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2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Xuancheng Du ◽  
Bingqing Jia ◽  
Weijie Wang ◽  
Chengmei Zhang ◽  
Xiangdong Liu ◽  
...  

AbstractThe management of diabetic ulcer (DU) to rescue stalled wound healing remains a paramount clinical challenge due to the spatially and temporally coupled pathological wound microenvironment that features hyperglycemia, biofilm infection, hypoxia and excessive oxidative stress. Here we present a pH-switchable nanozyme cascade catalysis (PNCC) strategy for spatial–temporal modulation of pathological wound microenvironment to rescue stalled healing in DU. The PNCC is demonstrated by employing the nanozyme of clinically approved iron oxide nanoparticles coated with a shell of glucose oxidase (Fe3O4-GOx). The Fe3O4-GOx possesses intrinsic glucose oxidase (GOx), catalase (CAT) and peroxidase (POD)-like activities, and can catalyze pH-switchable glucose-initiated GOx/POD and GOx/CAT cascade reaction in acidic and neutral environment, respectively. Specifically, the GOx/POD cascade reaction generating consecutive fluxes of toxic hydroxyl radical spatially targets the acidic biofilm (pH ~ 5.5), and eradicates biofilm to shorten the inflammatory phase and initiate normal wound healing processes. Furthermore, the GOx/CAT cascade reaction producing consecutive fluxes of oxygen spatially targets the neutral wound tissue, and accelerates the proliferation and remodeling phases of wound healing by addressing the issues of hyperglycemia, hypoxia, and excessive oxidative stress. The shortened inflammatory phase temporally coupled with accelerated proliferation and remodeling phases significantly speed up the normal orchestrated wound-healing cascades. Remarkably, this Fe3O4-GOx-instructed spatial–temporal remodeling of DU microenvironment enables complete re-epithelialization of biofilm-infected wound in diabetic mice within 15 days while minimizing toxicity to normal tissues, exerting great transformation potential in clinical DU management. The proposed PNCC concept offers a new perspective for complex pathological microenvironment remodeling, and may provide a powerful modality for the treatment of microenvironment-associated diseases. Graphical Abstract


2021 ◽  
Vol 23 (1) ◽  
pp. 353
Author(s):  
Holger Lörchner ◽  
Juan M. Adrian-Segarra ◽  
Christian Waechter ◽  
Roxanne Wagner ◽  
Maria Elisa Góes ◽  
...  

Oncostatin M (OSM) and leukemia inhibitory factor (LIF) signaling protects the heart after myocardial infarction (MI). In mice, oncostatin M receptor (OSMR) and leukemia inhibitory factor receptor (LIFR) are selectively activated by the respective cognate ligands while OSM activates both the OSMR and LIFR in humans, which prevents efficient translation of mouse data into potential clinical applications. We used an engineered human-like OSM (hlOSM) protein, capable to signal via both OSMR and LIFR, to evaluate beneficial effects on cardiomyocytes and hearts after MI in comparison to selective stimulation of either LIFR or OSMR. Cell viability assays, transcriptome and immunoblot analysis revealed increased survival of hypoxic cardiomyocytes by mLIF, mOSM and hlOSM stimulation, associated with increased activation of STAT3. Kinetic expression profiling of infarcted hearts further specified a transient increase of OSM and LIF during the early inflammatory phase of cardiac remodeling. A post-infarction delivery of hlOSM but not mOSM or mLIF within this time period combined with cardiac magnetic resonance imaging-based strain analysis uncovered a global cardioprotective effect on infarcted hearts. Our data conclusively suggest that a simultaneous and rapid activation of OSMR and LIFR after MI offers a therapeutic opportunity to preserve functional and structural integrity of the infarcted heart.


2021 ◽  
Author(s):  
Paul W Blair ◽  
Joost Brandsma ◽  
Josh G. Chenoweth ◽  
Stephanie A. Richard ◽  
Nusrat J. Epsi ◽  
...  

OBJECTIVES: The relationships between baseline clinical phenotypes and the cytokine milieu of the peak inflammatory phase of coronavirus 2019 (COVID-19) are not yet well understood. We used Topological Data Analysis (TDA), a dimensionality reduction technique to identify patterns of inflammation associated with COVID-19 severity and clinical characteristics. DESIGN: Exploratory analysis from a multi-center prospective cohort study. SETTING: Eight military hospitals across the United States between April 2020 and January 2021. PATIENTS: Adult (≥18 years of age) SARS-CoV-2 positive inpatient and outpatient participants were enrolled with plasma samples selected from the putative inflammatory phase of COVID-19, defined as 15-28 days post symptom onset. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Concentrations of 12 inflammatory protein biomarkers were measured using a broad dynamic range immunoassay. TDA identified 3 distinct inflammatory protein expression clusters. Peak severity (outpatient, hospitalized, ICU admission or death), Charlson Comorbidity Index (CCI), and body mass index (BMI) were evaluated with logistic regression for associations with each cluster. The study population (n=129, 33.3% female, median 41.3 years of age) included 77 outpatient, 31 inpatient, 16 ICU-level, and 5 fatal cases. Three distinct clusters were found that differed by peak disease severity (p <0.001), age (p <0.001), BMI (p<0.001), and CCI (p=0.001). CONCLUSIONS: Exploratory clustering methods can stratify heterogeneous patient populations and identify distinct inflammation patterns associated with comorbid disease, obesity, and severe illness due to COVID-19.


2021 ◽  
Vol 12 ◽  
Author(s):  
Melissa S. O’Brien ◽  
Jason J. McDougall

Serine proteases are elevated in arthritic joints where they can cleave protease activated receptors (PARs) to modulate pain and inflammation. Activation of protease-activated receptor 4 (PAR4) has been implicated in inflammatory joint pain. Whether PAR4 is involved in osteoarthritis (OA) pain has not yet been explored. The aim of this study was to compare the role of PAR4 in modulating early versus late stage OA pain using two models of OA viz. monoiodoacetate (MIA) and medial meniscal transection (MMT). G-ratio calculation and electron microscopy analysis revealed saphenous nerve demyelination and structural damage during late stage but not early OA in both models. Using immunohistochemistry, neuronal expression of PAR4 was higher in early versus late OA. Systemic administration of the PAR4 antagonist pepducin P4pal10 reduced both secondary allodynia (von Frey hair algesiometry) and joint nociceptor firing (single unit recordings) in MMT and MIA animals compared to vehicle-treated animals in early OA. The PAR4 antagonist was ineffective at altering pain or joint afferent firing in post-inflammatory OA. During the acute phase of the models, joint inflammation as determined by laser speckle contrast analysis and intravital microscopy could be partially blocked by pepducin P4pal10. Compared to late-stage disease, inflammatory cytokines were elevated in early MIA and MMT rats. These findings suggest that PAR4 may be a viable target to treat the pain of early onset OA or during episodic inflammatory flares.


Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 3
Author(s):  
Anugraha Gandhirajan ◽  
Sanjoy Roychowdhury ◽  
Vidula Vachharajani

Sepsis and septic shock are the leading causes of death among hospitalized patients in the US. The immune response in sepsis transitions from a pro-inflammatory and pro-oxidant hyper-inflammation to an anti-inflammatory and cytoprotective hypo-inflammatory phase. While 1/3rd sepsis-related deaths occur during hyper-, a vast majority of sepsis-mortality occurs during the hypo-inflammation. Hyper-inflammation is cytotoxic for the immune cells and cannot be sustained. As a compensatory mechanism, the immune cells transition from cytotoxic hyper-inflammation to a cytoprotective hypo-inflammation with anti-inflammatory/immunosuppressive phase. However, the hypo-inflammation is associated with an inability to clear invading pathogens, leaving the host susceptible to secondary infections. Thus, the maladaptive immune response leads to a marked departure from homeostasis during sepsis-phases. The transition from hyper- to hypo-inflammation occurs via epigenetic programming. Sirtuins, a highly conserved family of histone deacetylators and guardians of homeostasis, are integral to the epigenetic programming in sepsis. Through their anti-inflammatory and anti-oxidant properties, the sirtuins modulate the immune response in sepsis. We review the role of sirtuins in orchestrating the interplay between the oxidative stress and epigenetic programming during sepsis.


Author(s):  
Aashriya Jha ◽  
Varsha Patond

Background: Frozen shoulder is a commonly occurring disease of the population. It is also referred to as shoulder capsulitis. It causes pain and stiffness of the shoulder and dominant in left shoulder. Various things are still unclear regarding the treatment and causes of this disease. It is a painful and n quickly healed disease. Patients show recovery but are often unable to regain their full potential movements. Painful stiffness of the shoulder is an ill-described medical entity, this is hard to evaluate and sensitive to treat. The nomenclature sed and consists of phrinclude cluding frozen shoulder, adhesive capsulitis, focal dystrophy, stiff shoulder, shriveled shoulder, and following. Apart from its idiopathic form, the disease can be initiated with the resource of the usage of trauma, infection, tumor, radiation, systemic and neighborhood metabolic concerns. Patho- anatomically, the common place region denominates an inflammatory vascular proliferation found with the resource of the usage thickening, scarring, and retraction of the joint cover. Summary: The inflammatory technique frequently begins to evolved on the rotator language and can increase to the subacromial space. Clinical analysis is primarily based totally records and bodily examination. Generally, the onset of ache precedes the belief of a discounted variety of movement with the aid of using weeks or months. In early ranges of ailment, the inflammatory form of ache dominates, the patient's most important criticism is ache at night. In the later stage, variety of movement step by step decreases. Patients no longer frequently whine approximately decreased movement, likely due to its gradual onset. Conclusion: Treatment options are a mixture of mobilization carrying sports with intra-articular steroids, hydraulic distension of the joint capsule, manipulation below anaesthesia,arthroscopic and/or open arthrosis.The appropriate preference of protocol is really as critical as its correct timing. In the inflammatory phase, competitive invasive protocols are uncommon, but deleterious and therefore need to be taken into consideration. New anti- angiogenic outlets also can moreover enhance beneficial effects and shorten the rehabilitation phase.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Andrej Sikoski ◽  
Krish Jayapranu ◽  
Hong-Ming Zhou ◽  
Yunglong Liu ◽  
Xiaoling Xuei ◽  
...  

While playing a critical role in skin wound healing, the inflammatory phase of this process is poorly understood. To gain a better understanding of the inflammatory phase of wound healing, we developed an ex vivo skin culture model of skin injury-induced inflammation. Previous work in our laboratory showed ex vivo culture of human skin induces an interleukin 1 alpha (IL-1α)-dependent response characterized by increased transcript and protein levels for the inflammatory cytokines/chemokines, IL-6, CXCL1, and CSF3. However, the cellular sources of these factors in ex vivo cultured human skin have not been determined. Prior work with ex vivo cultured mouse skin and single cell RNA sequencing suggested fibroblasts and endothelial cells were potential cellular sources for these inflammatory mediators. The current studies used spatial transcriptomics analysis of ex vivo cultured human skin to localize the IL-1α target cell populations/skin tissue regions that produce IL-6, CXCL1 and CSF3. The Visium Gene Expression Solution platform (10x Genomics Inc.) was used to generate spatial transcriptomics data from skin specimens preserved immediately after biopsy or after skin culture for 24 hours. Loupe Browser version 5.1.0 (10x Genomics Inc) was used for data analysis to identify and characterize cell populations/regions expressing IL6, CXCL1, and CSF3 and associated differentially expressed genes (including cell type-specific transcripts). Notably, these IL-1α-induced transcripts were localized to the parent dermis region cluster. Analysis of subclusters in the dermal region showed differential expression of these inflammatory transcripts in regions enriched with either or both fibroblast and endothelial cell specific-type markers. Potential novel markers of this inflammatory response, like SOD2, were identified and warrant future investigation. Subsequent studies in identifying the targets of IL-1α in skin inflammation is called for, as they may lead to better understanding of this processes in wound healing and better clinical outcomes.


2021 ◽  
Vol 23 (4) ◽  
pp. 301-305
Author(s):  
Ana Flávia Spadaccini Silva ◽  
Jéssica Lúcio da Silva ◽  
Danielle Gregorio ◽  
Rodrigo Antonio Carvalho Andraus ◽  
Luciana Prado Maia

AbstractMuscle injuries are frequent, both in the practice of exercises and in the work environment, and after the injury, healing begins. The inflammatory phase of muscle healing is accompanied by an increase in the production of reactive oxygen species (ROS), and a reduction in the antioxidant activity of defense enzymes. This imbalance between both can generate oxidative stress, which can cause oxidative damage by directly affecting vital cellular constituents, such as lipids, proteins and DNA, in addition to interfering negatively in the muscle cells differentiation . Therefore, substances or therapies that stimulate antioxidant repair and defense are crucial to keep the levels of free radical production low, and to minimize factors that delay or prevent tissue recovery, among these therapies photo biomodulation has stood out. The objective of this literature review is to clarify the FBM effect on oxidative stress and muscle repair. Therefore, a search was carried out in the databases of Pubmed, Scielo, Lilacs and PEDro, using the keywords “Photo biomodulation”, “low power laser”, “muscle repair”, “oxidative stress”, and in English were ”Photo biomodulation”, “low level laser therapy”, “muscle repair” and “oxidative stress”. The texts that addressed the research topic, published between 2000 and 2020, were chosen. After analyzing the articles, it was possible to observe that photo biomodulation, despite presenting a great variety of parameters, moment of application and irradiation protocol found in the literature, shows beneficial results in the repair muscle and in the reduction of oxidative stress and fatigue markers. Keywords: Low-Level Light Therapy. Oxidative Stress. Edema. ResumoLesões musculares são frequentes, tanto na prática de exercícios como no ambiente de trabalho, sendo que após a lesão, inicia a cicatrização. A fase inflamatória da cicatrização muscular é acompanhada do aumento da produção de espécies reativas de oxigênio (ERO) e uma redução da atividade antioxidante das enzimas de defesa. Este desequilíbrio entre ambos pode gerar o estresse oxidativo, que leva a danos e atingi diretamente constituintes celulares vitais, como lipídios, proteínas e DNA, além de interferir negativamente na diferenciação das células musculares. Portanto, substâncias ou terapias que estimulem a reparação e a defesa antioxidante são cruciais para manter os níveis de produção de radicais livres baixos, e minimizar os fatores que atrasam ou impedem a recuperação do tecido, dentre estas terapias a fotobiomodulação tem se destacado. O objetivo da presente revisão de literatura é esclarecer o efeito da FBM sobre o estresse oxidativo e o reparo muscular. Sendo assim, realizou-se uma pesquisa nas bases de dados da Pubmed, Scielo, Lilacs e PEDro, utilizando as palavras-chave “Fotobiomodulação”, “laser de baixa potência”, “reparo muscular”, “estresse oxidativo”, e em inglês foram “photobiomodulation”, “low level laser therapy”, “muscle repair” e “oxidative stress”. Foram escolhidos os textos que abordavam o tema da pesquisa, publicados entre 2000 e 2020. Analisando os artigos foi possível observar que a fotobiomodulação apesar de apresentar grande variedade de parâmetros, momento de aplicação e protocolo de irradiação encontrados na literatura, mostra resultados benéficos no reparo muscular e na diminuição de marcadores do estresse oxidativo e fadiga. Palavras-chave: Terapia com Luz de Baixa Intensidade. Estresse Oxidativo. Edema.


2021 ◽  
Vol 16 ◽  
Author(s):  
Gennaro D'Amato ◽  
Isabella Annesi-Maesano ◽  
Marilyn Urrutia-Pereira ◽  
Stefano Del Giacco ◽  
Nelson A. Rosario Filho ◽  
...  

Thunderstorm-triggered asthma (TA) can be defined as the occurrence of acute asthma attacks immediately following a thunderstorm during pollen seasons. Outbreaks have occurred across the world during pollen season with the capacity to rapidly inundate a health care service, resulting in potentially catastrophic outcomes for allergicpatients. TA occurs when specific meteorological and aerobiological factors combine to affect predisposed atopic patients with IgE-mediated sentitization to pollen allergens. Thunderstorm outflows can concentrate aeroallergens, most commonly grass pollen but also other pollens such as Parietaria and moulds in TA, at ground level to release respirable allergenic particles after rupture by osmotic shock related to humidity and rainfall. Inhalation of high concentrations of these aeroallergens by sensitized individuals can induce early asthmatic responses which can be followed by a late inflammatory phase. There is evidence that, during pollen season, thunderstorms can induce allergic asthma outbreaks, sometimes also severe asthma crisis and sometimes deaths in patients suffering from pollen allergy. It has been observed that changes in the weather such as rain or humidity may induce hydratation of pollen grains during pollen seasons and sometimes also their fragmentation which generates atmospheric biological aerosols carrying allergens. Asthma attacks are induced for the high concentration at ground level of pollen grains which may release allergenic particles of respirable size after rupture by osmotic shock. In other words, it is a global health problem observed in several cities and areas of the world that can strike without sufficient warning, inducing sometimes severe clinical consequences also with deaths of asthma patients. Due to constant climate change, future TA events are likely to become more common, more disastrous and more unpredictable, as a consequence it is important to have deep knowledge on this topic to prevent asthma attacks. Other environmental factors, such as rapid changes in temperature and agricultural practices, also contribute to causing TA.


Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3267
Author(s):  
Gaëtan Juban ◽  
Bénédicte Chazaud

Efferocytosis, i.e., engulfment of dead cells by macrophages, is a crucial step during tissue repair after an injury. Efferocytosis delineates the transition from the pro-inflammatory phase of the inflammatory response to the recovery phase that ensures tissue reconstruction. We present here the role of efferocytosis during skeletal muscle regeneration, which is a paradigm of sterile tissue injury followed by a complete regeneration. We present the molecular mechanisms that have been described to control this process, and particularly the metabolic control of efferocytosis during skeletal muscle regeneration.


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