scholarly journals Mitochondria: Potential Targets for Osteoarthritis

2020 ◽  
Vol 7 ◽  
Author(s):  
Xingjia Mao ◽  
Panfeng Fu ◽  
Linlin Wang ◽  
Chuan Xiang
Keyword(s):  
Mitochondrial Function ◽  
Treatment Strategies ◽  
Cartilage Regeneration ◽  
Cartilage Degeneration ◽  
Research Field ◽  
Mitochondrial Dysfunctions ◽  
Joint Disorder ◽  
Global Status ◽  
Novel Treatment Strategies

Osteoarthritis (OA) is a common and disabling joint disorder that is mainly characterized by cartilage degeneration and narrow joint spaces. The role of mitochondrial dysfunction in promoting the development of OA has gained much attention. Targeting endogenous molecules to improve mitochondrial function is a potential treatment for OA. Moreover, research on exogenous drugs to improve mitochondrial function in OA based on endogenous molecular targets has been accomplished. In addition, stem cells and exosomes have been deeply researched in the context of cartilage regeneration, and these factors both reverse mitochondrial dysfunctions. Thus, we hypothesize that biomedical approaches will be applied to the treatment of OA. Furthermore, we have summarized the global status of mitochondria and osteoarthritis research in the past two decades, which will contribute to the research field and the development of novel treatment strategies for OA.

scholarly journals Translational Research Studies Unraveling the Origins of Psoriatic Arthritis: Moving Beyond Skin and Joints

2021 ◽  
Vol 8 ◽  
Author(s):  
Janne W. Bolt ◽  
Chaja M. J. van Ansenwoude ◽  
Ihsan Hammoura ◽  
Marleen G. van de Sande ◽  
Lisa G. M. van Baarsen
Keyword(s):  
Psoriatic Arthritis ◽  
Translational Research ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Treatment Strategies ◽  
Continuous Treatment ◽  
Adaptive Immune Cells ◽  
Novel Treatment Strategies

Patients with psoriatic arthritis (PsA) are suffering from a decreased quality of life despite currently available treatments. In the latest years, novel therapies targeting the IL-17/IL-23 and TNF pathways improved clinical outcome. Despite this, remission of disease is not achieved in a considerable group of patients, continuous treatment is very often required to reach clinical remission, and prevention of PsA in patients with psoriasis (PsO) is currently impossible. A better understanding of PsA pathogenesis is required to develop novel treatment strategies that target inflammation and destruction more effectively and at an early stage of the disease, or even before clinically manifest disease. The skin is considered as one of the sites of onset of immune activation, triggering the inflammatory cascade in PsA. PsO develops into PsA in 30% of the PsO patients. Influenced by environmental and genetic factors, the inflammatory process in the skin, entheses, and/or gut may evolve into synovial tissue inflammation, characterized by influx of immune cells. The exact role of the innate and adaptive immune cells in disease pathogenesis is not completely known. The involvement of activated IL-17A+ T cells could implicate early immunomodulatory events generated in lymphoid organs thereby shaping the pathogenic inflammatory response leading to disease. In this perspective article, we provide the reader with an overview of the current literature regarding the immunological changes observed during the earliest stages of PsA. Moreover, we will postulate future areas of translational research aimed at increasing our knowledge on the molecular mechanisms driving disease development, which will aid the identification of novel potential therapeutic targets to limit the progression of PsA.

scholarly journals Protein kinase J regulates Rv0642c expression and sensitivity to rifampicin of mycobacteria

2021 ◽  
Author(s):  
Kishore Kumar Srivastava ◽  
Diwakar Kumar Singh ◽  
Sameer Tiwari ◽  
Kumari Kripalata
Keyword(s):  
Rational Design ◽  
Treatment Strategies ◽  
Host Immune System ◽  
Intracellular Growth ◽  
Methyltransferase Activity ◽  
Knock Out ◽  
Long Duration ◽  
Highly Sensitive ◽  
Novel Treatment Strategies

Mycobacterium tuberculosis (M.tb) persists for long-duration inside the human host in both active and latent form by modulating the immune response. The mechanisms employed by M.tb to survive inside the host and evade the host immune system need to be explored in greater depth for the rational design of novel treatment strategies. The phosphorylation and methylation of biomolecules need to be addressed in mycobacteria because it has an important role in infection establishment and persistence. In the present study, we elaborate on the role of PknJ in the slow growth of BCG and its association with mmaA4 protein during extracellular and intracellular growth. The pknJ knock-out (KO) BCG has been used to decode the functional significance in mycobacteria. The mmaA4 expression and methyltransferase activity is decreased in knocked-out BCG strain (pknJ-/-) during extracellular growth, while mmaA4 expression and methyltransferase activity is increased during intracellular growth of mycobacteria. The knocked-out BCG strain is highly sensitive to the rifampicin antibiotics during extracellular growth in compared to control. A significant association of pknJ and mmaA4 was found in our studies during the growth and intracellular persistence of mycobacteria.

Mucosal Dendritic Cell Subsets Control HIV-1’s Viral Fitness

2020 ◽  
Vol 7 (1) ◽  
pp. 385-402
Author(s):  
Bernadien M. Nijmeijer ◽  
Catharina J.M. Langedijk ◽  
Teunis B.H. Geijtenbeek
Keyword(s):  
Dendritic Cell ◽  
Sexual Transmission ◽  
Treatment Strategies ◽  
Viral Fitness ◽  
Immunodeficiency Virus ◽  
Novel Treatment Strategies ◽  
Hiv 1 ◽  
Selection Of

Dendritic cell (DC) subsets are abundantly present in genital and intestinal mucosal tissue and are among the first innate immune cells that encounter human immunodeficiency virus type 1 (HIV-1) after sexual contact. Although DCs have specific characteristics that greatly enhance HIV-1 transmission, it is becoming evident that most DC subsets also have virus restriction mechanisms that exert selective pressure on the viruses during sexual transmission. In this review we discuss the current concepts of the immediate events following viral exposure at genital mucosal sites that lead to selection of specific HIV-1 variants called transmitted founder (TF) viruses. We highlight the importance of the TF HIV-1 phenotype and the role of different DC subsets in establishing infection. Understanding the biology of HIV-1 transmission will contribute to the design of novel treatment strategies preventing HIV-1 dissemination.

scholarly journals Emerging Role of Extracellular Vesicles and Cellular Communication in Metastasis

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3429
Author(s):  
Aisling Forder ◽  
Chi-Yun Hsing ◽  
Jessica Trejo Vazquez ◽  
Cathie Garnis
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Treatment Strategies ◽  
Metastatic Niche ◽  
Novel Treatment ◽  
Membrane Bound ◽  
Novel Treatment Strategies

Communication between cancer cells and the surrounding stromal cells of the tumor microenvironment (TME) plays a key role in promoting metastasis, which is the major cause of cancer death. Small membrane-bound particles called extracellular vesicles (EVs) are released from both cancer and stromal cells and have a key role in mediating this communication through transport of cargo such as various RNA species (mRNA, miRNA, lncRNA), proteins, and lipids. Tumor-secreted EVs have been observed to induce a pro-tumorigenic phenotype in non-malignant cells of the stroma, including fibroblasts, endothelial cells, and local immune cells. These cancer-associated cells then drive metastasis by mechanisms such as increasing the invasiveness of cancer cells, facilitating angiogenesis, and promoting the formation of the pre-metastatic niche. This review will cover the role of EV-mediated signaling in the TME during metastasis and highlight the therapeutic potential of targeting these pathways to develop biomarkers and novel treatment strategies.

scholarly journals Challenging a Misnomer? The Role of Inflammatory Pathways in Inflammatory Breast Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Riley J. Morrow ◽  
Nima Etemadi ◽  
Belinda Yeo ◽  
Matthias Ernst
Keyword(s):  
Breast Cancer ◽  
Inflammatory Breast Cancer ◽  
Locally Advanced ◽  
Treatment Strategies ◽  
Molecular Evidence ◽  
Her2 Positive ◽  
Extrinsic Factors ◽  
Cancer Subtypes ◽  
Novel Treatment Strategies

Inflammatory breast cancer is a rare, yet highly aggressive form of breast cancer, which accounts for less than 5% of all locally advanced presentations. The clinical presentation of inflammatory breast cancer often differs significantly from that of noninflammatory breast cancer; however, immunohistochemistry reveals few, if any, distinguishing features. The more aggressive triple-negative and HER2-positive breast cancer subtypes are overrepresented in inflammatory breast cancer compared with noninflammatory breast cancer, with a poorer prognosis in response to conventional therapies. Despite its name, there remains some controversy regarding the role of inflammation in inflammatory breast cancer. This review summarises the current molecular evidence suggesting that inflammatory signaling pathways are upregulated in this disease, including NF-κB activation and excessive IL-6 production among others, which may provide an avenue for novel therapeutics. The role of the tumor microenvironment, through tumor-associated macrophages, infiltrating lymphocytes, and cancer stem cells is also discussed, suggesting that these tumor extrinsic factors may help account for the differences in behavior between inflammatory breast cancer and noninflammatory breast cancer. While there are various novel treatment strategies already underway in clinical trials, the need for further development of preclinical models of this rare but aggressive disease is paramount.

FMRP Modulates Activity-Dependent Spine Plasticity by Binding Cofilin1 mRNA and Regulating Localization and Local Translation

2019 ◽  
Vol 29 (12) ◽  
pp. 5204-5216 ◽  
Author(s):  
Jonas Feuge ◽  
Franziska Scharkowski ◽  
Kristin Michaelsen-Preusse ◽  
Martin Korte
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Treatment Strategies ◽  
Actin Dynamics ◽  
Actin Remodeling ◽  
Dendritic Spine Morphology ◽  
Novel Treatment Strategies ◽  
Activity Dependent ◽  
Spine Plasticity

Abstract Multiple variants of intellectual disability, e.g., the Fragile X Syndrome are associated with alterations in dendritic spine morphology, thereby pointing to dysregulated actin dynamics during development and processes of synaptic plasticity. Surprisingly, although the necessity of spine actin remodeling was demonstrated repeatedly, the importance and precise role of actin regulators is often undervalued. Here, we provide evidence that structural and functional plasticity are severely impaired after NMDAR-dependent LTP in the hippocampus of Fmr1 KO mice. We can link these defects to an aberrant activity-dependent regulation of Cofilin 1 (cof1) as activity-dependent modulations of local cof1 mRNA availability, local cof1 translation as well as total cof1 expression are impaired in the absence of FMRP. Finally, we can rescue activity-dependent structural plasticity in KO neurons by mimicking the regulation of cof1 observed in WT cells, thereby illustrating the potential of actin modulators to provide novel treatment strategies for the Fragile X Syndrome.

scholarly journals Role of subnetworks mediated by $$\hbox {TNF}\alpha$$, IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rakesh Pandey ◽  
Yusur Al-Nuaimi ◽  
Rajiv Kumar Mishra ◽  
Sarah K. Spurgeon ◽  
Marc Goodfellow
Keyword(s):  
Complex Network ◽  
Immune Cells ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Tnf Alpha ◽  
Cell Network ◽  
Novel Treatment ◽  
Future Drug ◽  
Novel Treatment Strategies

AbstractPsoriasis is a chronic inflammatory skin disease clinically characterized by the appearance of red colored, well-demarcated plaques with thickened skin and with silvery scales. Recent studies have established the involvement of a complex signalling network of interactions between cytokines, immune cells and skin cells called keratinocytes. Keratinocytes form the cells of the outermost layer of the skin (epidermis). Visible plaques in psoriasis are developed due to the fast proliferation and unusual differentiation of keratinocyte cells. Despite that, the exact mechanism of the appearance of these plaques in the cytokine-immune cell network is not clear. A mathematical model embodying interactions between key immune cells believed to be involved in psoriasis, keratinocytes and relevant cytokines has been developed. The complex network formed of these interactions poses several challenges. Here, we choose to study subnetworks of this complex network and initially focus on interactions involving $$\hbox {TNF}_{\alpha }$$ TNF α , IL-23/IL-17, and IL-15. These are chosen based on known evidence of their therapeutic efficacy. In addition, we explore the role of IL-15 in the pathogenesis of psoriasis and its potential as a future drug target for a novel treatment option. We perform steady state analyses for these subnetworks and demonstrate that the interactions between cells, driven by cytokines could cause the emergence of a psoriasis state (hyper-proliferation of keratinocytes) when levels of $$\hbox {TNF}_{\alpha }$$ TNF α , IL-23/IL-17 or IL-15 are increased. The model results explain and support the clinical potentiality of anti-cytokine treatments. Interestingly, our results suggest different dynamic scenarios underpin the pathogenesis of psoriasis, depending upon the dominant cytokines of subnetworks. We observed that the increase in the level of IL-23/IL-17 and IL-15 could lead to psoriasis via a bistable route, whereas an increase in the level of $$\hbox {TNF}_{\alpha }$$ TNF α would lead to a monotonic and gradual disease progression. Further, we demonstrate how this insight, bistability, could be exploited to improve the current therapies and develop novel treatment strategies for psoriasis.

scholarly journals The Role of Fatty Acid Metabolites in Vaginal Health and Disease: Application to Candidiasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Silke Baldewijns ◽  
Mart Sillen ◽  
Ilse Palmans ◽  
Paul Vandecruys ◽  
Patrick Van Dijck ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Effective Means ◽  
Significant Proportion ◽  
Treatment Strategies ◽  
Short Chain Fatty Acids ◽  
Acid Metabolites ◽  
Vaginal Health ◽  
Novel Treatment Strategies ◽  
Fatty Acid Metabolites

Although the vast majority of women encounters at least one vaginal infection during their life, the amount of microbiome-related research performed in this area lags behind compared to alternative niches such as the intestinal tract. As a result, effective means of diagnosis and treatment, especially of recurrent infections, are limited. The role of the metabolome in vaginal health is largely elusive. It has been shown that lactate produced by the numerous lactobacilli present promotes health by limiting the chance of infection. Short chain fatty acids (SCFA) have been mainly linked to dysbiosis, although the causality of this relationship is still under debate. In this review, we aim to bring together information on the role of the vaginal metabolome and microbiome in infections caused by Candida. Vulvovaginal candidiasis affects near to 70% of all women at least once in their life with a significant proportion of women suffering from the recurrent variant. We assess the role of fatty acid metabolites, mainly SCFA and lactate, in onset of infection and virulence of the fungal pathogen. In addition, we pinpoint where lack of research limits our understanding of the molecular processes involved and restricts the possibility of developing novel treatment strategies.

PD-L1 ≥ 50% lung cancer refractory to PD-1 inhibition: the role of salvage chemo-immunotherapy combination

Immunotherapy ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 363-369
Author(s):  
Francesco Gelsomino ◽  
Francesco Facchinetti ◽  
Monia Sisi ◽  
Teresa Zielli ◽  
Marcello Tiseo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Performance Status ◽  
Treatment Strategies ◽  
Tumor Burden ◽  
First Line ◽  
Radiological Response ◽  
Novel Treatment Strategies ◽  
Line Setting ◽  
Nsclc Patients

Novel treatment strategies incorporating PD-1/PD-L1 inhibitors in the first-line setting of advanced non-small-cell lung cancer (NSCLC) provided relevant improvements in survival outcomes. Among NSCLC patients with PD-L1 tumor proportion score ≥50%, identifying the ones to be addressed to pembrolizumab monotherapy or chemo-immunotherapy combinations is a matter of debate, taking into account the risks of overtreatment and toxicity. Here we report the clinical stories of four NSCLC patients with PD-L1 tumor proportion score ≥50% and good performance status, sharing high tumor burden including serosal involvement. After having rapidly progressed on first-line PD-1/PD-L1 inhibitors, they achieved major clinical and radiological response to pembrolizumab-chemotherapy combination. These cases prove the feasibility and effectiveness of salvage chemo-immunotherapy in pembrolizumab-refractory NSCLC patients.

scholarly journals A Breath of Fresh Air in the Fog of Antimicrobial Resistance: Inhaled Polymyxins for Gram-Negative Pneumonia

Antibiotics ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 27 ◽  
Author(s):  
Mark Biagi ◽  
David Butler ◽  
Xing Tan ◽  
Samah Qasmieh ◽  
Eric Wenzler
Keyword(s):  
Potential Role ◽  
Treatment Strategies ◽  
Comprehensive Overview ◽  
Gram Negative ◽  
Novel Treatment ◽  
Pharmacodynamic Profile ◽  
Inhaled Antibiotics ◽  
Novel Treatment Strategies ◽  
Significant Attention

Despite advancements in therapy, pneumonia remains the leading cause of death due to infectious diseases. Novel treatment strategies are desperately needed to optimize the antimicrobial therapy of patients suffering from this disease. One such strategy that has recently garnered significant attention is the use of inhaled antibiotics to rapidly achieve therapeutic concentrations directly at the site of infection. In particular, there is significant interest in the role of inhaled polymyxins for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia, due to their retained activity against multi-drug resistant Gram-negative pathogens, including Acinetobacter baumannii and Pseudomonas aeruginosa. This review will provide a comprehensive overview of the pharmacokinetic/pharmacodynamic profile, clinical outcomes, safety, and potential role of inhaled polymyxins in clinical practice.

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