therapeutic concept
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2022 ◽  
Author(s):  
Jennifer C. Veilleux ◽  
Katherine C. Hyde ◽  
Kaitlyn D. Chamberlain ◽  
Danielle E. Higuera ◽  
Regina E. Schreiber ◽  
...  

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 98
Author(s):  
Andreas von Knethen ◽  
Ulrike Heinicke ◽  
Volker Laux ◽  
Michael J. Parnham ◽  
Andrea U. Steinbicker ◽  
...  

Acute respiratory distress syndrome (ARDS) is a major cause of patient mortality in intensive care units (ICUs) worldwide. Considering that no causative treatment but only symptomatic care is available, it is obvious that there is a high unmet medical need for a new therapeutic concept. One reason for a missing etiologic therapy strategy is the multifactorial origin of ARDS, which leads to a large heterogeneity of patients. This review summarizes the various kinds of ARDS onset with a special focus on the role of reactive oxygen species (ROS), which are generally linked to ARDS development and progression. Taking a closer look at the data which already have been established in mouse models, this review finally proposes the translation of these results on successful antioxidant use in a personalized approach to the ICU patient as a potential adjuvant to standard ARDS treatment.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi201-vi201
Author(s):  
Trang Nguyen ◽  
Enyuan Shang ◽  
Salveena Schiffgens ◽  
Consuelo Torrini ◽  
Elena Bianchetti ◽  
...  

Abstract Activation of the mitochondrial ClpP protease is an innovative therapeutic concept and the identification of synthetic lethal interactions may foster the development of novel therapies for glioblastoma (GBM). By integration of a transcriptome, metabolite and U-13C-glucose tracing analyses, we showed that activation of the mitochondrial ClpP protease through constitutively active ClpP (Y118A) or utilization of second-generation imipridone compounds (ONC206 and ONC212) in combination with genetic interference of HDAC1 and HDAC2 as well as with global (Panobinostat) and selective (Romidepsin) HDAC inhibitors caused synergistic reduction of viability in established, neuro-sphere and patient-derived xenograft (PDX) cultures of human GBM, which was mediated by interference with tricarboxylic acid cycle activity and GBM cell respiration. Notably, human astrocytes were significantly less susceptible to the combination treatment of HDAC-inhibitors and ClpP activators. The reduction of GBM viability occurred independent of TP53 status and was accompanied by activation of cell death with apoptotic features along with cleavage of caspases regulated chiefly by Bcl-xL and Mcl-1. Importantly, knockdown of the ClpP protease or ectopic expression of a ClpP D190A mutant almost completely rescued from the inhibition of oxidative energy metabolism as well as from the reduction of cellular viability by ClpP activators and the combination treatment, suggesting critical involvement of this protein. Finally, utilizing GBM PDX models, we demonstrated that the combination treatment of HDAC-inhibitors and imipridones reduced tumor growth and prolonged host survival more potently than single treatments or vehicle in vivo. Collectively, these observations suggest that the efficacy of HDAC inhibitors might be significantly enhanced through ClpP activators in model systems of human GBM.


Author(s):  
Yuka Ikeda ◽  
Kurumi Taniguchi ◽  
Nozomi Nagase ◽  
Ai Tsuji ◽  
Yasuko Kitagishi ◽  
...  

Excessive reactive oxygen species (ROS) may cause oxidative stress which is involved in aging and in the pathogenesis of various human diseases. Whereas unregulated levels of the ROS may be harmful, regulated basal level of ROS are even necessary to support cellular functions as a second messenger for homeostasis under physiological conditions. Therefore, redox medicine could develop as a new therapeutic concept for human health-benefits. Here, we introduce the involvement of ROS on the crossroads of stemness, senescence, and carcinogenesis in a stem cell and cancer cell biology. Amazingly, the anti-proliferative (APRO) family anti-proliferative proteins characterized by immediate early growth responsive genes may also be involved in the crossroads machinery. The biological functions of APRO proteins (APROs) seem to be quite intricate, however, which might be a key modulator of microRNAs (miRNAs). Given the crucial roles of ROS and APROs for pathophysiological functions, upcoming novel therapeutics should include vigilant modulation of the redox state. Next generation of medicine including regenerative medicine and/or cancer therapy will likely comprise strategies for altering the redox environment with the APROs via the modulation of miRNAs as well as with the regulation of ROS of cells in a sustainable manner.


2021 ◽  
Vol 15 ◽  
Author(s):  
Yasuhiro Ogawa ◽  
Seioh Ezaki ◽  
Nobutake Shimojo ◽  
Satoru Kawano

Sepsis is a potentially lethal condition characterized by systemic inflammation and multiple organ failure, and sepsis-associated encephalopathy (SAE) is an independent risk factor for mortality in patients with sepsis. We previously reported that orexin improved survival in an animal model of sepsis by acting in the brain. Peripherally administered orexin entered the brain under the conditions of systemic inflammation because of BBB dysfunction and produced survival-related effects. As a therapeutic concept, we hypothesized that orexin treatment enhances recovery from sepsis by restoring reduced orexin levels in cerebrospinal fluid (CSF). Here, we report that CSF orexin levels were reduced in a 63-year-old woman with sepsis. The patient presented with coma, fever, headache, vomiting, and seizures upon arrival at the emergency room. She had a history of subarachnoid hemorrhage which led to the development of hydrocephalus, and as a consequence, a ventriculoperitoneal shunt (VP shunt) tube had been installed to ameliorate the complication. Physical examinations showed dehydration and abnormality of circulation, arterial blood gas analysis showed insufficient oxygenation, blood tests showed an inflammatory response, liver injury, kidney injury, hyperkalemia, and hyperglycemia, and radio graphical examinations showed mild hydrocephalus and several old microinfarctions. She was diagnosed with sepsis because her Sequential Organ Failure Assessment (SOFA) score was 13 and Enterococcus faecalis was isolated form her blood and CSF. Status epilepticus, hyperglycemia, and sepsis-associated encephalopathy were considered possible causes of coma. Her CSF could be safely sampled because she had a VP shunt, although it is ethically difficult to sample CSF routinely from patients with sepsis. Reduced CSF orexin levels gradually recovered as she recovered from sepsis. Unexpectedly, orexin was detected in the blood, which is unusual in healthy humans. Blood orexin was not detected after recovery from sepsis. This result may imply that orexin leaks into the blood because of BBB dysfunction. To the best of our knowledge, this is the first report investigating orexin levels in the CSF and blood of a patient with sepsis, and the data obtained from this case may provide a new understanding of the pathophysiology of SAE.


2021 ◽  
Author(s):  
Jennifer Veilleux ◽  
Katherine C Hyde ◽  
Kaitlyn Chamberlain ◽  
Danielle Baker ◽  
regina schreiber ◽  
...  

Cognitive reappraisal is an emotion regulation strategy with significant empirical support. However, it is also true that many people have difficultly using cognitive reappraisal—and any cognitive strategy that requires significant mental effort—while experiencing intense emotions. Per the tenants of emotion-regulation flexibility, we provide information on a therapeutic concept we call the “thinking threshold” which helps clients identify the level of emotional distress at which their thinking becomes impaired. When clients are above the “thinking threshold” they are guided to use behavioral and bodily-focused emotion regulation strategies, and to use cognitive reappraisal and problem solving when below the “thinking threshold.” In this paper, we outline the rationale for considering emotion-regulation flexibility with clients, identify why level of emotional intensity is an important context to consider when helping clients identify effective emotion regulation strategies, and review research supporting the notion that effortful cognitive strategies are less effective at high levels of emotional distress. We also describe how we teach clients to use the “thinking threshold” concept and provide a brief case study demonstrating the utility of the concept with a client. Finally, we review ways in which the “thinking threshold” could be tailored and adapted alongside acceptance-based approaches, and we describe future directions for both empirical examination of the “thinking threshold” as well as expansion within clinical practice.


2021 ◽  
pp. 2101798
Author(s):  
Ilona E. Kammerl ◽  
Sophie Hardy ◽  
Claudia Flexeder ◽  
Andrea Urmann ◽  
Julia Peierl ◽  
...  

Immune cells contain a specialised type of proteasome, i.e. the immunoproteasome, which is required for intracellular protein degradation. Immunoproteasomes are key regulators of immune cell differentiation, inflammatory activation and autoimmunity. Immunoproteasome function in peripheral immune cells might be altered by smoking and in COPD thereby affecting immune cell responses.We here analysed the expression and activity of proteasome complexes in peripheral blood mononuclear cells (PBMC) isolated from healthy male young smokers as well as from patients with severe COPD and compared them to matching controls. Proteasome expression was upregulated in COPD patients as assessed by RT-qPCR and mass spectrometry-based proteomics analysis. Proteasome activity was quantified using activity-based probes and native gel analysis. We observed distinct activation of immunoproteasomes in the peripheral blood cells of young male smokers and severely ill COPD patients. Native gel analysis and linear regression modeling confirmed robust activation and elevated assembly of 20S proteasomes, which correlated significantly with reduced lung function parameters in COPD patients. The immunoproteasome was distinctly activated in COPD patients upon inflammatory cytokine stimulation of PBMCs in vitro. Inhibition of the immunoproteasome reduced proinflammatory cytokine expression in COPD-derived blood immune cells.Given the crucial role of chronic inflammatory signalling and the emerging involvement of autoimmune responses in COPD, therapeutic targeting of the immunoproteasome might represent a novel therapeutic concept for COPD.


2021 ◽  
Vol 22 (14) ◽  
pp. 7359
Author(s):  
Chiara De Santis ◽  
Martin Götte

microRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Let-7d is a microRNA of the conserved let-7 family that is dysregulated in female malignancies including breast cancer, ovarian cancer, endometrial cancer, and cervical cancer. Moreover, a dysregulation is observed in endometriosis and pregnancy-associated diseases such as preeclampsia and fetal growth restriction. Let-7d expression is regulated by cytokines and steroids, involving transcriptional regulation by OCT4, MYC and p53, as well as posttranscriptional regulation via LIN28 and ADAR. By downregulating a wide range of relevant mRNA targets, let-7d affects cellular processes that drive disease progression such as cell proliferation, apoptosis (resistance), angiogenesis and immune cell function. In an oncological context, let-7d has a tumor-suppressive function, although some of its functions are context-dependent. Notably, its expression is associated with improved therapeutic responses to chemotherapy in breast and ovarian cancer. Studies in mouse models have furthermore revealed important roles in uterine development and function, with implications for obstetric diseases. Apart from a possible utility as a diagnostic blood-based biomarker, pharmacological modulation of let-7d emerges as a promising therapeutic concept in a variety of female disease conditions.


2021 ◽  
Vol 15 (3) ◽  
pp. 91-97
Author(s):  
A. E. Karateev

One of the primary tasks for a doctor when meeting a patient for the first time is to gain his affection and trust. It is not always possible during the first visit to make an accurate diagnosis and prescribe pathogenetic therapy, because this often requires a deep additional examination. However, it is imperative to demonstrate knowledge and confidence, provide psychological support and alleviate the suffering of the patient, especially in the case of rheumatic disease accompanied by severe pain. Such a patient should be immediately prescribed adequate analgesic therapy. The main tool for controlling pain in diseases of the joints and spine are non-steroidal anti-inflammatory drugs. Moreover, their prescription should be deliberate and balanced, taking into account the clinical picture and comorbid pathology.The article presents two clinical observations, illustrating the formation of a diagnostic and therapeutic concept at an outpatient appointment.


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