Single-Port One Anastomosis Sleeve Gastrectomy with Transit Bipartition: Initial Experience and Technique.

BACKGROUND: Sleeve gastrectomy with transit bipartition (SG-TB) procedure has been gaining traction recently. While being a relatively novel procedure, it shows potentials to improve the standalone SG outcomes, such as diabetes remission and reflux. This article aims to show insights on performing SG-TB in one anastomosis fashion (SG-OATB) and single-port approach. METHODS: Three patients who underwent laparoscopic single-port SG-OATB at our hospital were included. The parameters included in this study comprised of age, gender, height, weight, body mass index (BMI), type 2 diabetes mellitus (T2DM) assessment, gastroesophageal reflux disease (GERD) assessment, length of the small bowel, the duration of the procedure, and 30-day readmission rate. RESULTS: The mean preoperative assessments for the three patients were as follows: two females vs. one male; age 38.7 ± 5.5 years old; weight 105.7 ± 5.4 kg; height 1.64 ± 0.11 m; BMI 39.3 ± 4.7 kg/m2; fasting blood glucose 6.7 ± 1.2 mmol/L; glycosylated hemoglobin level 7.1 ± 1.3%; GERD-Questionnaire score 6.3 ± 1.5; two patients with esophagitis grade A and B following endoscopy. The total duration of the procedure was 170.0 ± 26.5 min; there was no need for conversion to multiple-port in all patients. The 30-day readmission rate for all patients was 0%. CONCLUSION: In our small cases of patients, single-port SG-OATB is feasible and safe. We found the closure of the anastomosis defect to be most technically demanding. To understand better the outcome of single-port SG-OATB, studies with larger sample and longer follow-up will be needed in the future.

Suture repair versus mesh repair in elderly populations with incarcerated or strangulated groin hernia.

Tension-free hernia repair is the gold standard for groin hernia repair. However, the optimal surgical treatment for incarcerated or strangulated groin hernia in elderly populations is controversial. The aim of this study is to compare the clinical efficacy of mesh repair and suture repair in the treatment of incarcerated or strangulated groin hernia in elderly patients. Patients ≥ 65 years who underwent urgent surgical repair for incarcerated or strangulated groin hernia from January 2012 to June 2022 were included. Patients' demographic data and postoperative outcomes were retrospectively analyzed. Patients with limited life expectancy were screened from the elderly population for subgroup analysis. A total of 103 patients (median age: 84 years old, range 65-96; mean follow-up time: 36.8 ± 24.8 months) were included, involving 42 cases in the suture repair group and 61 cases in the mesh repair group. Suture repair and mesh repair had similar lengths of ICU and hospital stay, and rates of small bowel resection, chronic pain, surgical site infection, and surgical-related death. However, suture repair had a significantly higher recurrence rate than mesh repair (7% vs. 2%, P = 0.04). In our subgroup analysis, for patients with limited life expectancy (41 patients; median age: 88 years old, range: 80-96), suture repair had no statistical difference in postoperative outcomes compared with mesh repair. Mesh repair is suitable for elderly patients with acutely incarcerated or strangulated groin hernias. However, for elderly patients with limited life expectancy, suture repair and mesh repair showed similar clinical outcomes.

Co-, N-doped carbon dot nanozymes based on an untriggered ROS generation approach for anti-biofilm activities and in vivo anti-bacterial treatment.

Bacterial infections originating from food, water, and soil are widely recognized as significant global public health concerns. Biofilms are implicated in approximately two-thirds of bacterial infections. In recent times, nanomaterials have emerged as potential agents for combating biofilms and bacteria, with many of them being activated by light and H2O2 to generate reactive oxygen species (ROS). However, this energy-consuming and extrinsic substrate pattern poses many challenges for practical application. Consequently, there is a pressing need to develop methods for the untriggered generation of ROS to effectively address biofilm and bacterial infections. In this study, we investigated the oxidase-like activity of the Co,N-doped carbon dot (CoNCD) nanozyme, which facilitated the oxidation of ambient O2 to generate 1O2 in the absence of light and H2O2 supplementation; this resulted in effective biofilm cleavage and enhanced bactericidal effects. CoNCDs could become a potential candidate for wound healing and treatment of acute peritonitis in vivo, which can be primarily attributed to the spontaneous production of ROS. This study presents a convenient ROS generator that does not necessitate any specific triggering conditions. The nanozyme properties of CoNCDs exhibit significant promise as a potential remedy for diseases, specifically as an anti-biofilm and anti-bacterial agent.

A novel self-assembled nucleobase-nanofiber platform of CDN to activate the STING pathway for synergistic cancer immunotherapy.

2', 3'-cGAMP (CDN) as cGAS-STING pathway agonist is extensively used in tumor treatment. However, due to its negatively charged nature (containing two phosphate groups) and high hydrophilicity, CDN faces challenges in crossing cell membranes, resulting in reduced efficiency of its use. Additionally, CDN is susceptible to inactivation through phosphodiesterase hydrolysis. Therefore, the development of a new drug delivery system for CDN is necessary to prevent hydrolysis and enhance targeted accumulation in tumors, as well as improve cellular uptake for STING activation. In this study, we have developed peptide-polymer nanofibers (PEG-Q11) that incorporate thymine (T) and arginine (R) residues to facilitate complexation with CDN through the principles of Watson-Crick base pairing with thymine and favorable electrostatic interactions and bidentate hydrogen bonding with arginine side chains. The entrapment efficiency (EE) of PEG-Q11T3R4@CDN was found to be 51% higher than that of PEG-Q11@CDN. Due to its favorable biocompatibility, PEG-Q11T3R4@CDN was employed for immunotherapy in mouse CT26 tumors. In local tumor treatment, the administration of PEG-Q11T3R4@CDN at a low dose and through a single injection exhibited inhibitory effects. Furthermore, the local injection of PEG-Q11T3R4@CDN resulted in systemic therapeutic responses, effectively suppressing tumor metastasis by activating CD8 + T cells to target distant tumors. This research not only underscores the potential of PEG-Q11T3R4@CDN as an efficient therapeutic agent but also highlights its ability to achieve long-lasting systemic therapeutic outcomes following local treatment. Consequently, PEG-Q11T3R4@CDN represents a promising strategy for immunization.

Routine gastric suspension technique in single-port sleeve gastrectomy procedure.

BACKGROUND: Due to limited technical demand, single-port sleeve gastrectomy (SPSG) is a feasible laparoscopic technique for sleeve gastrectomy (SG). Nonetheless, difficulties exist when performing the single-port technique, and in this study, we aim to describe a slight maneuver that can improve the SPSG procedure. METHODS: Patients who underwent laparoscopic SG between January 2022 and May 2023 at our hospital were included. The patients were classified into two groups: (1) SPSG and (2) multiple-port SG (MPSG). The parameters for this analysis were the patients' age, gender, weight, body mass index (BMI), conversion rate, drainage placement, 30-day readmission rate, and postoperative complications. Postoperative one-month and three-month percentages of total weight loss (%TWL) were calculated and compared. RESULTS: 171 patients were included in this study: (1) the SPSG group (n = 96) and (2) the MPSG group (n = 75). No statistically significant difference was observed within the preoperative (age, gender, height, weight, and BMI) and the perioperative parameters between SPSG and MPSG (operation time, drainage placement, 30-day readmission) (p > 0.05). Per Clavien-Dindo's grading, two patients in the SPSG group suffered grade 1 complications; for the MPSG group, one patient sustained grade 2 and another suffered grade 3b complication. No statistical significance was observed on the %TWL between the two groups (p > 0.05). CONCLUSION: Our study found that performing SPSG in specific patient is feasible and non-inferior when compared to the MPSG. Further studies will be needed to elucidate better the efficacy and safety of performing SPSG.

Remodeling of Tumor Microenvironment by Nanozyme Combined cGAS-STING Signaling Pathway Agonist for Enhancing Cancer Immunotherapy.

Nanozymes and cyclic GMP-AMP synthase (cGAS) the stimulator of interferon genes (STING) signaling pathway, as powerful organons, can remodel the tumor microenvironment (TME) to increase efficacy and overcome drug resistance in cancer immunotherapy. Nanozymes have the potential to manipulate the TME by producing reactive oxygen species (ROS), which lead to positive oxidative stress in tumor cells. Cyclic dinucleotide (2',3'-cGAMP), as a second messenger, exists in the TME and can regulate it to achieve antitumor activity. In this work, Co,N-doped carbon dots (CoNCDs) were used as a model nanozyme to evaluate the properties of the anti-tumor mechanism, and effective inhibition of S180 tumor was achieved. Based on CoNCDs' good biocompatibility and therapeutic effect on the tumor, we then introduced the cGAS-STING agonist, and the combination of the CoNCDs and STING agonist significantly inhibited tumor growth, and no significant systemic toxicity was observed. The combined system achieved the enhanced tumor synergistic immunotherapy through TME reprogramming via the peroxidase-like activity of the CoNCDs and cGAS-STING signaling pathway agonist synergistically. Our work provides not only a new effective way to reprogram TME in vivo, but also a promising synergic antitumor therapy strategy.

NiCo LDH nanozymes with selective antibacterial activity against Gram-negative bacteria for wound healing.

Bacterial infections have been a major threat to human health. Especially, Gram-negative (G-) bacterial infections have been an increasing problem worldwide. The overuse of antibiotics leads to an emergence of drug resistance, and thus the development of novel antimicrobial agents is important, particularly against G- bacteria. Nanozymes use reactive oxygen species (ROS) to kill bacteria, reducing the risk of bacterial resistance and providing new opportunities to meet the challenges of strain selectivity. Here, we synthesized NiCo layered double hydroxide (LDH) nanozymes, which exhibit selective antibacterial activity based on their peroxide-like (POD-like) activity. To obtain the highest antibacterial activity, the POD-like activity of NiCo LDH nanozyme was further optimized by tuning the ratio of nickel and cobalt, and Ni4Co6 LDHs showed the highest POD activity and antibacterial activity. More importantly, Ni4Co6 LDHs can achieve selective sterilization of G- bacteria due to their electrostatic adsorption and hydrophilic interactions with the bacterial cell wall. Animal experiments further indicated that the healing of G- bacteria-infected wounds was effectively promoted without damaging their normal biological tissues. In conclusion, we provide a selective antibacterial agent through a simple strategy, which provides a new direction for the application of nanozymes.

Synthetic Versus Biological Mesh in Ventral Hernia Repair and Abdominal Wall Reconstruction: A Systematic Review and Recommendations from Evidence-Based Medicine.

AIM: To compare the efficacy and safety of synthetic and biological meshes in ventral hernia repair (VHR) and abdominal wall reconstruction (AWR). METHODS: We screened all clinical trials that reported the application of synthetic and biological meshes in VHR and AWR using Medline, Web of Science, and Embase (Ovid). Only comparative studies with similar baselines such as age, sex, body mass index, degree of wound contamination, and hernia defects between the intervention and control groups were included. Effect sizes with 95% confidence were pooled using a random- or fixed-effects model based on the size of heterogeneity. A sensitivity analysis was performed to test the stability of the results. RESULTS: Ten studies with 1305 participants were included. Biological meshes were associated with significantly higher recurrence rate (OR, 2.09; 95% CI 1.42-3.08; I2 = 50%), surgical site infection (OR, 1.47; 95% CI 1.10-1.97; I2 = 30%), higher re-admission rate (OR, 1.51; 95% CI 1.05-2.17; I2 = 50%), and longer length of hospital stay (SMD, 0.37; 95% CI 0.10-0.65; I2 = 72%). Similar surgical site occurrence, re-operation rate, and mesh explantation rate were observed among biological and synthetic meshes. Biological meshes have no difference in recurrence rate as compared to synthetic meshes, between the clean-contaminated, and contamination-infected fields (OR, 1.41; 95% CI 0.41-4.87 vs 3.00; 95% CI 1.07-8.46; P = 0.36). CONCLUSION: Synthetic meshes are a safe alternative to biological meshes for VHR and AWR. Considering the high cost of biological meshes, synthetic meshes are more appropriate for the VHR and AWR.

Reconstruction of Abdominal Wall Defect with Composite Scaffold of 3D Printed ADM/PLA in a Rat Model.

Abdominal wall defects are a frequently occurring condition in surgical practice. The most important are material structure and biocompatibility. In this study, polylactic acid (PLA) mesh composited with a 3D printing of acellular dermal matrix (ADM) material is used to repair abdominal wall defects. The results show that the adhesion score of ADM/PLA composite scaffolds is smaller than PLA meshes. Immunohistochemical assessment reveals that the ADM/PLA composite scaffold can effectively reduce the inflammatory response at the contact surface between the meshes and the abdominal organs. And the ADM/PLA composite scaffold can effectively reduce the expression levels of the inflammation-related factors IL-6 and IL-10. In addition, the ADM/PLA composite scaffold repair is rich in the expression levels of tissue regeneration-related factors vascular endothelial growth factor and transforming growth factor ß. Thus, ADM/PLA composite scaffolds can effectively reduce surrounding inflammation to effectively promote the repair of abdominal wall defects.

Synthetic K+ Channels Constructed by Rebuilding the Core Modules of Natural K+ Channels in an Artificial System.

Different types of natural K+ channels share similar core modules and cation permeability characteristics. In this study, we have developed novel artificial K+ channels by rebuilding the core modules of natural K+ channels in artificial systems. All the channels displayed high selectivity for K+ over Na+ and exhibited a selectivity sequence of K+ ≈Rb+ during the transport process, which is highly consistent with the cation permeability characteristics of natural K+ channels. More importantly, these artificial channels could be efficiently inserted into cell membranes and mediate the transmembrane transport of K+ , disrupting the cellular K+ homeostasis and eventually triggering the apoptosis of cells. These findings demonstrate that, by rebuilding the core modules of natural K+ channels in artificial systems, the structures, transport behaviors, and physiological functions of natural K+ channels can be mimicked in synthetic channels.

N-acetylcysteine Ameliorates Vancomycin-induced Nephrotoxicity by Inhibiting Oxidative Stress and Apoptosis in the in vivo and in vitro Models.

Background: Oxidative stress-related apoptosis is considered as the key mechanism implicated in the pathophysiology of nephrotoxicity with vancomycin (VCM) therapy. We evaluated the possible effects of N-acetylcysteine (NAC) on VCM-induced nephrotoxicity and the underlying mechanism. Methods: VCM-induced nephrotoxicity was established using HK-2 cells and SD rats and observed by measuring cell survival, kidney histological changes, renal function and kidney injury related markers (KIM-1 and NGAL). Oxidative stress, renal cell apoptosis and the involved signaling pathways were also evaluated. Results: In model rats, NAC could protect against VCM-induced acute kidney injury with histological damage, renal dysfunction, and increased Cre and BUN levels. In HK-2 cells, VCM-induced decreased cell viability was restored by NAC. In addition, increased expression of caspase-3, KIM-1 and NGAL suffering from VCM was also reversed by NAC in vivo and in vitro. NAC inhibited ROS production, decreased cell apoptosis by decreasing the Bax/Bcl-2 ratio and caspase-3 expression in HK-2 cells and regulated oxidative stress indicators in the kidney by decreasing GSH, SOD and CAT activity and increasing MDA levels. Furthermore, NAC could effectively reverse VCM-associated increased P38 MAPK/JNK phosphorylation. Conclusions: The results demonstrated that NAC had a protective effect against nephrotoxicity from VCM by inhibiting oxidative stress and apoptosis via P38 MAPK/JNK.

Designing Double-Layer Multimaterial Composite Patch Scaffold with Adhesion Resistance for Hernia Repair.

Hernia repair mesh is associated with a number of complications, including adhesions and limited mobility, due to insufficient mechanical strength and nonresorbability. Among them, visceral adhesions are one of the most serious complications of patch repair. In this study, a degradable patch with an antiadhesive layer is prepared for hernia repair by 3D printing and electrospinning techniques using polycaprolactone, polyvinyl alcohol, and soybean peptide (SP). The study into the physicochemical properties of the patch is found that it has adequate mechanical strength requirements (16 N cm-1 ) and large elongation at break, which are superior than commercial polypropylene patches. In vivo and in vitro experiments show that human umbilical vein endothelial cells proliferated well on composite patches, and showed excellent biocompatibility with the host and little adhesion through a rat abdominal wall defect model. In conclusion, the results of this study show that composite patch can effectively reduce the occurrence of adhesions, while the addition of SP in the patch further enhances its biocompatibility. It is believed that a regenerative biological patch with great potential in hernia repair provides a new strategy for the development of new biomimetic biodegradable patches.

Alginate/Gelatin-Based Hydrogel with Soy Protein/Peptide Powder for 3D Printing Tissue-Engineering Scaffolds to Promote Angiogenesis.

In recent years, 3D bioprinting has attracted broad research interest in biomedical engineering and clinical applications. However, there are two issues need to be solved urgently at present, the development of ink is the first pressing thing for 3D printing tissue engineering scaffold, other thing is the promotion of angiogenesis in the scaffold. Therefore, a gelatin/sodium alginate-based hydrogel with protein-rich is developed here, which is prepared by gelatin, sodium alginate, and soy protein/soy peptide powder. The prepared inks exhibit excellent shear-thinning behavior, which contribute to extrusion-based printing; also shown good crosslinking ability by calcium chloride. The macroporous composite scaffolds are printed by 3D printing using the developed ink and the physicochemical properties of the scaffolds are evaluated. Moreover, the cytocompatibility of printed scaffold is characterized by using human umbilical vein epidermal cells, results show that the scaffolds with soy protein and soy peptide powder can promote cell attach, spread, migration, and proliferation. The further research of chicken embryo allantoic membrane assay and animal experiment are carried, and results present that the scaffold can promote the growth of neo-vessels in the scaffold, which means the developed ink with soy protein and soy peptide powder has great potential for angiogenesis.

Adipose-Derived Stem Cells Based on Electrospun Biomimetic Scaffold Mediated Endothelial Differentiation Facilitating Regeneration and Repair of Abdominal Wall Defects via HIF-1α/VEGF Pathway.

Application of synthetic or biological meshes is the main therapy for the repair and reconstruction of abdominal wall defects, a common disease in surgery. Currently, no ideal materials are available, and there is an urgent need to find appropriate ones to satisfy clinical needs. Electrospun scaffolds have drawn attention in soft tissue reconstruction. In this study, we developed a novel method to fabricate a composite electrospun scaffold using a thermoresponsive hydrogel, poly (N-isopropylacrylamide)-block-poly (ethylene glycol), and a biodegradable polymer, polylactic acid (PLA). This scaffold provided not only a high surface area/volume ratio and a three-dimensional fibrous matrix but also high biocompatibility and sufficient mechanical strength, and could simulate the native extracellular matrix and accelerate cell adhesion and proliferation. Furthermore, rat adipose-derived stem cells (ADSCs) were seeded in the composite electrospun scaffold to enhance the defect repair and regeneration by directionally inducing ADSCs into endothelial cells. In addition, we found early vascularization in the process was regulated by the hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway. In our study, overexpression of HIF-1α/VEGF in ADSCs using a lentivirus system promoted early vascularization in the electrospun scaffolds. Overall, we expect our composite biomimetic scaffold method will be applicable and useful in abdominal wall defect regeneration and repair in the future.

Histone Methyltransferase SETD1A Induces Epithelial-Mesenchymal Transition to Promote Invasion and Metastasis Through Epigenetic Reprogramming of Snail in Gastric Cancer.

Aberrant epigenetic modification induces oncogene expression and promotes cancer development. The histone lysine methyltransferase SETD1A, which specifically methylates histone 3 lysine 4 (H3K4), is involved in tumor growth and metastasis, and its ectopic expression has been detected in aggressive malignancies. Our previous study reported that SETD1A promotes gastric cancer (GC) proliferation and tumorigenesis. However, the function and molecular mechanisms of SETD1A in GC metastasis remain to be elucidated. In this study, we found that overexpression of SETD1A promoted GC migration and invasion, whereas knockdown of SETD1A suppressed GC migration and invasion in vitro. Moreover, knockdown of SETD1A suppressed GC epithelial-mesenchymal transition (EMT) by increasing the expression of epithelial marker E-cadherin and decreasing the expression of mesenchymal markers, including N-cadherin, Fibronectin, Vimentin, and α-smooth muscle actin (α-SMA). Mechanistically, knockdown of SETD1A reduced the EMT key transcriptional factor snail expression. SETD1A was recruited to the promoter of snail, where SETD1A could methylate H3K4. However, knockdown of SETD1A decreased the methylation of H3K4 on the snail promoter. Furthermore, SETD1A could be a coactivator of snail to induce EMT gene expression. Rescue of snail restored SETD1A knockdown-induced GC migration and invasion inhibition. In addition, knockdown of SETD1A suppressed GC metastasis in vivo. In summary, our data revealed that SETD1A mediated the EMT process and induced metastasis through epigenetic reprogramming of snail.

Surgical treatment strategy for locally advanced colorectal cancer with abdominal wall invasion.

BACKGROUND: The incidence of abdominal wall metastasis from colorectal cancer (CRC) is very low, but it has a poor prognosis. Despite the advances in radiotherapy, chemotherapy, and targeted therapy, patient prognosis has not improved significantly. Through surgical treatment, some patients with locally advanced CRC with abdominal wall invasion can achieve tumor-free survival or an improved quality of life. METHODS: The clinical data of 15 patients in our department from January 2015 to January 2020 were retrospectively analyzed. All patients underwent preoperative three-dimensional reconstruction of the tumor and abdominal wall after discussion with a multidisciplinary team (MDT). Patient information, including tumor size, defect size, operation time, intraoperative bleeding, hospital stay, and other factors, was collected. RESULTS: All 15 patients underwent resection followed by reconstruction for locally advanced CRC with abdominal wall invasion. The average tumor area and abdominal wall defects were 98.13±71.70 and 270.07±101.95 cm2, respectively; and accurate abdominal wall classification and zoning were obtained for all patients. The average operation time was 431.7±189.2 min, and the average blood loss was 513.3±244.6 mL. The recurrence rates in the incisional hernia and abdominal wall were 6.0% and 13.3%, respectively. The patient survival rate was 87.7%. CONCLUSIONS: Surgical treatment of locally advanced CRC with abdominal wall invasion is feasible, but requires accurate and comprehensive preoperative evaluation.

Application of 3D Visualization Technology in Complex Abdominal Wall Defects.

PURPOSE: To explore the value of medical three-dimensional visualization technology in precise preoperative assessment of complex abdominal wall defects. METHODS: The clinical data of 30 patients were analyzed retrospectively from November 2017 to December 2020 in our department. Ten patients had abdominal wall hernias and 20 patients suffered from abdominal wall tumors. CT examination was performed, and data were stored in the form of DICOM. Three-dimensional reconstruction and related data analysis were performed by Medraw software, which can accurately show the calculation of the abdominal wall defect area, abdominal wall defect classification and zoning. RESULTS: The ratio of the volume of the hernia sac to the whole abdominal volume in 10 patients with abdominal wall hernia was 4.75%. The average ratio of defect area to the whole abdominal wall in 16 patients suffered from abdominal wall tumors was 17.68%. Preoperative three-dimensional reconstruction can accurately obtain an average abdominal wall defect area of 227.83 ± 157.33 cm2 and accurate abdominal wall classification and zoning. Combined with clinical information, we can develop personalized surgical plans for patients. The average operating time was 5.39 ± 2.71 h, respectively, and the average hospital stay was 22.77 ± 11.59 days. The mean follow-up time was 21.09 ± 9.72 months. The incidence of postoperative complications was 23.33% (7/30). The recurrence rates of incisional hernias and abdominal wall tumors were 20.00% (2/10) and 15.00% (3/20), respectively. The patient survival rate was 86.67% (26/30). CONCLUSION: Three-dimensional visualization technology can be used for the accurate evaluation of patients with complex abdominal defects before surgery and can help surgeons design personalized surgical plans for patients.

Huperzine A lowers intraocular pressure via the M3 mAChR and provides retinal neuroprotection via the M1 mAChR: a promising agent for the treatment of glaucoma.

BACKGROUND: Glaucoma is a neurodegenerative disease that shares similar pathological mechanisms with Alzheimer's disease (AD). Drug treatments for glaucoma increasingly rely upon both lowering of intraocular pressure (IOP) and optic nerve protection, as lowering of IOP alone has been unsatisfactory. Huperzine A (HupA) is an acetylcholinesterase inhibitor (AChEI) used for AD. This study investigated the potential of HupA as a treatment for glaucoma. METHODS: The ability of HupA to lower IOP via causing pupil constriction was assessed using New Zealand rabbits. The retinal neuroprotective effects of HupA were assessed in vivo using rat retinas subjected to ischemia-reperfusion (I/R) and in vitro using primary retinal neurons (PRNs) suffering from oxygen-glucose deprivation (OGD). RESULTS: HupA caused pupil constriction in a dose-time dependent manner which was reversed by the nonselective muscarinic acetylcholine receptor (mAChR) antagonist atropine and the selective M3 mAChR antagonist 4-DAMP. However, HupA had no effect on isolated iris muscle tension and calcium flow indicating an indirect M3 mAChR mediated effect. HupA exerted a neuroprotective effect against I/R and OGD to attenuate the retinal pathological lesion, improve retinal neuronal cell viability, reverse oxidative stress injury by increasing GSH levels and SOD activity, and decreasing MDA content and reduce the retinal neuronal apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 expression with no effect on the calcium flow tests. The effects were abolished by atropine and the selective M1 mAChR antagonist pirenzepine in OGD-induced PRNs suggesting an indirect M1 mAChR-mediated effect via inhibiting AChE activity to increase endogenous ACh level. Furthermore, HupA increased phosphorylated AKT level and decreased the levels of phosphorylated JNK, P38 MAPK and ERK via M1 mAChR antagonists indicating an involvement of activating the M1 mAChR and the downstream AKT/MAPK signaling pathway in the protective effects of HupA. CONCLUSIONS: HupA could significantly decrease IOP via activating M3 mAChR indirectly and produce retinal neuroprotective effect through M1 mAChR/AKT/MAPK by increasing endogenous ACh level. These investigations demonstrated that HupA was an effective drug in glaucoma treatment and the clinical application of HupA and other AChEIs for glaucoma patients should be further investigated.

A lysosome-targetable two-photon excited near-infrared fluorescent probe for visualizing hypochlorous acid-involved arthritis and its treatment.

Lysosome of phagocyte is the main site of hypochlorous acid (HClO) production, and HClO can be employed as the biomarker for the diagnosis and treatment evaluation of arthritis. In recent years, developing fluorescent probes for lysosomal HClO has attracted considerable attention, but most of them still have some defects, such as autofluorescence, phototoxicity and photobleaching because of their excitation and emission located in short-wavelength region. Due to the advantages of two-photon fluorescent probes with near-infrared emissions, a lysosome-targetable two-photon fluorescent probe (Lyso-TP-HClO) with a near-infrared emission was reported in this paper. Lyso-TP-HClO has a high selectivity and a high sensitivity to HClO in the linear range (10.0 × 10-8 to 5.0 × 10-6 M), with a detection limit of 3.0 × 10-8 M. Due to the two-photon excited near-infrared emission, Lyso-TP-HClO has excellent imaging performances, such as small autofluorescence, excellent photostability, and large imaging depth. Furthermore, Lyso-TP-HClO was successfully employed for visualizing lysosomal HClO in bacteria-infected cells. At last, we have successfully used Lyso-TP-HClO to image the arthritis and evaluate the treatment of arthritis in mice. All the results confirm that Lyso-TP-HClO is a useful chemical tool for imaging of lysosomal HClO, the diagnosis of arthritis, and treatment evaluation of arthritis.

A two-photon excited near-infrared fluorescent probe for imaging peroxynitrite during drug-induced hepatotoxicity and its remediation.

Drug-induced liver injury (DILI) has been a hot issue of public health, owing to its unpredictability and serious harm to public health. Peroxynitrite (ONOO-) is an important biomarker for the assessment and diagnosis of DILI. In this article, based on a kind of rhodamine analogue with a near-infrared (NIR) emission (610 nm-800 nm) and a two-photon absorption cross section (54 GM), a two-photon excited NIR fluorescence probe (NIR-ONOO) for ONOO- was developed. With a high selectivity and a high sensitivity to ONOO-, NIR-ONOO has a linear range for detection of ONOO- from 5.0 × 10-8 to 1.0 × 10-5 M, a good detection limit (15 nM) and a large fluorescence enhancement (340-fold). In addition, NIR-ONOO has been used to monitor ONOO- in cells with satisfactory results. Because of its two-photon excied NIR emission, NIR-ONOO also showed excellent performances for imaging ONOO- including low autofluorescence, stable and persistent fluorescence, and a deep penetration (204 µm). Finally, NIR-ONOO was successfully employed to image ONOO- in inflammatory mouse, drug-induced hepatotoxicity in cells and its remediation. All the results indicated that NIR-ONOO is a powerful chemical tool to image ONOO- and assay drug-induced hepatotoxicity.