Exploring the mechanisms of Qingdu Fang for the treatment of cervical HR-HPV using UPLC-QTOF-MS, network pharmacology, and cell experimentation.

Background: Qingdu Fang (QDF) is a traditional Chinese herbal formula with remarkable clinical effect in the treatment of HR-HPV, but its mechanism remains unclear. In this study, UPLC-QTOF-MS was used to detect its components, network pharmacology was used to explore the traditional Chinese medicine monomers and their related targets for the treatment of HR-HPV in QDF. Molecular docking and in vitro experiments were performed to verify the results. Methods: QDF constituents and active compounds were identified using UPLC-QTOF-MS analysis. TCMSP and GeneCard databases were used to identify active components, targets, and potential therapeutic targets in HR-HPV. PPI network was constructed using the String database to analyze protein-protein interactions. Cytoscape3.7.2 was used to construct PPI networks, while GO enrichment and KEGG pathway analyses with R. The effect of QDF on H8 cell proliferation was measured using the CCK-8 method, and apoptosis and cell cycle was assessed with flow cytometry. The effects of QDF on PI3K/AKT pathway were detected by Western blotting. Results: A total of 27 compounds were identified on QDF by UPLC-QTOF-MS. Base on Network pharmacology,a total of 254 target genes are involved in the action of QDF on cervical HR-HPV. PPI analysis suggested that TP53, JUN, AKT1, STAT3, TNF and IL6 were potential targets for QDF treatment of HR-HPV. Molecular docking shows that two compounds have strong binding activity with AKT1. CCK-8 and morphological observation have shown that QDF inhibits H8 cell proliferation in a dose-dependent manner. Flow cytometry experiments suggest that QDF induces apoptosis and cell cycle arrest in H8 cells. Western blotting experiments reveal that QDF inhibits the PI3K/AKT signaling pathway. Conclusion: QDF has a multi-faceted therapeutic approach for HR-HPV, targeting inflammation, oxidation, and apoptosis. It induces apoptosis in H8 cells by inhibiting the PI3K/AKT pathway.

Green Guidewire Combined with Epidural Needle-Saline Separating Minimize Invasiveness and Optimize Outcomes in Single-Port Laparoscopic Treatment for Pediatric Inguinal Hernia.

Objective: To investigate the application value, feasibility, and safety of modified single-port laparoscopic surgery in the treatment of pediatric inguinal hernia. Methods: One hundred and twenty cases of children with indirect inguinal hernia admitted from 2017 to 2022 were enrolled in the Control and Observation groups, with 80 and 40 cases, respectively. They underwent traditional open high ligation of the hernia sac and modified single-port laparoscopic high ligation of the hernia sac, respectively. The operation duration, surgical incision size, intraoperative bleeding, postoperative hospital stay, first ambulation time, and hospitalization expenses were compared between the two groups, as well as the incidence of surgical complications in the two groups. Results: The surgical incision size, intraoperative bleeding, postoperative hospital stay, and first ambulation time of the Observation group were less than those of the Control group. There was no significant difference in operation duration or hospitalization expenses between the two groups. Only two cases in the Observation group showed suture knot reactions after surgery, with no incision infection, inguinal hematoma, iatrogenic cryptorchidism, etc. The overall incidence of complications in the Observation group was lower than that of the Control group. Conclusion: Modified single-port laparoscopic surgery for inguinal hernia in children has the advantages of minimal invasiveness, and enhanced recovery, along with fewer complications and recurrence, hence it is worthy of recommendation in clinical practice.

Surface ligand-regulated renal clearance of MRI/SPECT dual-modality nanoprobes for tumor imaging.

BACKGROUND: The general sluggish clearance kinetics of functional inorganic nanoparticles tend to raise potential biosafety concerns for in vivo applications. Renal clearance is a possible elimination pathway for functional inorganic nanoparticles delivered through intravenous injection, but largely depending on the surface physical chemical properties of a given particle apart from its size and shape. RESULTS: In this study, three small-molecule ligands that bear a diphosphonate (DP) group, but different terminal groups on the other side, i.e., anionic, cationic, and zwitterionic groups, were synthesized and used to modify ultrasmall Fe3O4 nanoparticles for evaluating the surface structure-dependent renal clearance behaviors. Systematic studies suggested that the variation of the surface ligands did not significantly increase the hydrodynamic diameter of ultrasmall Fe3O4 nanoparticles, nor influence their magnetic resonance imaging (MRI) contrast enhancement effects. Among the three particle samples, Fe3O4 nanoparticle coated with zwitterionic ligands, i.e., Fe3O4@DMSA, exhibited optimal renal clearance efficiency and reduced reticuloendothelial uptake. Therefore, this sample was further labeled with 99mTc through the DP moieties to achieve a renal-clearable MRI/single-photon emission computed tomography (SPECT) dual-modality imaging nanoprobe. The resulting nanoprobe showed satisfactory imaging capacities in a 4T1 xenograft tumor mouse model. Furthermore, the biocompatibility of Fe3O4@DMSA was evaluated both in vitro and in vivo through safety assessment experiments. CONCLUSIONS: We believe that the current investigations offer a simple and effective strategy for constructing renal-clearable nanoparticles for precise disease diagnosis.

Pulsatile flow increases METTL14-induced m 6 A modification and attenuates septic cardiomyopathy: an experimental study.

INTRODUCTION: Septic cardiomyopathy is a sepsis-mediated cardiovascular complication with severe microcirculatory malperfusion. Emerging evidence has highlighted the protective effects of pulsatile flow in case of microcirculatory disturbance, yet the underlying mechanisms are still elusive. The objective of this study was to investigate the mechanisms of N 6 -methyladenosine (m 6 A) modification in the alleviation of septic cardiomyopathy associated with extracorporeal membrane oxygenation (ECMO)-generated pulsatile flow. METHODS: Rat model with septic cardiomyopathy was established and was supported under ECMO either with pulsatile or non-pulsatile flow. Peripheral perfusion index (PPI) and cardiac function parameters were measured using ultrasonography. Dot blot assay was applied to examine the m 6 A level, while qRT-PCR, Western blot, immunofluorescence, and immunohistochemistry were used to measure the expressions of related genes. RNA immunoprecipitation assay was performed to validate the interaction between molecules. RESULTS: The ECMO-generated pulsatile flow significantly elevates microcirculatory PPI, improves myocardial function, protects the endothelium, and prolongs survival in rat models with septic cardiomyopathy. The pulsatile flow mediates the METTL14-mediated m 6 A modification to zonula occludens-1 (ZO-1) mRNA (messenger RNA), which stabilizes the ZO-1 mRNA depending on the presence of YTHDF2. The pulsatile flow suppresses the PI3K-Akt signaling pathway, of which the downstream molecule Foxo1, a negative transcription factor of METTL14, binds to the METTL14 promoter and inhibits the METTL14-induced m 6 A modification. CONCLUSION: The ECMO-generated pulsatile flow increases METTL14-induced m 6 A modification in ZO-1 and attenuates the progression of septic cardiomyopathy, suggesting that pulsatility might be a new therapeutic strategy in septic cardiomyopathy by alleviating microcirculatory disturbance.

Pooling sputum samples for the Xpert MTB/RIF assay: a practical screening strategy for highly infectious tuberculosis cases.

The Xpert MTB/RIF test (Xpert) can help in the accurate screening of tuberculosis, however, its widespread use is limited by its high cost and lack of accessibility. Pooling of sputum samples for testing is a strategy to cut expenses and enhance population coverage but may result in a decrease in detection sensitivity due to the dilution of Mycobacterium tuberculosis (Mtb) by sample mixing. We investigated how the mixing ratio affected the detection performance of Xpert. We used frozen sputum samples that had been kept after individual Xpert assays of the sputa from Mtb-confirmed TB patients and non-TB patients. Our results showed that the overall sensitivity of the Xpert pooling assay remained higher than 80% when the mixing ratio was between 1/2 and 1/8. When the mixing ratio was raised to 1/16, the positive detection rate fell to 69.0%. For patients with either a high sputum Mtb smear score ≥ 2+, a time-to-positive culture ≤ 10 days, or an Xpert test indicating a high or medium abundance of bacteria, the pooling assay positivity rates were 93.3%, 96.8%, and 100% respectively, even at a 1/16 mixing ratio. For participants with cavities and cough, the pooling assay positivity rates were 86.2% and 90.0% at a 1/8 ratio, higher than for those without these signs. Our results show that the Xpert pooled assay has a high overall sensitivity, especially for highly infectious patients. This pooling strategy with lower reagent and labor costs could support TB screening in communities with limited resources, thereby facilitating reductions in the community transmission and incidence of TB worldwide.

Unveiling the Biologically Dynamic Degradation of Iron Oxide Nanoparticles via a Continuous Flow System.

Nanomaterials are increasingly being employed for biomedical applications, necessitating a comprehensive understanding of their degradation behavior and potential toxicity in the biological environment. This study utilizes a continuous flow system to simulate the biologically relevant degradation conditions and investigate the effects of pH, protein, redox species, and chelation ligand on the degradation of iron oxide nanoparticles. The morphology, aggregation state, and relaxivity of iron oxide nanoparticles after degradation are systematically characterized. The results reveal that the iron oxide nanoparticles degrade at a significantly higher rate under the acidic environment. Moreover, incubation with bovine serum albumin enhances the stability and decreases the dissolution rate of iron oxide nanoparticles. In contrast, glutathione accelerates the degradation of iron oxide nanoparticles, while the presence of sodium citrate leads to the fastest degradation. This study reveals that iron oxide nanoparticles undergo degradation through various mechanisms in different biological microenvironments. Furthermore, the dissolution and aggregation of iron oxide nanoparticles during degradation significantly impact their relaxivity, which has implications for their efficacy as magnetic resonance imaging contrast agents in vivo. The results provide valuable insights for assessing biosafety and bridge the gap between fundamental research and clinical applications of iron oxide nanoparticles.

Association of Cardiac Valve Calcification and 1-year Mortality after Lower-extremity Amputation in Diabetic Patients: A Retrospective Study.

BACKGROUND: Cardiac valve calcification predisposes patients to a higher risk of adverse cardiovascular events. This study aimed to investigate the association between cardiac valve calcification and 1-year mortality in diabetic patients after lower-extremity amputation. METHODS: This was a retrospective study conducted on the clinical data of diabetic patients who underwent lower-extremity amputation admitted to the Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China for diabetic foot ulcers needed lower extremity amputation surgery between July 2017 and March 2021. Detailed preoperative medical assessments were performed and recorded. Cardiac valve calcification was assessed using echocardiography at baseline. Oneyear follow-up assessments were conducted and included clinical visits, hospital record assessments, and telephone reviews to obtain the survival status of patients. RESULTS: Ninety-three diabetic patients participated in the study. The 1-year follow-up mortality rate after amputation was 24.7%. Compared to the survival group, the prevalence of cardiac valve calcification and the Revised Cardiac Risk Index [RCRI] were higher in the mortality group. In the Cox regression analysis, cardiac valvular calcification [HR=3.427, 95% CI=1.125- 10.443, P=0.030] was found to be an independent predictor of all-cause mortality after amputation. In addition, the patients with both aortic valve calcification and mitral annular calcification had a higher all-cause mortality rate [50%]. Receiver operator characteristic curve analysis showed a stronger predictive ability when using a combination of calcified valve number and RCRI [AUC=0.786 95%, CI=0.676-0.896, P=0.000]. CONCLUSION: In diabetic patients after lower-extremity amputation, cardiac valve calcification was associated with all-cause mortality during 1-year follow-up. Combination of calcified valve number and RCRI score showed a stronger predictive value for mortality.

Severe noncardiogenic pulmonary edema after cardiopulmonary bypass: Case report.

Lung injury is a common complication after cardiopulmonary bypass (CPB). However, cases of noncardiogenic pulmonary edema in which the patient ultimately requires extracorporeal membrane oxygenation (ECMO) support are uncommon. A 54-year-old man was admitted to the hospital with shortness of breath after activity and paroxysmal dyspnoea at night for 3 months. Infective endocarditis and acute heart failure were diagnosed. The patient underwent emergency surgery including aortic valve replacement, mitral valve replacement, tricuspid valve repair, and ventricular septal defect correction. It's noteworthy that the patient experienced significant pulmonary edema during the surgery and within 8 hours postoperatively, with over 3000 mL of yellow-clear fluid aspirated from the trachea and bronchi. The patient eventually recovered through ECMO V-V mode treatment. Inflammatory markers were markedly elevated during the perioperative period, and blood smear revealed Gram-positive bacterial infection. Blood NGS testing detected Streptococcus pneumoniae infection. Despite various factors contributing to the patient's pulmonary edema, it is hypothesized that the edema is related to uncontrolled inflammatory response and cytokine storm. Therefore, when significant pulmonary edema occurs during surgery, swift and decisive actions are necessary to avoid missing the optimal rescue window. If required, the use of ECMO is an effective final treatment option.

Risk factors of major bleeding detected by machine learning method in patients undergoing liver resection with controlled low central venous pressure technique.

BACKGROUND: Controlled low central venous pressure (CLCVP) technique has been extensively validated in clinical practices to decrease intraoperative bleeding during liver resection process; however, no studies to date have attempted to propose a scoring method to better understand what risk factors might still be responsible for bleeding when CLCVP technique was implemented. METHODS: We aimed to use machine learning to develop a model for detecting the risk factors of major bleeding in patients who underwent liver resection using CLCVP technique. We reviewed the medical records of 1077 patients who underwent liver surgery between January 2017 and June 2020. We evaluated the XGBoost model and logistic regression model using stratified K-fold cross-validation (K = 5), and the area under the receiver operating characteristic curve, the recall rate, precision rate, and accuracy score were calculated and compared. The SHapley Additive exPlanations was employed to identify the most influencing factors and their contribution to the prediction. RESULTS: The XGBoost classifier with an accuracy of 0.80 and precision of 0.89 outperformed the logistic regression model with an accuracy of 0.76 and precision of 0.79. According to the SHapley Additive exPlanations summary plot, the top six variables ranked from most to least important included intraoperative hematocrit, surgery duration, intraoperative lactate, preoperative hemoglobin, preoperative aspartate transaminase, and Pringle maneuver duration. CONCLUSIONS: Anesthesiologists should be aware of the potential impact of increased Pringle maneuver duration and lactate levels on intraoperative major bleeding in patients undergoing liver resection with CLCVP technique.   What is already known on this topic-Low central venous pressure technique has already been extensively validated in clinical practices, with no prediction model for major bleeding. What this study adds-The XGBoost classifier outperformed logistic regression model for the prediction of major bleeding during liver resection with low central venous pressure technique. How this study might affect research, practice, or policy-anesthesiologists should be aware of the potential impact of increased PM duration and lactate levels on intraoperative major bleeding in patients undergoing liver resection with CLCVP technique.

Exploring atherosclerosis imaging with contrast-enhanced MRI using PEGylated ultrasmall iron oxide nanoparticles.

Plaque rupture is a critical concern due to its potential for severe outcomes such as cerebral infarction and myocardial infarction, underscoring the urgency of noninvasive early diagnosis. Magnetic resonance imaging (MRI) has gained prominence in plaque imaging, leveraging its noninvasiveness, high spatial resolution, and lack of ionizing radiation. Ultrasmall iron oxides, when modified with polyethylene glycol, exhibit prolonged blood circulation and passive targeting toward plaque sites, rendering them conducive for MRI. In this study, we synthesized ultrasmall iron oxide nanoparticles of approximately 3 nm via high-temperature thermal decomposition. Subsequent surface modification facilitated the creation of a dual-modality magnetic resonance/fluorescence probe. Upon intravenous administration of the probes, MRI assessment of atherosclerotic plaques and diagnostic evaluation were conducted. The application of Flash-3D sequence imaging revealed vascular constriction at lesion sites, accompanied by a gradual signal amplification postprobe injection. T1-weighted imaging of the carotid artery unveiled a progressive signal ratio increase between plaques and controls within 72 h post-administration. Fluorescence imaging of isolated carotid arteries exhibited incremental lesion-to-control signal ratios. Additionally, T1 imaging of the aorta demonstrated an evolving signal enhancement over 48 h. Therefore, the ultrasmall iron oxide nanoparticles hold immense promise for early and noninvasive diagnosis of plaques, providing an avenue for dynamic evaluation over an extended time frame.

Self-standing boron nitride bulks enabled by liquid metals for thermal management.

Thermally conductive materials (TCMs) are highly desirable for thermal management applications to tackle the "overheating" concerns in the electronics industry. Despite recent progress, the development of high performance TCMs integrated with an in-plane thermal conductivity (TC) higher than 50.0 W (m K)-1 and a through-plane TC greater than 10.0 W (m K)-1 is still challenging. Herein, self-standing liquid metal@boron nitride (LM@BN) bulks with ultrahigh in-plane TC and through-plane TC were reported for the first time. In the LM@BN bulks, LM could serve as a bonding and thermal linker among the oriented BN platelets, thus remarkably accelerating heat transfer across the whole system. Benefiting from the formation of a unique structure, the LM@BN bulk achieved an ultrahigh in-plane TC of 82.2 W (m K)-1 and a through-plane TC of 20.6 W (m K)-1, which were among the highest values ever reported for TCMs. Furthermore, the LM@BN bulks exhibited superior compressive and leakage-free performances, with a high compressive strength (5.2 MPa) and without any LM leakage even after being crushed. It was also demonstrated that the excellent TCs of the LM@BN bulks made them effectively cool high-power light emitting diode modules. This work opens up one promising pathway for the development of high-performance TCMs for thermal management in the electronics industry.

Intraoperative accidental hypothermia as a probable cause of malignant ventricular arrhythmias in an elderly patient undergoing transurethral resection of prostate: A case report.

Background: Intraoperative hypothermia is a common but severe condition that is defined as a core body temperature below 36 °C. Accidental hypothermia can produce coagulopathy, immunosuppression and peripheral hypoperfusion that can ultimately lead to life-threatening ventricular arrhythmias and vital organ injury, and it is significantly associated with perioperative complications and mortality. Case description: We report the case of an 82-year-old man who presented with persistent ventricular tachycardia intraoperatively due to accidental hypothermia. The patient was diagnosed with benign prostatic hypertrophy and scheduled for transurethral resection of the prostate. Laboratory tests showed moderate anemia, and echocardiography indicated mild tricuspid and mitral regurgitation. The patient received general anesthesia with endotracheal intubation. Four hours after the start of surgery, the patient developed sudden ventricular tachycardia with severe hypotension. Arterial blood gas sampling indicated that there was no disturbance of electrolytes, acid-base balance or excessive bleeding. The rectal temperature was measured immediately, and the core temperature was 32 °C. The patient received antiarrhythmic therapy and rewarming measures. No additional ventricular arrhythmias appeared after the core temperature rose to 35 °C and the blood pressure returned to normal. The patient was transferred to the intensive care unit after surgery for further observation and was moved to the general ward the next day. He was discharged 4 days later without significant organ damage. Conclusions: Intraoperative hypothermia may increase ventricular arrhythmia risk, especially in elderly patients. Surgeons and anesthesiologists should pay more attention to preventing and reversing accidental hypothermia, necessitating aggressive efforts to maintain normothermia during surgery.

Intraoperative diagnosis of early lymphatic metastasis using neodymium-based rare-earth NIR-II fluorescence nanoprobe.

The high mortality of breast cancer is closely related to lymph node (LN) metastasis. Sentinel LNs (SLNs) are the first station where tumor cells metastasize through the lymphatic system. As such, achieving precise diagnosis of the early metastatic status of SLNs during surgery is of paramount importance for precision therapy of breast cancer. While invasive SLNs biopsy is the gold standard for evaluating the status of SLNs, its use is often time-consuming and may increase the risk of operation. It is still challenging to develop a means for rapid SLN metastasis diagnosis. Herein, NaGdF4:5%Nd@NaLuF4 rare earth nanoparticles (Gd:Nd-RENPs) with near-infrared-II (NIR-II) fluorescence and magnetic resonance imaging (MRI) properties were fabricated. With the nanoprobe, metastatic SLNs and lymph vessels (LVs) rapidly brighten and can be observed by the NIR-II imaging system, which is totally different from normal LNs and LVs. The remarkable contrast observed via NIR-II imaging serves to swiftly delineate metastatic SLNs from normal ones, subsequently guiding precise surgical resection of metastatic LNs in just 10 minutes. Furthermore, the consistency between the results obtained via MRI and NIR-II imaging further validates the dependability of this nanoprobe as a diagnostic tool for metastatic SLNs. Additionally, the Gd:Nd-RENPs exhibited good biocompatibility in vitro and in vivo. In this study, we demonstrated the advantages and prospects of NIR-II imaging for intraoperative early SLN metastasis assessment and shed light on the potential of the dual-modal Gd:Nd-RENPs as a nanoprobe.

Functional investigation and two-sample Mendelian randomization study of neuropathic pain hub genes obtained by WGCNA analysis.

Objective: Neuropathic pain as a complex chronic disease that occurs after neurological injury, however the underlying mechanisms are not clarified in detail, hence therapeutic options are limited. The purpose of this study was to explore potential hub genes for neuropathic pain and evaluate the clinical application of these genes in predicting neuropathic pain. Methods: Differentially expressed analysis and weighted gene co-expression network analysis (WGCNA) was used to explore new neuropathic pain susceptibility modules and hub genes. KEGG and GO analyses was utilized to explore the potential role of these hub genes. Nomogram model and ROC curves was established to evaluate the diagnostic efficacy of hub genes. Additionally, the correlation of IL-2 with immune infiltration was explored. Finally, a Mendelian randomization study was conducted to determine the causal effect of IL-2 on neuropathic pain based on genome-wide association studies. Results: WGCNA was performed to establish the networks of gene co-expression, screen for the most relevant module, and screen for 440 overlapping WGCNA-derived key genes. GO and KEGG pathway enrichment analyses demonstrated that the key genes were correlated with cytokine receptor binding, chemokine receptor binding, positive regulation of JAK-STAT cascade, chemokine-mediated signaling pathway, PI3K-AKT pathway and chemokine pathway. Through Cytoscape software, top ten up-regulated genes with high scores were IL2, SMELL, CCL4, CCR3, CXCL1, CCR1, HGF, CXCL2, GATA3, and CRP. In addition, nomogram model performed well in predicting neuropathic pain risk, and with the ROC curve, the model was showed to be effective in diagnosis. Finally, IL2 was selected and we observed that IL2 was causally associated with immune cell infiltrates in trigeminal neuralgia. In inverse variance weighting, we found that IL2 was associated with the risk of trigeminal neuralgia with an OR of 1.203 (95% CI = 1.004-1.443, p = 0.045). Conclusion: We constructed a WGCNA-based co-expression network and identified neuropathic pain-related hub genes, which may offer further insight into pre-symptomatic diagnostic approaches and may be useful for the study of molecular mechanisms for understanding neuropathic pain risk genes.

Biomimetic Upconversion Nanoplatform Synergizes Photodynamic Therapy and Enhanced Radiotherapy against Tumor Metastasis.

The easy recurrence and high metastasis of fatal tumors require the development of a combination therapy, which is able to overcome the drawbacks of monomodal strategies such as surgery, photodynamic therapy (PDT), and radiotherapy (RT). Taking the complementary advantages of PDT and RT, we present herein the integration of lanthanide-doped upconversion nanoparticles (UCNPs) with chlorin e6 (Ce6)-imbedded RBC membrane vesicles as a near-infrared-induced PDT agent for achieving synchronous depth PDT and RT with reduced radiation exposure. In such a nanoagent, gadolinium-doped UCNPs with strong X-ray attenuation ability act not only as a light transductor to activate the loaded photosensitizer Ce6 to allow PDT but also as a radiosensitizer to enhance RT. PDT with enhanced low-dose RT can achieve synergistic inhibition of tumor growth by producing reactive oxygen species to destroy local tumor cells and inducing strong T-cell-dependent immunogenic cell death to arrest systemic cancer metastasis. This combination of PDT and RT might be a potential appealing strategy for tumor eradication.

Vision for Ratiometric Nanoprobes: In Vivo Noninvasive Visualization and Readout of Physiological Hallmarks.

Lesion areas are distinguished from normal tissues surrounding them by distinct physiological characteristics. These features serve as biological hallmarks with which targeted biomedical imaging of the lesion sites can be achieved. Although tremendous efforts have been devoted to providing smart imaging probes with the capability of visualizing the physiological hallmarks at the molecular level, the majority of them are merely able to derive anatomical information from the tissues of interest, and thus are not suitable for taking part in in vivo quantification of the biomarkers. Recent advances in chemical construction of advanced ratiometric nanoprobes (RNPs) have enabled a horizon for quantitatively monitoring the biological abnormalities in vivo. In contrast to the conventional probes whose dependency of output on single-signal profiles restricts them from taking part in quantitative practices, RNPs are designed to provide information in two channels, affording a self-calibration opportunity to exclude the analyte-independent factors from the outputs and address the issue. Most of the conventional RNPs have encountered several challenges regarding the reliability and sufficiency of the obtained data for high-performance imaging. In this Review, we have summarized the recent progresses in developing highly advanced RNPs with the capabilities of deriving maximized information from the lesion areas of interest as well as adapting themselves to the complex biological systems in order to minimize microenvironmental-induced falsified signals. To provide a better outlook on the current advanced RNPs, nanoprobes based on optical, photoacoustic, and magnetic resonance imaging modalities for visualizing a wide range of analytes such as pH, reactive species, and different derivations of amino acids have been included. Furthermore, the physicochemical properties of the RNPs, the major constituents of the nanosystems and the analyte recognition mechanisms have been introduced. Moreover, the alterations in the values of the ratiometric signal in response to the analyte of interest as well as the time at which the highest value is achieved, have been included for most of RNPs discussed in this Review. Finally, the challenges as well as future perspectives in the field are discussed.

Reversing Acute Kidney Injury through Coordinated Interplay of Anti-Inflammation and Iron Supplementation.

Acute kidney injury (AKI) induced by ischemia reperfusion is closely related to mitochondrial dysfunction. Nicotinamide adenine dinucleotide (NAD+ ) can enhance the mitochondrial function and restrain the following inflammation, but it is hardly delivered and lacks renal targeting ability. To address these problems, herein, an ultrasmall Fe3 O4 nanoparticle is used as a carrier to deliver nicotinamide mononucleotide (NMN), a precursor of NAD+ . An outstanding sophistication of the current design is that once NMN is attached on the surface of Fe3 O4 nanoparticles through its phosphate group, the remaining part is structurally highly similar to nicotinamide riboside, which provides an opportunity to deliver the NAD+ precursor into renal cells through nicotinamide riboside kinase 1 on the cell membrane. It is demonstrated that NMN-loaded Fe3 O4 nanoparticles can effectively reverse AKI induced by ischemia reperfusion. In-depth studies indicate that a well-timed iron replenishment following anti-inflammation treatment plays a determined role in recovering AKI, which distinguishes the current study from previous strategies centering on anti-ROS (reactive oxygen species), anti-inflammation, or even iron elimination.

Intranasal Pathway for Nanoparticles to Enter the Central Nervous System.

Intranasal administration was previously proposed for delivering drugs for central nervous system (CNS) diseases. However, the delivery and elimination pathways, which are very imperative to know for exploring the therapeutic applications of any given CNS drugs, remain far from clear. Because lipophilicity has a high priority in the design of CNS drugs, the as-prepared CNS drugs tend to form aggregates. Therefore, a PEGylated Fe3O4 nanoparticle labeled with a fluorescent dye was prepared as a model drug and studied to elucidate the delivery pathways of intranasally administered nanodrugs. Through magnetic resonance imaging, the distribution of the nanoparticles was investigated in vivo. Through ex vivo fluorescence imaging and microscopy studies, more precise distribution of the nanoparticles across the entire brain was disclosed. Moreover, the elimination of the nanoparticles from cerebrospinal fluid was carefully studied. The temporal dose levels of intranasally delivered nanodrugs in different parts of the brain were also investigated.

Expression and Clinical Significance of Golgi Phosphoprotein 3 (GOLPH3) in Papillary Thyroid Carcinoma.

This study aimed to explore the correlation of Golgi phosphoprotein 3 (GOLPH3) levels in papillary thyroid carcinoma (PTC) and papillary thyroid microcarcinoma (PTMC) with clinicopathologic features. GOLPH3 expression was determined by western blotting in solid tumors and the adjacent normal thyroid tissues. Mammalian target of rapamycin (mTOR) and Ki-67 were examined by immunohistochemical staining. Significantly higher levels of GOLPH3 protein were observed in PTC and PTMC compared with the adjacent normal thyroid tissues ( P <0.001). GOLPH3 level was positively associated with lymph node metastasis and clinical stage in PTC ( P <0.05) and utterly related to the clinical stage in PTMC ( P =0.012). No correlation was observed between GOLPH3 level and other clinicopathologic parameters such as sex, local invasion, tumor number, and tumor size. The expression level of GOLPH3 protein in mTOR-positive PTC was significantly higher than in mTOR-negative PTC ( P =0.002 in PTC, P =0.022 in PTMC) and positively correlated with Ki-67 proliferation index in PTC via Pearson correlation analysis ( r =0.353, P =0.007 in PTC; r =0.583, P <0.001 in PTMC). In conclusion, the relative expression level of GOLPH3 protein was significantly higher in PTC and PTMC than in normal thyroid tissues and increased with cancer severity. It may provide adjunctive information for diagnosing and predicting prognosis in patients with PTC or PTMC.