset. The experimental results demonstrate that the proposed calibration method and the random-access strategy can improve both the qualitative and quantitative performance of velocimetry techniques and are also beneficial for understanding brain functions and diseases from the perspective of cerebral blood flow.

Photoacoustic expansion microscopy of melanosomes.

Optical resolution photoacoustic microscopy (OR-PAM) is a hybrid imaging method for visualizing organelles due to the high spatial resolution and abundant optical contrast. Usually, OR-PAM employs high numerical aperture (NA) objectives and high-frequency ultrasonic detectors to resolve three-dimensional (3D) microstructures of cells. Expansion microscopy (ExM) provides a nanoscale resolution by isotropically enlarging cells instead of utilizing ultrahigh NA objectives. In this Letter, we report the development of photoacoustic expansion microscopy (PA-ExM) that combines the advantages of OR-PAM and ExM for 3D organelle imaging using near-infrared light. We evaluate the performance of PA-ExM using label-free melanoma cells, where the image quality of melanosome distributions in expanded cells using a 40× objective is comparable to that of unexpanded cells using an oil-immersed 100× objective. The results suggest that PA-ExM possesses the great potential to study organelles.

Grafting a Polymer Coating Layer onto Li1.2 Ni0.13 Co0.13 Mn0.54 O2 Cathode by Benzene Diazonium Salts to Facilitate the Cycling Performance and High-Voltage Stability.

Li-rich Mn-based cathodes have been regarded as promising cathodes for lithium-ion batteries because of their low cost of raw materials (compared with Ni-rich layer structure and LiCoO2 cathodes) and high energy density. However, for practical application, it needs to solve the great drawbacks of Li-rich Mn-based cathodes like capacity degradation and operating voltage decline. Herein, an effective method of surface modification by benzene diazonium salts to build a stable interface between the cathode materials and the electrolyte is proposed. The cathodes after modification exhibit excellent cycling performance (the retention of specific capacity is 84.2% after 350 cycles at the current density of 1 C), which is mainly attributed to the better stability of the structure and interface. This work provides a novel way to design the coating layer with benzene diazonium salts for enhancing the structural stability under high voltage condition during cycling.

Human intestinal organoids from Cronkhite-Canada syndrome patients reveal link between serotonin and proliferation.

Cronkhite-Canada Syndrome (CCS) is a rare, noninherited polyposis syndrome affecting 1 in every million individuals. Despite over 50 years of CCS cases, the etiopathogenesis and optimal treatment for CCS remains unknown due to the rarity of the disease and lack of model systems. To better understand the etiology of CCS, we generated human intestinal organoids (HIOs) from intestinal stem cells isolated from 2 patients. We discovered that CCS HIOs are highly proliferative and have increased numbers of enteroendocrine cells producing serotonin (also known as 5-hydroxytryptamine or 5HT). These features were also confirmed in patient tissue biopsies. Recombinant 5HT increased proliferation of non-CCS donor HIOs and inhibition of 5HT production in the CCS HIOs resulted in decreased proliferation, suggesting a link between local epithelial 5HT production and control of epithelial stem cell proliferation. This link was confirmed in genetically engineered HIOs with an increased number of enteroendocrine cells. This work provides a new mechanism to explain the pathogenesis of CCS and illustrates the important contribution of HIO cultures to understanding disease etiology and in the identification of novel therapies. Our work demonstrates the principle of using organoids for personalized medicine and sheds light on how intestinal hormones can play a role in intestinal epithelial proliferation.

Chronic Exposure to Environmental Pollutant Ammonia Causes Damage to the Olfactory System and Behavioral Abnormalities in Mice.

Ammonia (NH3) is a major air pollutant. However, few studies have been extended beyond the histopathological changes in the olfactory mucosa to the impact of NH3 exposure on other parts of the olfactory system and olfactory functioning. Therefore, we assessed the effects of exogenous NH3 (either 20 ppm for the low exposure group or 200 ppm for the high exposure group) on the various parts of the olfactory system by histological observation, gene expression, immunochemistry, and chemical analyses. A total of 140 Institute of Cancer Research mice (4 weeks old), 70 females and 70 males (average body weight at the start: 21.5 ± 1.9 g), were used. The exposure lasted for 4 weeks, and the mice were exposed to the NH3 for 4 h per day. Our results showed that chronic exposure to NH3 damaged the olfactory system, with consequences for changing the foraging behavior and anxiety behavior. Our results also suggest that it is plausible that NH3 recruited T cells and activated microglia cells and astrocytes, leading to inflammation in the olfactory system. Increased release of proinflammatory cytokines (TNF-α, IL-1ß, IL-6, and interferon-γ) and reduced release of anti-inflammatory cytokines (IL-4 and IFN-beta) led to tissue damage and compromised the functions of the olfactory system.

Near-Infrared II Semiconducting Polymer Dots: Chain Packing Modulation and High-Contrast Vascular Imaging in Deep Tissues.

Fluorescence imaging in the second near-infrared (NIR-II) window has attracted considerable interest in investigations of vascular structure and angiogenesis, providing valuable information for the precise diagnosis of early stage diseases. However, it remains challenging to image small blood vessels in deep tissues because of the strong photon scattering and low fluorescence brightness of the fluorophores. Here, we describe our combined efforts in both fluorescent probe design and image algorithm development for high-contrast vascular imaging in deep turbid tissues such as mouse and rat brains with intact skull. First, we use a polymer blending strategy to modulate the chain packing behavior of the large, rigid, NIR-II semiconducting polymers to produce compact and bright polymer dots (Pdots), a prerequisite for in vivo fluorescence imaging of small blood vessels. We further developed a robust Hessian matrix method to enhance the image contrast of vascular structures, particularly the small and weakly fluorescent vessels. The enhanced vascular images obtained in whole-body mouse imaging exhibit more than an order of magnitude improvement in the signal-to-background ratio (SBR) as compared to the original images. Taking advantage of the bright Pdots and Hessian matrix method, we finally performed through-skull NIR-II fluorescence imaging and obtained a high-contrast cerebral vasculature in both mouse and rat models bearing brain tumors. This study in Pdot probe development and imaging algorithm enhancement provides a promising approach for NIR-II fluorescence vascular imaging of deep turbid tissues.

Functional Genomics of Gastrointestinal Escherichia coli Isolated from Patients with Cancer and Diarrhea.

We describe the epidemiology and clinical characteristics of 29 patients with cancer and diarrhea in whom Enteroaggregative Escherichia coli (EAEC) was initially identified by GI BioFire panel multiplex. E. coli strains were successfully isolated from fecal cultures in 14 of 29 patients. Six of the 14 strains were identified as EAEC and 8 belonged to other diverse E. coli groups of unknown pathogenesis. We investigated these strains by their adherence to human intestinal organoids, cytotoxic responses, antibiotic resistance profile, full sequencing of their genomes, and annotation of their functional virulome. Interestingly, we discovered novel and enhanced adherence and aggregative patterns for several diarrheagenic pathotypes that were not previously seen when co-cultured with immortalized cell lines. EAEC isolates displayed exceptional adherence and aggregation to human colonoids compared not only to diverse GI E. coli , but also compared to prototype strains of other diarrheagenic E. coli . Some of the diverse E. coli strains that could not be classified as a conventional pathotype also showed an enhanced aggregative and cytotoxic response. Notably, we found a high carriage rate of antibiotic resistance genes in both EAEC strains and diverse GI E. coli isolates and observed a positive correlation between adherence to colonoids and the number of metal acquisition genes carried in both EAEC and the diverse E. coli strains. This work indicates that E. coli from cancer patients constitute strains of remarkable pathotypic and genomic divergence, including strains of unknown disease etiology with unique virulomes. Future studies will allow for the opportunity to re-define E. coli pathotypes with greater diagnostic accuracy and into more clinically relevant groupings.

Clinicopathological features and correlation analysis of male breast cancer.

To analyze and compare the clinicopathological characteristics of male breast cancer (MBC) among Chinese patients and those from East Asia and other regions. Clinicopathological data from 3 kinds of data sources, including 31 MBC patients in Jiangsu Provincial Hospital (JPH) from 2014 to 2021 in China, 20 literature data on East Asian MBC patients from 2014 to 2021, and 3102 MBC patients registered in the surveillance, epidemiology, and end results (SEER) database from 2014 to 2019, were collected and retrospectively analyzed. The average ages of first-diagnosis MBC patients in JPH and East Asian patients were 59.7 and 62.3 years old, respectively, which were younger than those of SEER patients (66.5 years old). Between East Asian and SEER patients, the status or rates of main breast cancer type, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, breast subtype, and TNM stage were relatively close, and their differences were not statistically significant (P > .05). Differences were observed in chemotherapy, surgery, pathological grade, and lymph node positivity (P < .01). Furthermore, no statistically significant difference was observed between the JPH and East Asian patients (all P > .05). In JPH and SEER, linear regression relationships were observed between the lymph node positivity rate, tumor size, and histological grade. JPH and East Asian MBC patients were younger than SEER patients. Between East Asian and SEER patients, the status of the main breast cancer type, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, breast subtype, and TNM stage were similar, but there were differences in chemotherapy, surgery, pathological grade, and lymph node positivity. The findings of this study should prove to be helpful to deepen our understanding of East Asian MBC.

Is it safe for the spinal metastasis patients with preoperative deep vein thrombosis to use low-molecular-weight heparin before surgery? A prospective study.

Spine surgeons should weigh the risks of anticoagulants against their benefits in preventing deep venous thrombosis (DVT), as they may increase the risk of bleeding. Spinal metastasis patients undergoing decompression with fixation are at a high risk for DVT, which may occur preoperatively. Therefore, anticoagulants should be administered preoperatively. This study aimed to evaluate the safety of the administration of anticoagulants in treating spinal metastasis patients with preoperative DVT. Therefore, we prospectively investigated the prevalence of DVT in these patients. Patients who were diagnosed with preoperative DVT were included in an anticoagulant group. Subcutaneous low-molecular-weight heparin (LMWH) was administered. Patients without DVT were included in a non-anticoagulant group. Data on patient information, clinical parameters, blood test results, and bleeding complications were also collected. Moreover, the safety of anticoagulants was analyzed. The prevalence of preoperative DVT was 8.0%. None of the patients developed pulmonary thromboembolism. Furthermore, no significant differences in blood loss, drainage volume, hemoglobin levels, number of transfusions, or preoperative trans-catheter arterial embolization were observed between the two groups. None of the patients developed major bleeding. However, two patients experienced wound hematoma and one experienced incisional bleeding in the non-anticoagulant group. Therefore, LMWH is safe for spinal metastasis patients. Future randomized controlled trials should be conducted to evaluate the validity of perioperative prophylactic anticoagulation therapy in these patients.

Human Sapovirus Replication in Human Intestinal Enteroids.

Human sapoviruses (HuSaVs), like human noroviruses (HuNoV), belong to the Caliciviridae family and cause acute gastroenteritis in humans. Since their discovery in 1976, numerous attempts to grow HuSaVs in vitro were unsuccessful until 2020, when these viruses were reported to replicate in a duodenal cancer cell-derived line. Physiological cellular models allowing viral replication are essential to investigate HuSaV biology and replication mechanisms such as genetic susceptibility, restriction factors, and immune responses to infection. In this study, we demonstrate replication of two HuSaV strains in human intestinal enteroids (HIEs) known to support the replication of HuNoV and other human enteric viruses. HuSaVs replicated in differentiated HIEs originating from jejunum, duodenum and ileum, but not from the colon, and bile acids were required. Between 2h and 3 to 6 days postinfection, viral RNA levels increased up from 0.5 to 1.8 log10-fold. Importantly, HuSaVs were able to replicate in HIEs independent of their secretor status and histo-blood group antigen expression. The HIE model supports HuSaV replication and allows a better understanding of host-pathogen mechanisms such as cellular tropism and mechanisms of viral replication. IMPORTANCE Human sapoviruses (HuSaVs) are a frequent but overlooked cause of acute gastroenteritis, especially in children. Little is known about this pathogen, whose successful in vitro cultivation was reported only recently, in a cancer cell-derived line. Here, we assessed the replication of HuSaV in human intestinal enteroids (HIEs), which are nontransformed cultures originally derived from human intestinal stem cells that can be grown in vitro and are known to allow the replication of other enteric viruses. Successful infection of HIEs with two strains belonging to different genotypes of the virus allowed discovery that the tropism of these HuSaVs is restricted to the small intestine, does not occur in the colon, and replication requires bile acid but is independent of the expression of histo-blood group antigens. Thus, HIEs represent a physiologically relevant model to further investigate HuSaV biology and a suitable platform for the future development of vaccines and antivirals.

Split Ring Resonator Topology Based Microwave Induced Thermoacoustic Imaging (SRR-MTAI).

Microwave-induced thermoacoustic imaging (MTAI) using low-energy and long-wavelength microwave photons has great potential in detecting deep-seated diseases due to its unique ability of visualizing intrinsic electric properties of tissue in high resolution. However, the low contrast in conductivity between a target (e.g., a tumor) and the surroundings sets a fundamental limit for achieving a high imaging sensitivity, which significantly hinders its biomedical applications. To overcome this limit, we develop a split ring resonator (SRR) topology based MTAI (SRR-MTAI) approach to achieve highly sensitive detection by precise manipulation and efficient delivery of microwave energy. The in vitro experiments show that SRR-MTAI demonstrates an ultrahigh sensitivity of distinguishing a 0.4% difference in saline concentrations and a 2.5-fold enhancement of detecting a tissue target which mimicks a tumor embedded at a depth of 2 cm. The in vivo animal experiments conducted indicate that the imaging sensitivity between a tumor and the surrounding tissue is increased by 3.3-fold using SRR-MTAI. The dramatic enhancement in imaging sensitivity suggests that SRR-MTAI has the potential to open new avenues for MTAI to tackle a variety of biomedical problems that were impossible previously.

Fast Delivery of Multifunctional NIR-II Theranostic Nanoaggregates Enabled by the Photoinduced Thermoacoustic Process.

Multifunctional nanoaggregates are widely used in cancer phototheranostics. However, it is challenging to construct their multifunctionality with a single component, and deliver them rapidly and efficiently without complex modifications. Herein, a NIR-absorbing small molecule named TBT-2(TP-DPA) is designed and certify its theranostic potentials. Then, their nanoaggregates, which are simply encapsulated by DSPE-PEG, demonstrate a photothermal efficiency of 51% while keeping a high photoluminescence quantum yield in the NIR region. Moreover, the nanoaggregates can be excited and delivered by an 808 nm pulse laser to solid tumors within only 40 min. The delivery efficiency and theranostic efficacy are better than that of the traditional enhanced permeability and retention (EPR) effect (generally longer than 24 hours). This platform is first termed as the photoinduced thermoacoustic (PTA) process, and confirm its application requires both NIR-responsive materials and pulse laser irradiation. This study not only inspires the design of multifunctional nanoaggregates, but also offers a feasible approach to their fast delivery. The platform reported here provides a promising prospect to boost the development of multifunctional theranostic drugs and maximize the efficacy of used medicines for their clinical applications.

Plasmon Driven Nanocrystal Transformation by Aluminum Nano-Islands with an Alumina Layer.

The plasmonic photothermal effects of metal nanostructures have recently become a new priority of studies in the field of nano-optics. Controllable plasmonic nanostructures with a wide range of responses are crucial for effective photothermal effects and their applications. In this work, self-assembled aluminum nano-islands (Al NIs) with a thin alumina layer are designed as a plasmonic photothermal structure to achieve nanocrystal transformation via multi-wavelength excitation. The plasmonic photothermal effects can be controlled by the thickness of the Al2O3 and the intensity and wavelength of the laser illumination. In addition, Al NIs with an alumina layer have good photothermal conversion efficiency even in low temperature environments, and the efficiency will not decline significantly after storage in air for 3 months. Such an inexpensive Al/Al2O3 structure with a multi-wavelength response provides an efficient platform for rapid nanocrystal transformation and a potential application for the wide-band absorption of solar energy.

Androgen-deprivation therapy with leuprolide increases abdominal adiposity without causing cardiac dysfunction in middle-aged male mice: effect of sildenafil.

Androgen-deprivation therapy (ADT) is the primary systemic therapy for treating advanced or metastatic prostate cancer (PCa), which has improved survival outcomes in patients with PCa. However, ADT may develop metabolic and cardiovascular adverse events that impact the quality of life and lifespan in PCa survivors. The present study was designed to establish a murine model of ADT with a gonadotropin-releasing hormone (GnRH) agonist leuprolide and to investigate its effects on metabolism and cardiac function. We also examined the potential cardioprotective role of sildenafil (inhibitor of phosphodiesterase 5) under chronic ADT. Middle-aged male C57BL/6J mice received a 12-wk subcutaneous infusion via osmotic minipumps containing either saline or 18 mg/4 wk leuprolide with or without 1.3 mg/4 wk sildenafil cotreatment. Compared with saline controls, leuprolide treatment significantly reduced prostate weight and serum testosterone levels, confirming chemical castration in these mice. The ADT-induced chemical castration was not affected by sildenafil. Leuprolide significantly increased the weight of abdominal fat after 12-wk treatment without a change in total body weight, and sildenafil did not block the proadipogenic effect of leuprolide. No signs of left ventricular systolic and diastolic dysfunction were observed throughout the leuprolide treatment period. Interestingly, leuprolide treatment significantly elevated serum levels of cardiac troponin I (cTn-I), a biomarker of cardiac injury, and sildenafil did not abolish this effect. We conclude that long-term ADT with leuprolide increases abdominal adiposity and cardiac injury biomarker without cardiac contractile dysfunction. Sildenafil did not prevent ADT-associated adverse changes.

High resolution intravital photoacoustic microscopy reveals VEGF-induced bone regeneration in mouse tibia.

Osteogenesis and angiogenesis are essential for bone homeostasis and repair. Newly formed vessels convey osteogenic progenitors during bone regeneration. However, the lack of continuous and label-free visualization of the bone microvasculature has resulted in little understanding of the neovascular dynamics. Here, we take advantage of optical-resolution photoacoustic microscopy (ORPAM) for label-free, intravital, long-term observation of the bone vascular dynamics, including angiogenesis, remodeling and quantified angiogenic effect of locally-applied vascular endothelial growth factor (VEGF) in the murine tibial defect model. We employed ex vivo confocal microscopy and micro-computed tomography (micro-CT) imaging to verify the positive role of VEGF treatment. VEGF treatment increased the concentration of total hemoglobin, vascular branching, and vascular density, which correlated with more osteoprogenitors and increased bone formation within the defect. These data demonstrated ORPAM as a useful imaging tool that detected functional capillaries to understand hemodynamics, and revealed the effectiveness of locally delivered therapeutic agents with sufficient sensitivity, contributing to the understanding of spatiotemporal regulatory mechanisms on blood vessels during bone regeneration.

Procyanidin B2 alleviates oxidative stress-induced nucleus pulposus cells apoptosis through upregulating Nrf2 via PI3K-Akt pathway.

Oxidative stress can lead to nucleus pulposus cell (NPC) apoptosis, which is considered to be one of the main contributors to intervertebral disc degeneration (IVDD). Procyanidin B2 is a natural antioxidant that protects against oxidative stress. However, whether procyanidin B2 protects NPCs from oxidative stress remains unknown. In this study, we demonstrated that procyanidin B2 could reduce tert-butyl hydroperoxide-induced reactive oxygen species in rat NPCs and attenuate rat NPC apoptosis. Further experiments revealed that procyanidin B2 upregulated the expression of both nuclear factor erythroid 2-related factor 2 (Nrf2) and phosphorylation of protein kinase B (Akt). We then used silencing of Nrf2 and LY294002 to silence Nrf2 expression and block the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, respectively, and found that the protective roles of procyanidin B2 in NPCs were inhibited. Therefore, we demonstrated that procyanidin B2 alleviated rat NPC apoptosis induced by oxidative stress by upregulating Nrf2 via activation of the PI3K/Akt signaling pathway. This study provides a potential therapeutic approach for procyanidin B2 in IVDD, which might help in the development of new drugs for IVDD treatment.

Beyond Erectile Dysfunction: cGMP-Specific Phosphodiesterase 5 Inhibitors for Other Clinical Disorders.

Cyclic guanosine monophosphate (cGMP), an important intracellular second messenger, mediates cellular functional responses in all vital organs. Phosphodiesterase 5 (PDE5) is one of the 11 members of the cyclic nucleotide phosphodiesterase (PDE) family that specifically targets cGMP generated by nitric oxide-driven activation of the soluble guanylyl cyclase. PDE5 inhibitors, including sildenafil and tadalafil, are widely used for the treatment of erectile dysfunction, pulmonary arterial hypertension, and certain urological disorders. Preclinical studies have shown promising effects of PDE5 inhibitors in the treatment of myocardial infarction, cardiac hypertrophy, heart failure, cancer and anticancer-drug-associated cardiotoxicity, diabetes, Duchenne muscular dystrophy, Alzheimer's disease, and other aging-related conditions. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular, anticancer, and neurological benefits. In this review, we provide an overview of the current state of knowledge on PDE5 inhibitors and their potential therapeutic indications for various clinical disorders beyond erectile dysfunction.

Imaging-Guided Biomimetic M1 Macrophage Membrane-Camouflaged Magnetic Nanorobots for Photothermal Immunotargeting Cancer Therapy.

Biohybrid micro/nanorobots have demonstrated improved therapeutic outcomes for targeting and treating diseases in preclinical trials. However, in vivo applications remain challenging due to a lack of sufficient targeting. Based on evidence that immune cells play a role in the immune modulation in the tumor microenvironment, we developed M1 macrophage membrane-coated magnetic photothermal nanocomplexes (MPN) for photoacoustic (PA) imaging-guided tumor therapy. The MPN were able to inherit the protein from the original macrophage cells and exert a targeted immunosuppression role. Integrating black phosphorus quantum dots and DOX also greatly enhanced reactive oxygen species generation and chemo-phototherapy efficacy. The results suggest that the MPN can be employed as an excellent tumor immunotargeting nanorobotic platform for modulating the tumor microenvironment under PA imaging and magnetic guidance and, thus, exert synergistic therapeutic efficacies.