Bone Metastases: Molecular Mechanisms and Novel Therapeutic Interventions

Early adversity (EA) impairs myelin development in a manner that persists later in life across diverse mammalian species including humans, non-human primates, and rodents. These observations, coupled with the highly conserved nature of myelin development suggest that animal models can provide important insights into the molecular mechanisms by which EA impairs myelin development later in life and the impact of these changes on network connectivity, cognition, and behavior. However, this area of translational research has received relatively little attention and no comprehensive review is currently available to address these issues. This is particularly important given some recent mechanistic studies in rodents and the availability of new agents to increase myelination. The goals of this review are to highlight the need for additional pre-clinical work in this area and to provide specific examples that demonstrate the potential of this work to generate novel therapeutic interventions that are highly needed.

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Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

Clinical Science ◽

10.1042/cs20191213 ◽

2020 ◽

Vol 134 (17) ◽

pp. 2243-2262

Author(s):

Danlin Liu ◽

Gavin Richardson ◽

Fehmi M. Benli ◽

Catherine Park ◽

João V. de Souza ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Cardiovascular System ◽

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Molecular Targets ◽

Therapeutic Interventions ◽

Low Grade ◽

Cardiovascular Research ◽

Inflammatory Processes ◽

Ach Receptors

Abstract In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

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Wnt/beta-catenin and PI3K/Akt/mTOR Signaling Pathways in Glioblastoma: Two Main Targets for Drug Design: A Review

Current Pharmaceutical Design ◽

10.2174/1381612826666200131100630 ◽

2020 ◽

Vol 26 (15) ◽

pp. 1729-1741 ◽

Cited By ~ 4

Author(s):

Seyed H. Shahcheraghi ◽

Venant Tchokonte-Nana ◽

Marzieh Lotfi ◽

Malihe Lotfi ◽

Ahmad Ghorbani ◽

...

Keyword(s):

Signaling Pathways ◽

Molecular Mechanisms ◽

Cellular Proliferation ◽

Chemotherapy Resistance ◽

Wnt Signaling Pathway ◽

Therapeutic Interventions ◽

Beta Catenin ◽

Clinical Prognosis ◽

Invasion And Migration ◽

And Migration

: Glioblastoma (GBM) is the most common and malignant astrocytic glioma, accounting for about 90% of all brain tumors with poor prognosis. Despite recent advances in understanding molecular mechanisms of oncogenesis and the improved neuroimaging technologies, surgery, and adjuvant treatments, the clinical prognosis of patients with GBM remains persistently unfavorable. The signaling pathways and the regulation of growth factors of glioblastoma cells are very abnormal. The various signaling pathways have been suggested to be involved in cellular proliferation, invasion, and glioma metastasis. The Wnt signaling pathway with its pleiotropic functions in neurogenesis and stem cell proliferation is implicated in various human cancers, including glioma. In addition, the PI3K/Akt/mTOR pathway is closely related to growth, metabolism, survival, angiogenesis, autophagy, and chemotherapy resistance of GBM. Understanding the mechanisms of GBM’s invasion, represented by invasion and migration, is an important tool in designing effective therapeutic interventions. This review will investigate two main signaling pathways in GBM: PI3K/Akt/mTOR and Wnt/beta-catenin signaling pathways.

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The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases

Biology ◽

10.3390/biology9120485 ◽

2020 ◽

Vol 9 (12) ◽

pp. 485

Author(s):

Lorenzo Cuollo ◽

Fabrizio Antonangeli ◽

Angela Santoni ◽

Alessandra Soriani

Keyword(s):

Cancer Therapy ◽

Molecular Mechanisms ◽

Therapeutic Strategies ◽

Senescent Cell ◽

Pharmacological Intervention ◽

Tissue Microenvironment ◽

Age Related ◽

Secretory Phenotype ◽

Novel Therapeutic Strategies ◽

Novel Therapeutic

Cellular senescence represents a robust tumor-protecting mechanism that halts the proliferation of stressed or premalignant cells. However, this state of stable proliferative arrest is accompanied by the Senescence-Associated Secretory Phenotype (SASP), which entails the copious secretion of proinflammatory signals in the tissue microenvironment and contributes to age-related conditions, including, paradoxically, cancer. Novel therapeutic strategies aim at eliminating senescent cells with the use of senolytics or abolishing the SASP without killing the senescent cell with the use of the so-called “senomorphics”. In addition, recent works demonstrate the possibility of modifying the composition of the secretome by genetic or pharmacological intervention. The purpose is not to renounce the potent immunostimulatory nature of SASP, but rather learning to modulate it for combating cancer and other age-related diseases. This review describes the main molecular mechanisms regulating the SASP and reports the evidence of the feasibility of abrogating or modulating the SASP, discussing the possible implications of both strategies.

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Pathomechanisms in the Kidneys in Selected Protozoan Parasitic Infections

International Journal of Molecular Sciences ◽

10.3390/ijms22084209 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4209

Author(s):

Karolina Kot ◽

Natalia Łanocha-Arendarczyk ◽

Michał Ptak ◽

Aleksandra Łanocha ◽

Elżbieta Kalisińska ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Molecular Mechanisms ◽

Kidney Injury ◽

Therapeutic Interventions ◽

Parasitic Infections ◽

Injury Mechanisms ◽

Kidney Involvement ◽

Leishmania Spp ◽

Apoptosis Process ◽

Insight Into

Leishmaniasis, malaria, toxoplasmosis, and acanthamoebiasis are protozoan parasitic infections. They remain important contributors to the development of kidney disease, which is associated with increased patients’ morbidity and mortality. Kidney injury mechanisms are not fully understood in protozoan parasitic diseases, bringing major difficulties to specific therapeutic interventions. The aim of this review is to present the biochemical and molecular mechanisms in kidneys infected with Leishmania spp., Plasmodium spp., Toxoplasma gondii, and Acanthamoeba spp. We present available mechanisms of an immune response, oxidative stress, apoptosis process, hypoxia, biomarkers of renal injury in the serum or urine, and the histopathological changes of kidneys infected with the selected parasites. Pathomechanisms of Leishmania spp. and Plasmodium spp. infections have been deeply investigated, while Toxoplasma gondii and Acanthamoeba spp. infections in the kidneys are not well known yet. Deeper knowledge of kidney involvement in leishmaniasis and malaria by presenting their mechanisms provides insight into how to create novel and effective treatments. Additionally, the presented work shows gaps in the pathophysiology of renal toxoplasmosis and acanthamoebiasis, which need further research.

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Therapeutic Application of Monoclonal Antibodies in Pancreatic Cancer: Advances, Challenges and Future Opportunities

Cancers ◽

10.3390/cancers13081781 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1781

Author(s):

Gustavo A. Arias-Pinilla ◽

Helmout Modjtahedi

Keyword(s):

Pancreatic Cancer ◽

Monoclonal Antibodies ◽

Antibody Therapy ◽

Therapeutic Targets ◽

Poor Response ◽

Therapeutic Agents ◽

Therapeutic Interventions ◽

Western World ◽

Wide Range ◽

Novel Therapeutic

Pancreatic cancer remains as one of the most aggressive cancer types. In the absence of reliable biomarkers for its early detection and more effective therapeutic interventions, pancreatic cancer is projected to become the second leading cause of cancer death in the Western world in the next decade. Therefore, it is essential to discover novel therapeutic targets and to develop more effective and pancreatic cancer-specific therapeutic agents. To date, 45 monoclonal antibodies (mAbs) have been approved for the treatment of patients with a wide range of cancers; however, none has yet been approved for pancreatic cancer. In this comprehensive review, we discuss the FDA approved anticancer mAb-based drugs, the results of preclinical studies and clinical trials with mAbs in pancreatic cancer and the factors contributing to the poor response to antibody therapy (e.g. tumour heterogeneity, desmoplastic stroma). MAb technology is an excellent tool for studying the complex biology of pancreatic cancer, to discover novel therapeutic targets and to develop various forms of antibody-based therapeutic agents and companion diagnostic tests for the selection of patients who are more likely to benefit from such therapy. These should result in the approval and routine use of antibody-based agents for the treatment of pancreatic cancer patients in the future.

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Novel therapeutic interventions towards improved management of septic arthritis

BMC Musculoskeletal Disorders ◽

10.1186/s12891-021-04383-6 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Jian Wang ◽

Liucai Wang

Keyword(s):

Antibiotic Therapy ◽

Septic Arthritis ◽

Clinical Success ◽

Treatment Protocol ◽

Current Treatment ◽

Therapeutic Interventions ◽

Medical Emergency ◽

Success Rates ◽

Joint Infections ◽

Novel Therapeutic

AbstractSeptic arthritis (SA) represents a medical emergency that needs immediate diagnosis and urgent treatment. Despite aggressive treatment and rapid diagnosis of the causative agent, the mortality and lifelong disability, associated with septic arthritis remain high as close to 11%. Moreover, with the rise in drug resistance, the rates of failure of conventional antibiotic therapy have also increased. Among the etiological agents frequently isolated from cases of septic arthritis, Staphylococcus aureus emerges as a dominating pathogen, and to worsen, the rise in methicillin-resistant S. aureus (MRSA) isolates in bone and joint infections is worrisome. MRSA associated cases of septic arthritis exhibit higher mortality, longer hospital stay, and higher treatment failure with poorer clinical outcomes as compared to cases caused by the sensitive strain i.e methicillin-sensitive S. aureus (MSSA).In addition to this, equal or even greater damage is imposed by the exacerbated immune response mounted by the patient’s body in a futile attempt to eradicate the bacteria. The antibiotic therapy may not be sufficient enough to control the progression of damage to the joint involved thus, adding to higher mortality and disability rates despite the prompt and timely start of treatment. This situation implies that efforts and focus towards studying/understanding new strategies for improved management of sepsis arthritis is prudent and worth exploring.The review article aims to give a complete insight into the new therapeutic approaches studied by workers lately in this field. To the best of our knowledge studies highlighting the novel therapeutic strategies against septic arthritis are limited in the literature, although articles on pathogenic mechanism and choice of antibiotics for therapy, current treatment algorithms followed have been discussed by workers in the past. The present study presents and discusses the new alternative approaches, their mechanism of action, proof of concept, and work done so far towards their clinical success. This will surely help to enlighten the researchers with comprehensive knowledge of the new interventions that can be used as an adjunct therapy along with conventional treatment protocol for improved success rates.

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Molecular Alterations in Sporadic and SOD1-ALS Immortalized Lymphocytes: Towards a Personalized Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms22063007 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3007

Author(s):

Isabel Lastres-Becker ◽

Gracia Porras ◽

Marina Arribas-Blázquez ◽

Inés Maestro ◽

Daniel Borrego-Hernández ◽

...

Keyword(s):

Motor Neurons ◽

Molecular Mechanisms ◽

Cell Types ◽

Therapeutic Interventions ◽

Autophagic Flux ◽

Metabolic Disturbances ◽

Molecular Alterations ◽

Healthy Donors ◽

Inflammatory Profile ◽

Als Patients

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily transmitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase 1 (SOD1). A central question in ALS field is whether causative mutations display selective alterations not found in sALS patients, or they converge on shared molecular pathways. To identify specific and common mechanisms for designing appropriate therapeutic interventions, we focused on the SOD1-mutated (SOD1-ALS) versus sALS patients. Since ALS pathology involves different cell types other than MNs, we generated lymphoblastoid cell lines (LCLs) from sALS and SOD1-ALS patients and healthy donors and investigated whether they show changes in oxidative stress, mitochondrial dysfunction, metabolic disturbances, the antioxidant NRF2 pathway, inflammatory profile, and autophagic flux. Both oxidative phosphorylation and glycolysis appear to be upregulated in lymphoblasts from sALS and SOD1-ALS. Our results indicate significant differences in NRF2/ARE pathway between sALS and SOD1-ALS lymphoblasts. Furthermore, levels of inflammatory cytokines and autophagic flux discriminate between sALS and SOD1-ALS lymphoblasts. Overall, different molecular mechanisms are involved in sALS and SOD1-ALS patients and thus, personalized medicine should be developed for each case.

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Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy

Journal of the American Society of Nephrology ◽

10.1681/asn.2019080827 ◽

2020 ◽

Vol 31 (4) ◽

pp. 799-816 ◽

Cited By ~ 4

Author(s):

Barbara Mara Klinkhammer ◽

Sonja Djudjaj ◽

Uta Kunter ◽

Runolfur Palsson ◽

Vidar Orn Edvardsson ◽

...

Keyword(s):

Clinical Relevance ◽

Molecular Mechanisms ◽

Granulomatous Inflammation ◽

Kidney Injury ◽

Rare Condition ◽

Therapeutic Interventions ◽

Renal Tubules ◽

Rodent Models ◽

Adenine Phosphoribosyltransferase ◽

Reparative Process

BackgroundHereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown.MethodsUsing animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage. We also used knockout mice to investigate the role of TNF receptors 1 and 2 (TNFR1 and TNFR2), CD44, or alpha2-HS glycoprotein (AHSG), all of which are involved in the pathogenesis of other types of crystal-induced nephropathies.ResultsAdenine-enriched diet in mice induced 2,8-DHA nephropathy, leading to progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis. Kidney injury depended on crystal size. The smallest crystals were endocytosed by tubular epithelial cells. Crystals of variable size were excreted in urine. Large crystals obstructed whole tubules. Medium-sized crystals induced a particular reparative process that we term extratubulation. In this process, tubular cells, in coordination with macrophages, overgrew and translocated crystals into the interstitium, restoring the tubular luminal patency; this was followed by degradation of interstitial crystals by granulomatous inflammation. Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury. In mice, deletion of Tnfr1 significantly reduced tubular CD44 and annexin two expression, as well as inflammation, thereby ameliorating the disease course. In contrast, genetic deletion of Tnfr2, Cd44, or Ahsg had no effect on the manifestations of 2,8-DHA nephropathy.ConclusionsRodent models of the cellular and molecular mechanisms of 2,8-DHA nephropathy and crystal clearance have clinical relevance and offer insight into potential future targets for therapeutic interventions.

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Placental Vacuolar ATPase Function Is a Key Link between Multiple Causes of Preeclampsia

ISRN Obstetrics and Gynecology ◽

10.1155/2013/504173 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Dongxin Zhang ◽

Duyun Ye ◽

Hongxiang Chen

Keyword(s):

Molecular Mechanisms ◽

Renin Angiotensin System ◽

Vacuolar Atpase ◽

Therapeutic Interventions ◽

The Novel ◽

Lipoxin A4 ◽

Angiotensin System ◽

Dihydroxyvitamin D ◽

System 1 ◽

Multiple Causes

Preeclampsia, a relatively common pregnancy disorder, is one of the major causes of maternal and fetal morbidity and mortality. Despite numerous research, the etiology of this syndrome remains not well understood as the pathogenesis of preeclampsia is complex, involving interaction between genetic, immunologic, and environmental factors. Preeclampsia, originating in placenta abnormalities, is induced by the circulating factors derived from the abnormal placenta. Recent work has identified various molecular mechanisms related to placenta development, including renin-angiotensin system, 1, 25-dihydroxyvitamin D, and lipoxin A4. Interestingly, advances suggest that vacuolar ATPase, a key molecule in placentation, is closely associated with them. Therefore, this intriguing molecule may represent an important link between various causes of preeclampsia. Here, we review that vacuolar ATPase works as a key link between multiple causes of preeclampsia and discuss the potential molecular mechanisms. The novel findings outlined in this review may provide promising explanations for the causation of preeclampsia and a rationale for future therapeutic interventions for this condition.

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