Long-term Inhibition Research Articles

Conductive polyphenol microneedles coupled with electroacupuncture to accelerate wound healing and alleviate depressive-like behaviors in diabetes

Inflammation and depression are serious complications of diabetes that interact to form a feedback loop and may hinder diabetic wound healing. They share a common pathophysiological basis of abnormal interactions between diabetic wounds and the brain. Here, we propose a strategy combining electroacupuncture (EA) stimulation of the Dazhui acupoint (GV14) with polyphenol-mediated conductive hydrogel microneedles to promote diabetic wound healing and alleviate depression through local wound–brain interactions. The conductive microneedles comprised methacrylated gelatin, dopamine (DA), DA-modified poly(3,4-ethylenedioxythiophene), and Lycium barbarum polysaccharide. EA at GV14 activated the vagus–adrenal axis to inhibit systemic inflammation while DA coupled electrical signals for long-term inhibition of local wound inflammation. EA at GV14 was also found to elevate 5-hydroxytryptamine levels in rats with diabetic wounds, consequently mitigating depressive-like behaviors. Additionally, the polyphenol-mediated conductive hydrogel microneedles, and coupled with EA stimulation promoted healing of wound tissue and peripheral nerves. This strategy regulated both local and systemic inflammation while alleviating depressive-like behaviors in diabetic rats, providing a new clinical perspective for the treatment of diabetes-related and emotional disorders.

Exploring COX-Independent Pathways: A Novel Approach for Meloxicam and Other NSAIDs in Cancer and Cardiovascular Disease Treatment

As a fundamental process of innate immunity, inflammation is associated with the pathologic process of various diseases and constitutes a prevalent risk factor for both cancer and cardiovascular disease (CVD). Studies have indicated that several non-steroidal anti-inflammatory drugs (NSAIDs), including Meloxicam, may prevent tumorigenesis, reduce the risk of carcinogenesis, improve the efficacy of anticancer therapies, and reduce the risk of CVD, in addition to controlling the body’s inflammatory imbalances. Traditionally, most NSAIDs work by inhibiting cyclooxygenase (COX) activity, thereby blocking the synthesis of prostaglandins (PGs), which play a role in inflammation, cancer, and various cardiovascular conditions. However, long-term COX inhibition and reduced PGs synthesis can result in serious side effects. Recent studies have increasingly shown that some selective COX-2 inhibitors and NSAIDs, such as Meloxicam, may exert effects beyond COX inhibition. This emerging understanding prompts a re-evaluation of the mechanisms by which NSAIDs operate, suggesting that their benefits in cancer and CVD treatment may not solely depend on COX targeting. In this review, we will explore the potential COX-independent mechanisms of Meloxicam and other NSAIDs in addressing oncology and cardiovascular health.

Application of organic silicon quaternary ammonium salt (QSA) to reduce carbon footprint of sewers: Long-term inhibition on sulfidogenesis and methanogenesis

Sulfidogenic and methanogenic processes are undesirable in sewer management, yet the derived problems regarding organic losses are often neglected. Traditional chemical dosing methods aimed at sulfide and methane control commonly involve similar mechanisms of oxidation and/or precipitation. Moreover, previous focuses were centered on elevating control efficacy rather than investigating interactions between dosed chemicals and biofilms. In this work, organic silicon quaternary ammonium salt (QSA) of 75 mg-N/L was firstly applied in laboratory pressurized sewer reactors. After three dosing events, it took 20 days for sulfidogenic activities to recover to 50 % without further elevations. Meantime, methanogenic activities were stable ca. 11 % without significant inclinations to recover. Notably, consumption rate of chemical oxygen demand (COD) was suppressed to 50 % at most, and no microbial resistance to QSA but better control efficacy was observed. Characterizations of physicochemistry, microbial community and metabolism were conducted to elucidate mechanisms. Results showed that QSA was attached on sewer biofilms via electrostatic attraction to exert enduring control efficacy. Biofilms tended to become more hydrophobic and compact after QSA exposure. Microbial analyses indicated that relative abundances of microbes regarding hydrolysis, acidogenesis and methanogenesis were sharply decreased together with down-regulation of pivotal enzymatic activities. Additionally, denitrification batch tests initially suggested that the biodegradability of effluent was significantly enhanced, which ensured the safety of QSA dosing into sewers. Overall, results of this work were expected to lay a theoretical foundation on employing QSA to wastewater management.

Long-term FXa inhibition attenuates thromboinflammation after acute myocardial infarction and stroke by platelet proteome alteration

Long-term FXa inhibition attenuates thromboinflammation after acute myocardial infarction and stroke by platelet proteome alteration

Multi-year recurrent pericarditis disease duration in Italian patients: clinical outcomes after cessation of long-term IL-1 pathway inhibition provide insights for chronic management

Abstract Background Recurrent pericarditis (RP) is a chronic disease mediated by IL-1 often lasting for years, and specific tools to guide treatment duration with IL-1 pathway inhibition at the individual patient (pt) level are limited. The Phase 3 trial RHAPSODY and 2-year long-term extension (LTE) demonstrated that rilonacept reduced risk of recurrence over long-term treatment (1,2). At the conclusion of the LTE, after a median of 28 months of rilonacept treatment (non-US pts), Italian pts returned to standard management because rilonacept was not commercially available. Clinical outcomes after rilonacept cessation and washout were followed to inform disease persistence and time to recurrence. Purpose Multicentric analysis of RP event rates in Italian pts after stopping long-term rilonacept. Methods Clinical records from Italian RHAPSODY pts were examined for the 18-month period post-LTE (To). Primary outcome: pericarditis recurrence (defined by tertiary-center experts as pericarditis pain plus c-reactive protein [CRP] elevation). Secondary outcomes: time to recurrence and proportion of pts requiring re-initiation of IL-1 pathway inhibition. Safety outcomes: serious adverse events (SAEs). Results 17 Italian pts were observed (Table 1). At To, median [Q1-Q3] disease duration (time from index episode) was 48 [41-56] months, during which pts had received a median 28 [27-30] months of continuous rilonacept treatment (all were in Clinical Response, i.e., no pain, normalized CRP, and on rilonacept monotherapy). After rilonacept cessation at To, no pts received prophylactic treatment. 82.4% (14/17) of pts experienced confirmed pericarditis recurrences, with time to recurrence 8 [6-9] weeks. Half of these pts (n=7) were given oral medications (NSAIDS, colchicine [n=3] and/or steroids [n=4], of whom 1 steroid-treated pt failed and resumed IL-1 pathway inhibition). The other half (n=7) resumed IL-1 pathway inhibition directly upon recurrence. The remaining 17.6% (3/17) of pts had no pericarditis recurrences after To and remained off treatment during the observation period. No pts experienced SAEs. Neither recurrence frequency nor time to recurrence was significantly related to baseline disease characteristics or demographics. Conclusions This exploratory analysis shows that in pts with RP of even 4-years’ duration (including a median 28-months’ rilonacept treatment), the 80% recurrence rate after treatment cessation was indicative of severe persistent underlying disease. Time to pericarditis recurrence after rilonacept cessation (median 8 weeks) was consistent with the predicted gradual pharmacokinetic washout and previously-reported 8.6-week time to flare in RHAPSODY (1). Pericarditis recurrences in these pts with long disease duration and systemic inflammation were severe enough to necessitate re-initiation of advanced therapy. Further studies could quantify optimal treatment duration for pts achieving prolonged remission on IL-1 pathway inhibition.

Lipid-lowering therapy with Inclisiran in the real-world setting: initial data from a national health care service

Abstract Introduction Inclisiran, a first-in-class siRNA enabling long-term inhibition of PCSK9 synthesis, demonstrates good safety and efficacy profile in randomized clinical trials. Challenges for real-life use of inclisiran include limited access to therapy, injections by medical staff, lack of cardiovascular outcome data, and concern from adverse effects considering the novel mechanism and long-term activity. Real-life data on the potential to attain lipid-goals and reduce treatment gaps is lacking. We investigated the implementation of inclisiran in real-world clinical setting in Israel. Methods Data from a nationwide healthcare organization on patients initiating inclisiran therapy during the period of 3/2022-11/2023. Patients’ characteristics, efficacy, use of combination lipid-lowering therapies, and attainment of low-density lipoprotein cholesterol (LDL-C) goals, were evaluated. Results Inclisiran was initiated by 503 patients (57% women; mean age 66±11 years). Atherosclerotic cardiovascular disease was present in 54%, and peak historical LDL-C levels >190 mg/dL documented in 64%. Prior exposure to PCSK9 monoclonal antibodies was evident in 28%. Follow-up lipid profile >2 months after filling first prescription, was available in 397 patients (347 with ≥2 injections). In patients treated by inclisiran only (n=254), median LDL-C reduction from peak historical levels was 57% (IQR, 48%-67%), and from pre-injection levels 40% (19%-54%). In those with concomitant oral lipid-lowering therapies (n=143), median LDL-C reduction from peak levels was 66% (IQR, 55%-73%), and from pre-injection levels 46% (23%-59%) (Figure). LDL-C <70 mg/dL was attained by 39% and LDL-C <55 mg/dL by 21.9%. Of those treated with concomitant statin therapy, 38% attained LDL-C <55 mg/dL. Overall, 6.5% did not persist with inclisiran therapy after initial injection. Conclusions In real-life practice, inclisiran showed good efficacy with positive short-term adherence. However, attainment rates of lipid-goals were suboptimal due to limited use of combination lipid-lowering therapy and high-rates of severe hypercholesterolemia in our patient population cohort.Waterfall Plot of LDL-C (%) Reduction

Synergistic inhibition effect and mechanism of an inhibitor for entire process inhibition of coal spontaneous combustion

Traditional coal spontaneous combustion (CSC) inhibitors, while effective, have limitations such as frequent application or short-term efficacy. To this end, we developed a slow-release and water-soluble synergistic inhibitor (SWSI) to achieve long-term CSC inhibition. The SWSI was formulated by integrating synergistic antioxidants (SA) composed of ascorbic acid (AsA) and Fe-superoxide dismutase (Fe-SOD) dissolved in a super absorbent polymer (SAP) encapsulated within hydrogel microcapsules. The effectiveness of SWSI was evaluated through simultaneous thermal analysis and in-situ free radical tests. The formulation optimization demonstrated that AsA and Fe-SOD had the maximum synergistic inhibition effect at a 1:1 molar ratio. The optimal SA: SAP ratio of 3:1 achieved the lowest oxygen consumption rate and highest inhibition rate. The encapsulation formulation, consisting of 3% SA, 6% PAM, 1% CaCl2, and 0.5% citric acid, generated the highest swelling ratio. Simultaneous thermal analysis and in-situ free radical tests indicated that SWSI greatly increased feature temperatures and the apparent activation energy, lowered reaction heat, and substantially reduced free radical concentration in the full oxidation process. The newly developed SWSI offers a significant advancement in long-term CSC prevention by integrating physical and chemical inhibition, which provides sustained and effective inhibition throughout the entire oxidation process.

Diagnostic Accuracy of Neurocognitive and Executive Functions to Discriminate Women With and Without Fibromyalgia Syndrome: A Secondary Analysis.

Objective: The aim of the current study was to determine the capability of neurocognitive variables and executive functions to differentiate women with and without fibromyalgia syndrome (FMS). Methods: A secondary diagnostic accuracy analysis was conducted. A battery of neurocognitive and executive function tests (the D2 Attention test, the Rey-Osterrieth Complex Figure for visual perception, "Digits D/R/I" tests of the WAIS-IV battery for working memory, the 5-Digit test for mental inhibition, the Symbol Search for processing speed, and the Zoo Test for planning/decision-making) were collected in 129 women with FMS and 111 without FMS. The area under the receiver operating characteristic (ROC) curve, optimal cut-off point, sensitivity, specificity, and positive and negative likelihood ratios (LR) for each variable were calculated. Results: Between-group differences were identified in ROCF_Copy (p = 0.043), ROCF_Recall (p = 0.004), d2_TR (p = 0.019), d2_TA (p = 0.007), d2_TOT (p = 0.005), d2_CON (p = 0.004), d2_C (p = 0.042), Symbol Search (p = 0.008), Decoding _FDT (p = 0.001), Retrieving_FDT (p = 0.001), and Inhibiting_FDT (p = 0.024). The result showed that FDT-based outcomes (Retrieving_FDT: ROC 0.739, sensitivity 85.3%, specificity 48.6%; Decoding_FDT: ROC 0.724, sensitivity 50.4%, specificity 16.2%; Inhibiting_FDT: ROC 0.708, sensitivity 56.6%, specificity 22.5%) were the variables able to differentiate between women with and without FMS. Conclusions: Although women with FMS exhibited deficits in attention, long-term visual memory, processing speed, and mental inhibition when compared with women without FMS, only mental inhibition scores showed moderate diagnostic accuracy to discriminate between women with and without FMS. Future studies investigating these results in clinical settings are needed to identify the clinical relevance of these findings.

Multi-Omics Mendelian Randomization Study Investigating the Impact of PCSK9 and HMGCR Inhibition on Type 2 Diabetes Across Five Populations.

The prevalence of type 2 diabetes (T2D) varies among populations of different race/ethnicity. The influence of genetically-proxied lipoprotein cholesterol (LDL-C) lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA Reductase (HMGCR) on T2D in non-European populations is not well established.A drug-target Mendelian randomization (MR) approach was used to assess the effects of PCSK9 and HMGCR inhibition on T2D risk and glycemic traits in five populations: East Asian (EAS), South Asian (SAS), Hispanic (HISP), African (AFR), and European (EUR). Our study did not find relationships between genetically-proxied PCSK9 inhibition and T2D risk in EAS (odds ratio [OR]=1.02, [0.95-1.10]), SAS (OR=1.05, [0.97-1.14]), HISP (OR=1.03, [0.94-1.12]), or EUR (OR=1.04, [0.98-1.11]). However, in AFR, primary analyses suggested an increased risk of T2D due to PCSK9 inhibition (OR=1.53, [1.058-2.22], P-value=0.024), although this was not supported in sensitivity analyses. Genetically-proxied HMGCR inhibition was associated with an increased risk of T2D in SAS (OR=1.44, [1.30-1.61], P-value=9.8×10-12), EAS (OR=1.36, [1.22-1.51], P-value=4.2×10-10), and EUR (OR=1.52, [1.21-1.90], P-value=3.3×10-4). These results were consistent across various sensitivity analyses, including colocalization, indicating a robust finding. The findings indicate a neutral impact of long-term PCSK9 inhibition on T2D and glycemic markers in most non-European populations, with a potential increased risk in AFR cohorts. By contrast, HMGCR inhibition increased the risk of T2D in South Asian, East Asian, and European cohorts, underscoring the need to consider diversity in genetic research on metabolic diseases.

Effects of artemisinin sustained-release algaecides on in-situ cyanobacterial inhibition and microbes-floating plants dominated ecosystem functions in artificial landscape lake

The artemisinin sustained-release algaecides (ASAs) have been proven to be a safe and effective mean of inhibiting cyanobacteria in laboratory experiments. However, their effectiveness and impacts on ecosystem functions (EF) in natural waters are still unclear. In this study, the in-situ inhibitory effect of ASAs on cyanobacteria in natural waters was investigated over a period of 110 days to assess EF impacts dominated by microbes and floating plants. The results indicated that ASAs had a long-term inhibitory effect on cyanobacteria. ASAs did not affect sediment but increased TOC and TP in the water column in 2-10 days. Microbial diversity and network analyses indicated that ASAs enhanced bacterial diversity, network complexity, and hub-bacteria in networks. Metabolic pathway predictions and CCA analysis showed that ASAs maintained the stability of EF by enhancing the metabolic capacities of bacteria, and the relationships between metabolic microorganisms and environmental factors. PLS-PM revealed that ASAs primarily drove bacterial resistance to cyanobacteria, which was the key mechanism for its long-term inhibition of cyanobacteria. However, the early outbreak of floating plants was not conducive to the long-term inhibition of cyanobacteria by ASAs. This study provides new insights into the mechanisms and ecological impacts of cyanobacterial inhibition by ASAs in complex aquatic environments.

Grandpa, tell me a story! Narrative ability in healthy aging and its relationship with cognitive functions and Theory of Mind

ABSTRACT Healthy aging affects the linguistic and cognitive abilities involved in narrative production. However, few studies provided a comprehensive assessment of narrative skills in aging and their association with cognitive and Theory of Mind (ToM) functions. We explored how aging influences narrative skills, at both micro- (i.e. lexical and grammatical) and macrolinguistic (i.e. pragmatic and discourse) levels. Sixty healthy adults divided into three age-groups (20–40, 65–75, 76–86 years old) were administered tasks assessing narrative production skills, executive functions (EFs), and ToM. A network approach was used to explore how micro- and macrolinguistic skills were associated to different cognitive and ToM functions. The analyses revealed age-related effects on various aspects of language production, including phonology, semantic retrieval, sentence complexity, coherence, cohesion, and lexical informativeness. Moreover, a significant relationship was found between linguistic measures, ToM skills and cognitive functions such as working and long-term memory and inhibition.

Abstract C022: Elucidation and exploitation of RAS-inhibitor dependent macropinocytic regulation in pancreatic ductal adenocarcinoma

Abstract Alteration of essential metabolic pathways is a major mechanism by which oncogenic KRAS promotes tumor development and growth in pancreatic ductal adenocarcinoma (PDAC). KRAS- driven PDAC is dependent on nutrient scavenging pathways, including macropinocytosis and autophagy to fuel the metabolic demand of rapid proliferation. Thus, these metabolic processes are attractive targets for the development of treatments for PDAC. Acute KRAS loss results in downregulation of macropinocytosis in PDAC. Additionally, our lab demonstrated that KRAS loss or inhibition of ERK MAPK signaling decreased glucose consumption and glycolysis but increased autophagy, thereby enhancing dependency on autophagy for survival and growth. Accordingly, dual ERK MAPK and autophagy inhibition (via chloroquine) synergistically enhanced anti-tumor efficacy in PDAC. However, early clinical data has demonstrated that resistance to this treatment arises over time through unknown mechanisms. We observed that both autophagy induction and macropinocytosis downregulation are transient following RAS, MEK, or ERK inhibition—with autophagic and macropinocytic activity returning to or surpassing basal levels after within two weeks of treatment. Furthermore, we found that prolonged pharmacological inhibition of RAS, MEK, or ERK pathway consistently resulted in significant upregulation of macropinocytosis. We propose that prolonged MAPK inhibition upregulates macropinocytosis over time, consequently abrogating dependency on autophagy and therefore reducing sensitivity to autophagy inhibition. Furthermore, we found that chloroquine, which is commonly thought of as a lysosomotropic drug, does not prevent degradation of proteins engulfed via macropinocytosis. Together our data suggests that upregulation of macropinocytosis may mediate resistance to the combination of ERK MAPK inhibition and chloroquine. With the recent advance in development RAS inhibitors, the resistance mechanisms by which PDAC can overcome RAS inhibitor treatment is a major focus of the field. Given the dependence of PDAC on macropinocytic uptake for tumorigenic growth, it is imperative to understand how long-term treatment with RAS inhibitors regulate macropinocytosis. We demonstrated that PDAC cells with acquired resistance to RAS inhibition exhibit a 2- to 10-fold increase in macropinocytic uptake. We found that upregulated macropinocytosis following long-term RAS or MAPK inhibition is accompanied by increased albumin uptake and sensitivity to albumin-bound paclitaxel (nab-paclitaxel), a therapeutic that is included in the current standard of care for PDAC patients. These results suggest that RAS inhibitor pretreatment or concurrent treatment with nab-paclitaxel may represent a strategy to improve this current PDAC treatment. We conclude that a more complete understanding of the regulation of essential metabolic pathways following both acute and sustained RAS inhibition will better inform future RAS inhibitor combination therapies. Citation Format: Ryan Robb, Sarah Ackermann, Khalilah Taylor, Runying Yang. Elucidation and exploitation of RAS-inhibitor dependent macropinocytic regulation in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C022.

Time dependent anti-corrosion and anti-scaling efficiency of polyepoxysuccinic acid inhibitor in simulated hard water

In this study, the time-dependent performance of a phosphorus-free corrosion and scale inhibitor primarily composed of polyoxyuccinic acid (PESA) and zinc salts was investigated in a laboratory-simulated hard water environment. Long-term static scale inhibition tests and corrosion rotation coupon tests were conducted under two temperature conditions, 45 °C and 80 °C, following established literature standards. Changes in water quality, scale morphology, metal corrosion status, and electrochemical impedance were monitored using calcium ion concentration analysis, optical microscopy imaging, X-ray diffraction (XRD), and electrochemical testing. The study revealed a progressive decline in the corrosion and scale inhibition efficiency of the phosphorus-free inhibitor in simulated hard water with calcium carbonate hardness levels of 300, 400, and 500 mg/L over time. Moreover, higher water hardness accelerated corrosion onset, suggesting that calcium carbonate deposition promotes metal corrosion under the experimental conditions. Density functional theory (DFT) calculations indicated that PESA chemically adsorbs onto both metal and calcite surfaces, underscoring its dual role in corrosion and scale inhibition. These findings underscore the intrinsic corrosion and scale inhibition capabilities of PESA, complementing its synergistic film-forming properties with Zn2+.

PH-responsive mupirocin-loaded hybrid nanoparticles in hydrogel and film forming spray against resistant bacterial wound infections

The aim of this work was to fabricate smart Mupirocin loaded Lipid Polymeric Hybrid Nanoparticles (MUP-LPHNs) based hydrogel and Film forming spray (FFS) for targeted release of MUP in response to wound pH. The MUP-LPHNs were optimized through design expert v.12. The optimized MUP-LPHNs had a particle size of 270.7 ± 3.20 nm with zeta potential of 17.05 ± 1.20 mV and entrapment efficiency of 88.0 ± 0.35 %. MUP-LPHNs showed no major chemical interaction, spherical morphology and amorphous nature as confirmed by FTIR, SEM and XRD, respectively. MUP-LPHNs were loaded to MUP-LPHNs based hydrogel (MUP-LPHNs-HG) and MUP-LPHNs based film forming spray (MUP-LPHNs-FFS) with successful characterization. In vitro release data confirmed sustained and pH dependent release from both MUP-LPHNs-HG and MUP-LPHNs-FFS as higher release was observed at pH 7.4. MUP-LPHNs-HG and MUP-LPHNs-FFS showed high efficiency and long-term inhibition of Staphylococcus aureus (SA), Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (P. aeruginosa) with 4–6 fold increase in the antibacterial activity compared to MUP solution. MUP-LPHNs-HG and MUP-LPHNs-FFS exhibited both in vitro and in vivo wound pH contingent, sustained drug release. Moreover, the prepared nanocarriers systems flaunted significant therapeutic efficacy against MRSA infected wound model by significant reduction in bacterial load and wound area, increased hydroxy proline level and antioxidant enzymes and reduced proinflammatory cytokines. Similarly, immunohistochemistry, histopathological and trichrome assessment showed significant reduction in level of inflammatory markers, accelerated and enhanced re-epithelization, improved connective tissue remodeling and effectively promote collagen deposition with effective wound regeneration, respectively. It can be concluded that LPHNs could be a potential carrier system for enhancing the therapeutic efficacy of MUP against resistant bacterial wound infections.

Abstract AW12: Hyperinnervation and Immune-endocrine Interactions in Renal Arteriolar Hypertrophy during Inhibition of The Renin-Angiotensin System

Background: Chronic stimulation of renin cells by long-term use of renin-angiotensin system (RAS) inhibitors or renin deletion leads to concentric renal arteriolar hypertrophy frequently surrounded by immune-inflammatory cells. The disease is caused by the renin cells which increase in number and adopt an embryonic-secretory phenotype and induce the accumulation of smooth muscle cells that obstruct the vessels leading to ischemia. Normally, renin cells are innervated but it is unclear whether innervation of the renal arterial tree is affected under RAS inhibition. Hypothesis: Long-term RAS inhibition increases renal arteriolar innervation. Methods: We used two models of RAS inhibition: 1) Ren1 c-/- ; Ren1 c-Cre ; R26R mTmG mice studied at 3 months of age; 2) SMMHC CreERT2 ; R26R tdTomato ; Ren1 cYFP mice were treated with captopril for 6 months. We performed tissue clearing and 3D staining with an anti-tubulin β3 antibody. The expression of neurogenesis-related genes in renin lineage cells was examined using our previous single-cell RNA sequencing (scRNA-seq) data from mouse kidneys. We compared RNA expression of nerve growth factor (NGF) between Ren1 c−/− mice and control mice by qPCR and in situ hybridization (ISH). T cell infiltration was observed by immunostaining with anti-CD3 antibody. Results: 3-D imaging revealed that in both RAS inhibition models there was marked hyperinnervation. Renin cells expanded along and around the renal arterioles, and covered the glomeruli. Axons grew in numerous branches surrounding thickened afferent arterioles, bound tightly to renin cells and encasing the glomeruli. Our scRNA-seq data showed that Ngf , a gene important for neurogenesis and produced by immune cells, was highly expressed in renin cells. In Ren1 c−/− mice, expression of Ngf was significantly increased compared to controls (p=0.0054). ISH revealed that Ngf was highly expressed in Ren1 c−/− mice in the juxtaglomerular area and in the renal cortical stroma. Infiltration of T cells around affected arterioles was prominent in both models of RAS inhibition. Conclusion: Long-term inhibition of RAS leads to renal hyperinnervation, infiltration of immune cells and arteriolar hypertrophy. The identification of this neuro-immune-endocrine arterioles may help understand and treat vascular disease and hypertension.

Calorie restriction and rapamycin distinctly mitigate aging-associated protein phosphorylation changes in mouse muscles

Calorie restriction (CR) and treatment with rapamycin (RM), an inhibitor of the mTORC1 growth-promoting signaling pathway, are known to slow aging and promote health from worms to humans. At the transcriptome and proteome levels, long-term CR and RM treatments have partially overlapping effects, while their impact on protein phosphorylation within cellular signaling pathways have not been compared. Here we measured the phosphoproteomes of soleus, tibialis anterior, triceps brachii and gastrocnemius muscles from adult (10 months) and 30-month-old (aged) mice receiving either a control, a calorie restricted or an RM containing diet from 15 months of age. We reproducibly detected and extensively analyzed a total of 6960 phosphosites, 1415 of which are not represented in standard repositories. We reveal the effect of these interventions on known mTORC1 pathway substrates, with CR displaying greater between-muscle variation than RM. Overall, CR and RM have largely consistent, but quantitatively distinct long-term effects on the phosphoproteome, mitigating age-related changes to different degrees. Our data expands the catalog of protein phosphorylation sites in the mouse, providing important information regarding their tissue-specificity, and revealing the impact of long-term nutrient-sensing pathway inhibition on mouse skeletal muscle.

Effects of Carbon-Based Modified Materials on Soil Water and Fertilizer Retention and Pollution Control in Rice Root Zone

To seek an appropriate stabilization and remediation scheme for cadmium (Cd) and arsenic (As) pollution in farmland, a typical polluted soil sample was selected from a mining area in Southwest China for a soil box simulation experiment. Biochar (BC), a modified type of biochar made from rice husk with different mass ratios of ferric chloride and rice husk, was set up (the mass ratio of ferric chloride to rice husk was 1:9 (defined as LFB), 3:7 (defined as MFB), and 5:5 (defined as HFB) and the control group (BL)) to explore the effects of soil water and fertilizer loss, the bioavailability of Cd and As, and the bioenrichment effects of plant organs during the growth period of rice. The results showed that the porous structure and large specific surface area of biochar effectively regulated soil aggregate composition and improved soil water holding capacity. Compared to the BL treatment, soil water storage under the four carbon-based material control modes increased from 8.98% to 14.52%. Biochar has a strong ion exchangeability and can absorb soil ammonium, nitrogen, and phosphoric acid groups, effectively inhibiting the loss of soil fertilizer. Biochar improves soil pH and reduces the specific gravity of exchangeable Cd. In addition, the oxygen-containing functional groups in biochar can react with metals in a complex manner. The diethylenetriaminepentaacetic acid (DTPA) concentrations of Cd in soils treated with BC, LFB, MFB, and HFB were 79.69%, 72.92%, 64.58%, and 69.27% lower, respectively, than those treated with BL. In contrast, the Fe3+ in ferric chloride combines with As after hydrolysis and oxidation to form amorphous ferric arsenate precipitates or insoluble secondary minerals. Therefore, the curing effect of the modified biochar on As was more potent than that of applied biochar alone. In conclusion, ferric chloride-modified biochar can effectively inhibit the effects of water and fertilizer loss in farmland soil and realize cross-medium long-term inhibition and control of combined Cd and As pollution.

A Bimetallic Electro-Sensitizer Improves ROS Therapy by Relieving Autophagy-Induced ROS Tolerance and Immune Suppression.

Reactive oxygen species (ROS)-dependent monotherapy usually demonstrates poor therapeutic outcomes, due to the accompanied activation of protective autophagy in tumor cells, which results in ROS tolerance and immune suppression. In this study, a bimetallic electro-sensitizer, Pt-Ir NPs is constructed, loaded with the autophagy inhibitor chloroquine (Pt-Ir-CQ NPs), to enhance the effectiveness of electrotherapy by inhibiting autophagy and activating anti-tumor immune responses. This novel electrotherapy platform demonstrates unique advantages, particularly in the treatment of hypoxic and immunosuppressive tumors. First, the electro-sensitizer catalyzes water molecules into ROS under electric field, achieving tumor ablation through electrotoxicity. Second, the incorporated CQ inhibits the protective autophagy induced by electrotherapy, restoring the sensitivity of tumor cells to ROS and thereby enhancing the anti-tumor effects of electrotherapy. Third, Pt-Ir-CQ NPs enhance the functionality of antigen-presenting cells and immunogenic cells through inhibiting autophagy, synergistically activating the anti-tumor immune responses along with the immunogenic cell death (ICD) effect induced by electrotherapy. This study provides a novel approach for the effective ablation and long-term inhibition of solid tumors through flexible modulation by an exogenous electric field.

Self-Adapting Biomass Hydrogel Embodied with miRNA Immunoregulation and Long-Term Bacterial Eradiation for Synergistic Chronic Wound Therapy.

Chronic wound rescue is critical for diabetic patients but is challenging to achieve with a specific and long-term strategy. The prolonged bacterial inflammation is particularly prevalent in hyperglycemia-induced wounds, usually leading to severe tissue damage. Such a trend could further suffer from an environmental suitability provided by macrophages for persisting Staphylococcus aureus (S. aureus) and even deteriorate by their mutual reinforcement. However, the strategy of both suppressing bacteria growth and immunoreprogramming the inflammatory type of macrophages to break their vicious harm to wound healing is still lacking. Here, a self-adapting biomass carboxymethyl chitosan (CMC) hydrogel comprising immunomodulatory nanoparticles is reported to achieve Gram-negative/Gram-positive bacteria elimination and anti-inflammatory cytokines induction to ameliorate the cutaneous microenvironment. Mechanistically, antibacterial peptides and CMCs synergistically result in a long-term inhibition against methicillin-resistant S. aureus (MRSA) over a period of 7 days, and miR-301a reprograms the M2 macrophage via the PTEN/PI3Kγ/mTOR signaling pathway, consequently mitigating inflammation and promoting angiogenesis for diabetic wound healing in rats. In this vein, immunoregulatory hydrogel is a promising all-biomass dressing ensuring biocompatibility, providing a perspective to regenerate cutaneous damaged tissue, and repairing chronic wounds on skin.

Amphiphilic polysiloxane graft guanidine salts with a combination of low environmental toxicity and high antifungal activity

Banana Fusarium wilt is one of the most serious diseases that restricts the banana industry. How to achieve efficient, low toxicity, and long-term inhibition of pathogenic fungal spores (Fusarium oxysporum f. sp. cubense, race 4, Foc4) that grow in soil has become a challenge in the field of chemical control of plant diseases in recent years. Based on the special antimicrobial mechanism of guanidine salts, which can effectively inhibit microbes by forming transmembrane stomata on the plasma membrane, we were inspired to introduce hydrophilic guanidine salts to hydrophobic PDMS chains to potentially balance high antimicrobial activity and low environmental toxicity. In this work, a series of novel amphiphilic polysiloxane graft guanidine salts (PDMS-g-GH) were synthesized based on our previous works, i.e., polysiloxane graft primary amine salts (PDMS-g-AH), in which the primary amine salt groups were converted to guanidine salt groups. The molecular weight of the polymer, the grafting density of guanidine salts, the distribution of guanidine salt units on the main chain (random or block), the in vitro antifungal activities and the anti-Foc4 activities in soil, the adsorption characteristics in soil, and the environmental toxicity after soil adsorption were systematically studied. The results confirmed that compared with PDMS-g-AH, PDMS-g-GH showed stronger antifungal activity against Foc4 and long-term antifungal activity against Foc4 in soil, but its environmental toxicity was significantly reduced. These results support the potential application of PDMS-g-GH for the prevention and control of banana Fusarium wilt and other soil-borne fungal diseases.