Multicenter phase II study of moderate low-dose radiotherapy in indolent non-Hodgkin lymphoma: CLCG-iNHL-01 protocol.

Background: Radiotherapy is an effective treatment for indolent non-Hodgkin lymphoma (iNHL); however, the optimal radiotherapy dose remains to be determined. We hypothesize that a suitable dose may exist between 4 and 24 Gy. Methods: This prospective multicenter phase II trial intends to recruit 73 sites of iNHL patients, who will receive involved-site radiotherapy of 12 Gy in four fractions. The primary objective is the 6-month clinical complete response rate. Tumor tissue, blood and conjunctival specimens will be collected to identify potential predictive biomarkers. Discussion: The CLCG-iNHL-01 trial will evaluate the efficacy and toxicity of 12 Gy in patients with iNHL and provide information on a novel hypofractionation regimen of low-dose radiotherapy. Clinical Trial Registration: NCT05543070 (ClinicalTrials.gov).

In situ laser-assisted synthesis and patterning of graphene foam composites as a flexible gas sensing platform.

Gas-sensitive semiconducting nanomaterials (e.g., metal oxides, graphene oxides, and transition metal dichalcogenides) and their heterojunctions hold great promise in chemiresistive gas sensors. However, they often require a separate synthesis method (e.g., hydrothermal, so-gel, and co-precipitation) and their integration on interdigitated electrodes (IDE) via casting is also associated with weak interfacial properties. This work demonstrates in situ laser-assisted synthesis and patterning of various sensing nanomaterials and their heterojunctions on laser-induced graphene (LIG) foam to form LIG composites as a flexible and stretchable gas sensing platform. The porous LIG line or pattern with nanomaterial precursors dispensed on top is scribed by laser to allow for in situ growth of corresponding nanomaterials. The versatility of the proposed method is highlighted through the creation of different types of gas-sensitive materials, including transition metal dichalcogenide (e.g., MoS2), metal oxide (e.g., CuO), noble metal-doped metal oxide (e.g., Ag/ZnO) and composite metal oxides (e.g., In2O3/Cr2O3). By eliminating the IDE and separate heaters, the LIG gas sensing platform with self-heating also decreases the device complexity. The limit of detection (LOD) of the LIG gas sensor with in situ synthesized MoS2, CuO, and Ag/ZnO to NO2, H2S, and trimethylamine (TMA) is 2.7, 9.8, and 5.6 ppb, respectively. Taken together with the high sensitivity, good selectivity, rapid response/recovery, and tunable operating temperature, the integrated LIG gas sensor array can identify multiple gas species in the environment or exhaled breath.

Fabricating functional circuits on 3D freeform surfaces via intense pulsed light-induced zinc mass transfer.

Deployment of functional circuits on a 3D freeform surface is of significant interest to wearable devices on curvilinear skin/tissue surfaces or smart Internet-of-Things with sensors on 3D objects. Here we present a new fabrication strategy that can directly print functional circuits either transient or long-lasting onto freeform surfaces by intense pulsed light-induced mass transfer of zinc nanoparticles (Zn NPs). The intense pulsed light can locally raise the temperature of Zn NPs to cause evaporation. Lamination of a kirigami-patterned soft semi-transparent polymer film with Zn NPs conforming to a 3D surface results in condensation of Zn NPs to form conductive yet degradable Zn patterns onto a 3D freeform surface for constructing transient electronics. Immersing the Zn patterns into a copper sulfate or silver nitrate solution can further convert the transient device to a long-lasting device with copper or silver. Functional circuits with integrated sensors and a wireless communication component on 3D glass beakers and seashells with complex surface geometries demonstrate the viability of this manufacturing strategy.

Piper nigrum extract attenuates food allergy by decreasing Th2 cell response and regulating the Th17/Treg balance.

Piper nigrum is extensively utilized because of its antioxidation, antiallergic, antitumor, antiinflammatory, antidiarrhea, and gastrointestinal protection. We attempted to indicate whether the Piper nigrum extract (PNE) could alleviate ovalbumin (OVA)-induced food allergy, and to explore its potential mechanism. An OVA-induced food allergy mouse model was established, and different concentrations of PNE were administrated. Symptoms of food allergy, levels of immunoglobulin E (IgE), mucosal mast cell protease-1 (mMCP-1), and intestine pathological changes were assessed. Additionally, the expressions of T helper (Th) 2, Th17 and regulatory T (Treg)-associated cytokines and the proportion of Th17 and Treg cells in CD4+ T cells were measured. We found PNE attenuated symptoms of food allergy and decreased the levels of IgE and mMCP-1. In PNE group, the infiltration degree of inflammatory cells was ameliorated and the villi of small intestine were more complete. Moreover, the expressions of Th2 and Th17 cell-associated cytokines were down-regulated by PNE pretreatment, while the levels of Treg cell-associated cytokines were up-regulated. PNE decreased the number of Th17 cells, while increased the Tregs cells. PNE treatment dose-dependently improved the Th17/Treg balance. PNE plays a protective role in OVA-induced food allergy through inhibiting Th2 cell response and regulating the Th17/Treg balance.

Catalpol ameliorates advanced glycation end product-induced dysfunction of glomerular endothelial cells via regulating nitric oxide synthesis by inducible nitric oxide synthase and endothelial nitric oxide synthase.

Catalpol (Cat.) is an iridoid glucoside extracted from the root of Rehmannia glutinosa Libosch. In this study, we investigated whether Cat. could protect the mouse glomerular endothelial cells against the deleterious effect induced by advanced glycation end products (AGEs) and explored potential mechanisms. We found that 10 µM Cat. showed a protective effect on dead cells stimulated by AGEs. Cat. significantly decreased the expression of p-NF-κBp65 and inducible nitric oxide synthase (iNOS) and increased the expression of phosphorylated-endothelial nitric oxide synthase (p-eNOS; Ser1177), PI3K, p-Akt (Thr308), and total-Akt. Moreover, Cat. restored the integrity of glomerular endothelial barrier by increasing endothelial tight gap junction protein and ameliorated the endothelial hyperpermeability induced by AGEs via modulating the nitric oxide (NO) production. Additionally, Cat. attenuated the massive release of NO induced by AGEs, inhibiting the macrophage infiltration by modulating the NO production, accompanied by the decrease in the release of monocyte chemoattractant protein-1 and intercellular cell adhesion molecule-1 in vitro. Therefore, Cat. ameliorated AGEs-induced endothelial dysfunction via inhibiting the NF-κB/iNOS pathway and activating the PI3K/Akt/eNOS pathway. © 2019 IUBMB Life, 71(9):1268-1283, 2019.

SREBP1 promotes the invasion of colorectal cancer accompanied upregulation of MMP7 expression and NF-κB pathway activation.

BACKGROUND: Sterol-regulatory element binding protein 1 (SREBP1), an intracellular cholesterol sensor located in the endoplasmic reticulum, regulates the intracellular cholesterol by the Insig-Srebp-Scap pathway. Over-expression of SREBP1 can cause dyslipidemia. SREBP1 can regulate the metabolic pathway, and then promote the proliferation of tumor cells. However, there is no relevant research of metastasis and invasion in the field of colorectal cancer (CRC). METHODS: Expression of SREBP1 was manipulated in CRC cell lines with low and high level SREBP1 expression by transfectiong with plasmids containing the SREBP1 gene, or by shRNA. The effect of SREBP1 on cell migration was assayed. The expression of SREBP1, p65 and MMP7 were detected by western blot. Human umbilical vein endothelial cell was used for detection of angiogenesis by adding the culture supernatant from HT29 and SW620. The level of reactive oxygen species (ROS) was detected by Dihydroethidium (DHE) staining. NF-κB inhibitor SN50 was used to test the relationship of SREBP1, NF-κB pathway and MMP7. RESULTS: We found that the expression of SREBP1 in colon adenocarcinoma was significantly higher than that in noncancerous tissues, especially in the invasive tumor front including tumor budding. In vitro, SREBP1 over-expressed in colon cancer cell lines HT29 promoted angiogenesis in endothelial cells, increased ROS levels, phosphorylation of NF-κB-p65 and increases MMP7 expression. The effect of SREBP1 on expression of MMP7 was lost following treatment with the NF-κB inhibitor SN50. CONCLUSION: Our results suggest that SREBP1 can promote the invasion and metastasis of CRC cells by means of promoting the expression of MMP7 related to phosphorylation of p65.

Enhanced "learning to learn" through a hierarchical dual-learning system: the case of action video game players.

In contrast to conventional cognitive training paradigms, where learning effects are specific to trained parameters, playing action video games has been shown to produce broad enhancements in many cognitive functions. These remarkable generalizations challenge the conventional theory of generalization that learned knowledge can be immediately applied to novel situations (i.e., immediate generalization). Instead, a new "learning to learn" theory has recently been proposed, suggesting that these broad generalizations are attained because action video game players (AVGPs) can quickly acquire the statistical regularities of novel tasks in order to increase the learning rate and ultimately achieve better performance. Although enhanced learning rate has been found for several tasks, it remains unclear whether AVGPs efficiently learn task statistics and use learned task knowledge to guide learning. To address this question, we tested 34 AVGPs and 36 non-video game players (NVGPs) on a cue-response associative learning task. Importantly, unlike conventional cognitive tasks with fixed task statistics, in this task, cue-response associations either remain stable or change rapidly (i.e., are volatile) in different blocks. To complete the task, participants should not only learn the lower-level cue-response associations through explicit feedback but also actively estimate the high-level task statistics (i.e., volatility) to dynamically guide lower-level learning. Such a dual learning system is modelled using a hierarchical Bayesian learning framework, and we found that AVGPs indeed quickly extract the volatility information and use the estimated higher volatility to accelerate learning of the cue-response associations. These results provide strong evidence for the "learning to learn" theory of generalization in AVGPs. Taken together, our work highlights enhanced hierarchical learning of both task statistics and cognitive abilities as a mechanism underlying the broad enhancements associated with action video game play.

Ultraconformal Skin-Interfaced Sensing Platform for Motion Artifact-Free Monitoring.

Capable of directly capturing various physiological signals from human skin, skin-interfaced bioelectronics has emerged as a promising option for human health monitoring. However, the accuracy and reliability of the measured signals can be greatly affected by body movements or skin deformations (e.g., stretching, wrinkling, and compression). This study presents an ultraconformal, motion artifact-free, and multifunctional skin bioelectronic sensing platform fabricated by a simple and user-friendly laser patterning approach for sensing high-quality human physiological data. The highly conductive membrane based on the room-temperature coalesced Ag/Cu@Cu core-shell nanoparticles in a mixed solution of polymers can partially dissolve and locally deform in the presence of water to form conformal contact with the skin. The resulting sensors to capture improved electrophysiological signals upon various skin deformations and other biophysical signals provide an effective means to monitor health conditions and create human-machine interfaces. The highly conductive and stretchable membrane can also be used as interconnects to connect commercial off-the-shelf chips to allow extended functionalities, and the proof-of-concept demonstration is highlighted in an integrated pulse oximeter. The easy-to-remove feature of the resulting device with water further allows the device to be applied on delicate skin, such as the infant and elderly.

Colitis-accelerated colorectal cancer and metabolic dysregulation in a mouse model.

The connection between inflammation and colorectal cancer (CRC) has been well recognized, and numerous related molecular mechanisms have been uncovered. To gain further insight, we used BALB/c mice treated with azoxymethane (AOM) and dextran sulfate sodium salt (DSS) to establish a colitis-associated CRC model recapitulating tubulovillous adenoma with high-grade dysplasia at week 14. We evaluated the mice in four groups: a control group fed a standard diet; a group given DSS, in which we observed no tumor or dysplasia; a group given AOM, in which we observed few dysplastic foci despite repeated administrations of the carcinogen and a group given both AOM and DSS, in which our observations agreed with those of other studies that found accelerated colorectal carcinogenesis following DSS-induced colitis. We examined the messenger RNA and micro RNA (miRNA) expression profiles of the four groups. In colitis-associated CRC, we observed the dysregulation of many pathways, including the upregulation of Wnt signaling and CRC pathways and the downregulation of apoptosis. Also, most differentially expressed genes were significantly enriched in metabolic rather than immune/inflammation pathways/processes. Additionally, we demonstrated that the expression of several important miRNAs involved in both the inflammatory response and metabolism was dramatically altered during colitis-associated CRC. Gene network analysis and gene profile analysis confirmed a close relationship between metabolic and inflammatory genes in colitis-associated CRC. Thus, our study may provide a framework for identifying metabolic genes as targets of novel molecular-based therapies against CRC.

Radiotherapy in Philadelphia chromosome­positive acute lymphoblastic leukemia with pericardial invasion after transplantation: A case report.

The present report describes a case of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) with pericardial invasion following bone marrow transplantation. The patient exhibited recurrent pericardial effusion accompanied by wheezing symptoms. Despite undergoing multiple pericardial punctures and drainage procedures, pericardial injections, and systemic treatment, the patient continued to experience recurrent pericardial effusion. Ultimately, the patient underwent whole-heart radiotherapy, resulting in complete resolution of the pericardial effusion. After a follow-up period of 10 months, the pericardial effusion remained well-controlled, and there were no significant impairments in cardiac function. In conclusion, radiotherapy may be considered as a viable treatment option for refractory leukemia cases presenting with pericardial effusion.

Iontronic pressure sensor with high sensitivity over ultra-broad linear range enabled by laser-induced gradient micro-pyramids.

Despite the extensive developments of flexible capacitive pressure sensors, it is still elusive to simultaneously achieve excellent linearity over a broad pressure range, high sensitivity, and ultrahigh pressure resolution under large pressure preloads. Here, we present a programmable fabrication method for microstructures to integrate an ultrathin ionic layer. The resulting optimized sensor exhibits a sensitivity of 33.7 kPa-1 over a linear range of 1700 kPa, a detection limit of 0.36 Pa, and a pressure resolution of 0.00725% under the pressure of 2000 kPa. Taken together with rapid response/recovery and excellent repeatability, the sensor is applied to subtle pulse detection, interactive robotic hand, and ultrahigh-resolution smart weight scale/chair. The proposed fabrication approaches and design toolkit from this work can also be leveraged to easily tune the pressure sensor performance for varying target applications and open up opportunities to create other iontronic sensors.

Assessment of Anxiety, Depression, and Sleep Quality in Mothers of Children with Atopic Dermatitis: A Qualitative Questionnaire Study.

Purpose: To compare the anxiety, depression and sleep quality of mothers of healthy control children and mothers of children with atopic dermatitis (AD) of varying severity, both before and after treatment. Methods: A total of 120 parent-child dyads participated in the study. These dyads were divided into four subgroups of 30 patients each: mild AD, moderate AD, severe AD, and control groups. The children's symptoms, their mothers' psychological status, and their mothers' sleep quality were evaluated using the Scoring of Atopic Dermatitis (SCORAD), the Hospital Anxiety and Depression Scale (HADS), and the Pittsburgh Sleep Quality Index (PSQI), respectively, before and after a one-month comprehensive treatment. Results: SCORAD, representing differences in severity of children's AD, decreased significantly after one month's treatment (p < 0.001). Anxiety in mothers significantly decreased in all AD severity groups after treatment (p < 0.05). However, for depression, only the mothers in the mild and moderate AD groups showed a decrease after treatment (p < 0.05). The PSQI total score also decreased in the mild AD group after treatment (p < 0.05). Conclusion: The most severe effect was seen in the psychology and sleep quality of mothers of children with severe AD. After one month of treatment, the psychological health and sleep quality of the mothers in the mild AD group significantly improved, while those of mothers in the moderate and severe AD groups showed partial improvement.

Catalpol Prevents Glomerular Angiogenesis Induced by Advanced Glycation End Products via Inhibiting Galectin-3.

OBJECTIVE: The main characteristics of diabetic nephropathy (DN) at the early stage are abnormal angiogenesis of glomerular endothelial cells (GECs) and macrophage infiltration. Galectin-3 plays a pivotal role in the pathogenesis of DN via binding with its ligand, advanced glycation end products (AGEs). Catalpol, an iridoid glucoside extracted from Rehmannia glutinosa, has been found to ameliorate vascular inflammation, reduce endothelial permeability, and protect against endothelial damage in diabetic milieu. However, little is known about whether catalpol could exert an anti-angiogenesis and anti-inflammation effect induced by AGEs. METHODS: Mouse GECs (mGECs) and RAW 264.7 macrophages were treated with different concentrations of AGEs (0, 50, 100, 200 and 400 µg/mL) for different time (0, 6, 12, 24 and 48 h) to determine the optimal concentration of AGEs and treatment time. Cells were treated with catalpol (10 µmol/L), GB1107 (1 µmol/L, galectin-3 inhibitor), PX-478 (50 µmol/L, HIF-1α inhibitor), adenovirus-green fluorescent protein (Ad-GFP) [3×107 plaque-forming unit (PFU)/mL] or Ad-galectin-3-GFP (2×108 PFU/mL), which was followed by incubation with 50 µg/mL AGEs. The levels of galectin-3, vascular endothelial growth factor A (VEGFA) and pro-angiogenic factors angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), tunica interna endothelial cell kinase-2 (Tie-2) were detected by enzymelinked immunosorbent assay (ELISA). Cell counting kit-8 (CCK-8) assay was used to evaluate the proliferation of these cells. The expression levels of galectin-3, vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, and hypoxia-inducible factor-1α (HIF-1α) in mGECs and those of galectin-3 and HIF-1α in RAW 264.7 macrophages were detected by Western blotting and immunofluorescence (IF) staining. The rat DN model was established. Catalpol (100 mg/kg) or GB1107 (10 mg/kg) was administered intragastrically once a day for 12 weeks. Ad-galectin-3-GFP (6×107 PFU/mL, 0.5 mL) or Ad-GFP (6×106 PFU/mL, 0.5 mL) was injected into the tail vein of rats 48 h before the sacrifice of the animals. The expression of galectin-3, VEGFR1, VEGFR2, and HIF-1α in renal cortices was analyzed by Western blotting. The expression of galectin-3, F4/80 (a macrophage biomarker), and CD34 (an endothelium biomarker) in renal cortices was detected by IF staining, and collagen accumulation by Masson staining. RESULTS: The expression levels of galectin-3 and VEGFA were significantly higher in mGECs and RAW 264.7 macrophages treated with 50 µg/mL AGEs for 48 h than those in untreated cells. Catalpol and GB1107 could block the AGEs-induced proliferation of mGECs and RAW 264.7 macrophages. Over-expression of galectin-3 was found to reduce the inhibitory effect of catalpol on the proliferation of cells. Catalpol could significantly decrease the levels of Ang-1, Ang-2 and Tie-2 released by AGEs-treated mGECs, which could be reversed by over-expression of galectin-3. Catalpol could significantly inhibit AGEs-induced expression of galectin-3, HIF-1α, VEGFR1, and VEGFR2 in mGECs. The inhibitory effect of catalpol on galectin-3 in AGEs-treated mGECs was impaired by PX-478. Moreover, catalpol attenuated the AGEs-activated HIF-1α/galectin-3 pathway in RAW 264.7 macrophages, which was weakened by PX-478. Additionally, catalpol significantly inhibited the expression of galectin-3, macrophage infiltration, collagen accumulation, and angiogenesis in the kidney of diabetic rats. Over-expression of galectin-3 could antagonize these inhibitory effects of catalpol. CONCLUSION: Catalpol prevented the angiogenesis of mGECs and macrophage proliferation via inhibiting galectin-3. It could prevent the progression of diabetes-induced renal damage.

A wireless, solar-powered, optoelectronic system for spatial restriction-free long-term optogenetic neuromodulations.

Numerous wireless optogenetic systems have been reported for practical tether-free optogenetics in freely moving animals. However, most devices rely on battery-powered or coil-powered systems requiring periodic battery replacement or bulky, high-cost charging equipment with delicate antenna design. This leads to spatiotemporal constraints, such as limited experimental duration due to battery life or animals' restricted movement within specific areas to maintain wireless power transmission. In this study, we present a wireless, solar-powered, flexible optoelectronic device for neuromodulation of the complete freely behaving subject. This device provides chronic operation without battery replacement or other external settings including impedance matching technique and radio frequency generators. Our device uses high-efficiency, thin InGaP/GaAs tandem flexible photovoltaics to harvest energy from various light sources, which powers Bluetooth system to facilitate long-term, on-demand use. Observation of sustained locomotion behaviors for a month in mice via secondary motor cortex area stimulation demonstrates the notable capabilities of our device, highlighting its potential for space-free neuromodulating applications.

Direct Laser Writing of Microscale Metal Oxide Gas Sensors from Liquid Precursors.

Fabrication and processing approaches that facilitate the ease of patterning and the integration of nanomaterials into sensor platforms are of significant utility and interest. In this work, we report the use of laser-induced thermal voxels (LITV) to fabricate microscale, planar gas sensors directly from solutions of metal salts. LITV offers a facile platform to directly integrate nanocrystalline metal oxide and mixed metal oxide materials onto heating platforms, with access to a wide variety of compositions and morphologies including many transition metals and noble metals. The unique patterning and synthesis flexibility of LITV enable the fabrication of chemically and spatially tailorable microscale sensing devices. We investigate the sensing performance of a representative set of n-type and p-type LITV-deposited metal oxides and their mixtures (CuO, NiO, CuO/ZnO, and Fe2O3/Pt) in response to reducing and oxidizing gases (H2S, NO2, NH3, ethanol, and acetone). These materials show a broad range of sensitivities and notably a strong response of NiO to ethanol and acetone (407 and 301% R/R0 at 250 °C, respectively), along with a 5- to 20-fold sensitivity enhancement for CuO/ZnO to all gases measured over pure CuO, highlighting the opportunities of LITV for the creation of mixed-material microscale sensors.

Ultrathin crystalline-silicon-based strain gauges with deep learning algorithms for silent speech interfaces.

A wearable silent speech interface (SSI) is a promising platform that enables verbal communication without vocalization. The most widely studied methodology for SSI focuses on surface electromyography (sEMG). However, sEMG suffers from low scalability because of signal quality-related issues, including signal-to-noise ratio and interelectrode interference. Hence, here, we present a novel SSI by utilizing crystalline-silicon-based strain sensors combined with a 3D convolutional deep learning algorithm. Two perpendicularly placed strain gauges with minimized cell dimension (<0.1 mm2) could effectively capture the biaxial strain information with high reliability. We attached four strain sensors near the subject's mouths and collected strain data of unprecedently large wordsets (100 words), which our SSI can classify at a high accuracy rate (87.53%). Several analysis methods were demonstrated to verify the system's reliability, as well as the performance comparison with another SSI using sEMG electrodes with the same dimension, which exhibited a relatively low accuracy rate (42.60%).

Media Reports about Violence against Medical Care Providers in China.

Improper, unprofessional, or misleading media reports about violence against medical care providers (typically doctors and nurses) may provoke copycat incidents. To examine whether media reports about violence against medical care providers in China follow professional journalism recommendations, we identified 10 influential incidents of violence against medical care providers in China through a systematic strategy and used standardized internet-based search techniques to retrieve media reports about these events from 2007-2017. Reports were evaluated independently by trained coders to assess adherence to professional journalism recommendations using a 14-item checklist. In total, 788 eligible media reports were considered. Of those, 50.5% and 47.3%, respectively, failed to mention the real and complete names of the writer and editor. Reports improperly mentioned specific details about the time, place, methods, and perpetrators of violence in 42.1%, 36.4%, 45.4%, and 54.6% of cases, respectively. Over 80% of reports excluded a suggestion to seek help from professional agencies or mediation by a third party and only 3.8% of reports mentioned the perspectives of all three key informants about an event: medical care providers, patients, and hospital administrators. Of those that mentioned medical care providers, patient, and/or hospital administrator perspectives, less than 20% indicated they had obtained the interviewee's consent to include their perspective. We concluded that most reports about violence against medical care providers in the Chinese media failed to strictly follow reporting recommendations from authoritative media bodies. Efforts are recommended to improve adherence to professional guidelines in media reports about violence against medical care providers in China, as adherence to those guidelines is likely to reduce future violent events against medical care providers like doctors and nurses.

Catalpol ameliorates endothelial dysfunction and inflammation in diabetic nephropathy via suppression of RAGE/RhoA/ROCK signaling pathway.

Catalpol is an iridoid glycoside compound isolated from the root of Rehmannia glutinosa, which has been reported to be a promising candidate for the treatment of diabetic diseases. The present study aimed at investigating the effects and potential mechanism of catalpol on endothelial dysfunction and inflammation in diabetic nephropathy (DN). We constructed DN mice and advanced glycation end products (AGEs)-induced mouse glomerular endothelial cells (mGECs) injury model. The results demonstrated that catalpol effectively improved renal pathology and decreased levels of urine protein, serum creatinine, and blood urea nitrogen in DN mice. Catalpol significantly reduced endothelial dysfunction and inflammatory infiltration of macrophages in DN mice and AGEs-induced mGECs. To further study the protective mechanism of catalpol, we transfected DN mice with recombinant adeno-associated virus expressing receptor of AGEs (RAGE) and intervened AGEs-induced mGECs with inhibitors. Catalpol reversed endothelial dysfunction and inflammation aggravated by RAGE overexpression in DN mice. Meanwhile, catalpol significantly inhibited the RAGE/Ras homolog gene family member A (RhoA)/Rho-associated kinase (ROCK) pathway in DN mice with RAGE overexpression. Moreover, the combination of catalpol with inhibitors of RAGE, RhoA and ROCK exerted stronger anti-endothelial dysfunction and anti-macrophage infiltration effects on AGEs-induced mGECs compared with catalpol alone. In short, this study indicated that catalpol could ameliorate endothelial dysfunction and inflammation via suppression of RAGE/RhoA/ROCK pathway, hereby delaying the progression of DN.

Catalpol ameliorates diabetes-induced testicular injury and modulates gut microbiota.

AIMS: To explore the mechanisms of diabetes mellitus (DM)-induced testicular injury caused by modulation of testicular glycolysis and gut microbiota (GM), and evaluation of the efficacy of catalpol in reversing testicular morbidity. MAIN METHODS: A model of DM-induced testicular injury was established using a high-fat diet in KK-Ay mice. Microbial communities in the feces of mice in normal, model and catalpol (Cat) groups were analyzed by 16S gene sequencing. Correlations between the GM and lactate metabolism levels, lactate dehydrogenase activity, and indicators of testicular injury were analyzed. KEY FINDINGS: Cat significantly reduced general indicators of diabetes in mice with DM-induced reproductive injury, mitigated damage to the testicular tissue, and increased sperm count and motility. Additionally, the levels of products of glycolysis metabolism (e.g. lactate) increased following Cat treatment compared with the Model group. Disorders in the GM were also reversed in the Cat group. SIGNIFICANCE: Cat ameliorated DM-induced testicular injury in KK-Ay mice by increasing the energy available to germ cells through glycolysis, principally through modulation of the GM and a reduction in the quantities of associated pathogenic bacteria.

Loganin alleviates macrophage infiltration and activation by inhibiting the MCP-1/CCR2 axis in diabetic nephropathy.

BACKGROUND/AIMS: The theory of inflammation is one of the important theories in the pathogenesis of diabetic nephropathy (DN). We herein aimed to explore whether loganin affected macrophage infiltration and activation upon diabetic nephropathy (DN) by a spontaneous DN mice and a co-culture system of glomerular mesangial cells (GMCs) and macrophage cells (RAW264.7) which was induced by advanced glycation end products (AGEs). METHODS AND KEY FINDINGS: Loganin showed remarkable capacity on protecting renal from damage by mitigating diabetic symptoms, improving the histomorphology of the kidney, decreasing the expression of extracellular matrix such as FN, COL-IV and TGF-ß, reversing the production of IL-12 and IL-10 and decreasing the number of infiltrating macrophages in the kidney. Moreover, loganin showed markedly effects by suppressing iNOS and CD16/32 expressions (M1 markers), increasing Arg-1 and CD206 expressions (M2 markers), which were the phenotypic transformation of macrophage. These effects may be attributed to the inhibition of the receptor for AGEs (RAGE) /monocyte chemotactic protein-1 (MCP-1)/CC chemokine receptor 2 (CCR2) signaling pathway, with significantly down-regulated expressions of RAGE, MCP-1 and CCR2 by loganin. Loganin further decreased MCP-1 secretion when RAGE was silenced, which means other target was involved in regulating the MCP-1 expression. While loganin combinated with the inhibitor of CCR2 exerted stronger anti-inhibition effects of iNOS expression, suggesting that CCR2 was the target of loganin in regulating the activation of macrophages. SIGNIFICANCE: Loganin could ameliorate DN kidney damage by inhibiting macrophage infiltration and activation via the MCP-1/CCR2 signaling pathway in DN.