Parkinsonism-hyperpyrexia, a rare consequence of deep brain stimulator malfunction in advanced Parkinson's disease.

Parkinsonism-hyperpyrexia syndrome (PHS) is a rare neurological emergency that shares clinical features with neuroleptic malignant syndrome. It is usually due to sudden deprivation of dopaminergic treatment, although there are cases related to failure of the deep brain stimulation system.

The Emerging Role of Senotherapy in Cancer: A Comprehensive Review.

Senotherapy, a promising therapeutic strategy, has drawn a lot attention recently due to its potential for combating cancer. Senotherapy refers to the targeting of senescent cells to restore tissue homeostasis and mitigate the deleterious effects associated with senescence. Senolytic drugs represent a promising avenue in cancer treatment, with the potential to target and modulate senescent cells to improve patient outcomes. The review highlights the intricate interplay between the senescence-associated secretory phenotype (SASP) and the tumor microenvironment, emphasizing the role of senescent cells in promoting chronic inflammation, immune evasion, and tumor-cell proliferation. It then explores the potential of senotherapy as a novel strategy for cancer therapy. This review addresses the emerging evidence on the combination of senotherapy with conventional cancer treatments, such as chemotherapy and immunotherapy.

Natural Compounds as Integrative Therapy for Liver Protection against Inflammatory and Carcinogenic Mechanisms: From Induction to Molecular Biology Advancement.

The liver is exposed to several harmful substances that bear the potential to cause excessive liver damage ranging from hepatitis and non-alcoholic fatty liver disease to extreme cases of liver cirrhosis and hepatocellular carcinoma. Liver ailments have been effectively treated from very old times with Chinese medicinal herbal formulations and later also applied by controlled trials in Japan. However, these traditional practices have been hardly well characterized in the past till in the last decades when more qualified studies have been carried out. Modern advances have given rise to specific molecular targets which are specifically good candidates for affecting the intricate mechanisms that play a role at the molecular level. These therapeutic regimens that mainly affect the progression of the disease by inhibiting the gene expression levels or by blocking essential molecular pathways or releasing cytokines may prove to play a vital role in minimizing the tissue damage. This review, therefore, tries to throw light upon the variation in the therapies for the treatment of benign and malignant liver disease from ancient times to the current date. Nonetheless, clinical research exploring the effectiveness of herbal medicines in the treatment of benign chronic liver diseases as well as prevention and treatment of HCC is still warranted.

The Neurokinin-1 Receptor Is Essential for the Viability of Human Glioma Cells: A Possible Target for Treating Glioblastoma.

Background: Glioblastoma or glioma is the most common malignant brain tumor. Patients have a prognosis of approximately 15 months, despite the current aggressive treatment. Neurokinin-1 receptor (NK-1R) occurs naturally in human glioma, and it is necessary for the tumor development. Objective: The purpose of the study was to increase the knowledge about the involvement of the substance P (SP)/NK-1R system in human glioma. Methods: Cellular localization of NK-1R and SP was studied in GAMG and U-87 MG glioma cell lines by immunofluorescence. The contribution of both SP and NK-1R to the viability of these cells was also assessed after applying the tachykinin 1 receptor (TAC1R) or the tachykinin 1 (TAC1) small interfering RNA gene silencing method, respectively. Results: Both SP and the NK-1R (full-length and truncated isoforms) were localized in the nucleus and cytoplasm of GAMG and U-87 MG glioma cells. The presence of full-length NK-1R isoform was mainly observed in the nucleus, while the level of truncated isoform was higher in the cytoplasm. Cell proliferation was decreased when glioma cells were transfected with TAC1R siRNA, but not with TAC1. U-87 MG cells were more sensitive to the effect of the TAC1R inhibition than GAMG cells. The decrease in the number of glioma cells after silencing of the TAC1R siRNA gene was due to apoptotic and necrotic mechanisms. In human primary fibroblast cultured cells, TAC1R silencing by siRNA did not produce any change in cell viability. Conclusions: Our results show for the first time that the expression of the TAC1R gene (NK-1R) is essential for the viability of GAMG and U-87 MG glioma cells. On the contrary, the TAC1R gene is not essential for the viability of normal cells, confirming that NK-1R could be a promising and specific therapeutic target for the treatment of glioma.

Effects on goal directed behavior and habit in two animal models of Parkinson's disease.

Instrumental conditioning involves two different processes: Goal-directed behavior, characterized by its dependence on the causal relationship between action and outcome and the sensitivity of actions to changes in the value of the outcome; and habits, characterized for its persistence and insensitivity to changes after conditioning. It is known that the dopaminergic system is involved in both kind of learning. The present experiments analyzed two animal models of Parkinson's disease. The 6-OHDA model causes selective damage of the catecholaminergic neurons, specifically affecting the dopaminergic neurons in nigro-striatal system. This model simulates degenerative process symptomatology of Parkinson's disease. On the other hand, the LPS model generates an inflammation process in the infusion area. This model simulates the early symptoms of this disorder, including neuroinflammation and microglia activation. In order to validate both parkinsonian models, we studied if 6-OHDA and LPS models cause the same behavioral effects. The results showed that the 6-OHDA model interfered with the process involved in habit formation. In contrast, animals treated with LPS showed a goal-directed learning deficit. Differences between these models could be due to the different effects on Substantia Nigra neurons. 6-OHDA model might disrupt the nigrostriatal pathway, while LPS could interfere on efferences and afferences to Substantia Nigra.

Effect of Age and Lipoperoxidation in Rat and Human Adipose Tissue-Derived Stem Cells.

A wide range of clinical applications in regenerative medicine were opened decades ago with the discovery of adult stem cells. Highly promising adult stem cells are mesenchymal stem/stromal cells derived from adipose tissue (ADSCs), primarily because of their abundance and accessibility. These cells have multipotent properties and have been used extensively to carry out autologous transplants. However, the biology of these cells is not entirely understood. Among other factors, the regeneration capacity of these cells will depend on both their capacity of proliferation/differentiation and the robustness of the biochemical pathways that allow them to survive under adverse conditions like those found in damaged tissues. The transcription factors, such as Nanog and Sox2, have been described as playing an important role in stem cell proliferation and differentiation. Also, the so-called longevity pathways, in which AMPK and SIRT1 proteins play a crucial role, are essential for cell homeostasis under stressful situations. These pathways act by inhibiting the translation through downregulation of elongation factor-2 (eEF2). In order to deepen knowledge of mesenchymal stem cell biology and which factors are determinant in the final therapeutic output, we evaluate in the present study the levels of all of these proteins in the ADSCs from humans and rats and how these levels are affected by aging and the oxidative environment. Due to the effect of aging and oxidative stress, our results suggest that before performing a cell therapy with ADSCs, several aspects reported in this study such as oxidative stress status and proliferation and differentiation capacity should be assessed on these cells. This would allow us to know the robustness of the transplanted cells and to predict the therapeutic result, especially in elder patients, where probably ADSCs do not carry out their biological functions in an optimal way.

Targeting pro-senescence mitogen activated protein kinase (Mapk) enzymes with bioactive natural compounds.

Aging is a multifactorial universal process characterized by a gradual decrease in physiological and biochemical functions. Given that life expectancy is on the rise, a better understanding of molecular mechanisms of the aging process is necessary in order to develop anti-aging interventions. Uncontrolled cellular senescence promotes persistent inflammation and accelerates the aging process by decreasing tissue renewal, repair and regeneration. Senescence of immune cells, immunesenescence, is another hallmark of aging. Targeting pro-senescent enzymes increases survival and therefore the lifespan. Although the upregulation of Mitogen Activated Protein Kinases (MAPK) enzymes in aging is still controversial, increasing evidence shows that dysregulation of those enzymes are associated with biological processes that contribute to aging such as irreversible senescence. In this manuscript components of the MAPK pathway will be summarized, including extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38, as well as natural flavonoids, phenolic and diterpenoids with anti-senescence activity that shows positive effects on longevity and MAPK inhibition. Although more studies using additional aging models are needed, we suggest that these selected natural bioactive compounds that regulate MAPK enzymes and reduce senescent cells can be potentially used to improve longevity and prevent/treat age-related diseases.

Advantages and disadvantages of apoptosis in the aging process.

Researchers cannot predict as yet how long a human being can live. Life expectancy has been steadily increasing in the last century, but perhaps not always the quality of life in parallel with it. Future generations will be faced with the problems of an increased life expectancy along with the emergence of new age-related diseases. A deeper understanding of the aging process is crucial to ameliorate, if not to prevent, these projected new old-age diseases. One of the mechanisms responsible for healthy aging is through the effective maintenance of physiological, biochemical, and immunological functions. To carry this out, the organism needs to create new cells to replace old ones and to induce the disappearance of old and damaged cells. Apoptosis is involved in all these processes. However, if apoptosis is dysregulated, premature senescence-associated diseases are likely to appear. In our review, the focus will be on a better understanding of the role of apoptosis in the aging process. These signaling pathways will most assuredly be pharmacologically targeted in antiaging medicine therapies.

Dysregulation of the Hippo pathway signaling in aging and cancer.

Human beings are facing emerging degenerative and cancer diseases, in large part, as a consequence of increased life expectancy. In the near future, researchers will have to put even more effort into fighting these new challenges, one of which will be prevention of cancer while continuing to improve the aging process through this increased life expectancy. In the last few decades, relevance of the Hippo pathway on cancer has become an important study since it is a major regulator of organ size control and proliferation. However, its deregulation can induce tumors throughout the body by regulating cell proliferation, disrupting cell polarity, releasing YAP and TAZ from the Scribble complexes and facilitating survival gene expression via activation of TEAD transcription factors. This pathway is also involved in some of the most important mechanisms that control the aging processes, such as the AMP-activated protein kinase and sirtuin pathways, along with autophagy and oxidative stress response/antioxidant defense. This could be the link between two tightly connected processes that could open a broader range of targeted molecular therapies to fight aging and cancer. Therefore, available knowledge of the processes involved in the Hippo pathway during aging and cancer must necessarily be well understood.

Adipose-derived stem cells decreased microglia activation and protected dopaminergic loss in rat lipopolysaccharide model.

Adult stem cell therapy is being used extensively to rejuvenate damaged tissue. One important tissue source to obtain these cells is adipose, which contains cells called adipose-derived stem cells (ADSCs). These cells have a great therapeutic potential not only for their multipotent properties as well as for immunomodulatory effects on the immune system. Parkinson's disease is characterized as neurodegenerative disorder which etiology is undoubtedly related to neuroinflammation process. The properties of ADSCs can be used as a new tool in stem cells therapy to treat neurodegenerative disorders. However, their efficacies are still controversial. Some authors have reported neuroprotection effects, while others did not find differences or stem cells increased the damage. Our previous study showed that ADSCs can survive long time after transplantation, suggesting us some biological effects could need more time to be repaired. In this study, we assessed the neuroprotection 6 months after transplantation. Our results suggest ADSCs can protect the dopaminergic loss after lipopolysaccharide (LPS) injection both reducing the microglia activation and differentiating into dopaminergic cells.

Role of Melatonin in the Inflammatory Process and its Therapeutic Potential.

Melatonin is an indolamine synthesized and secreted by the pineal gland along with other extrapineal sources including immune system cells, the brain, skin and the gastrointestinal tract. Growing interest in this compound as a potential therapeutic agent in several diseases stems from its pleiotropic effects. Thus, melatonin plays a key role in various physiological activities that include regulation of circadian rhythms, immune responses, the oxidative process, apoptosis or mitochondrial homeostasis. Most of these processes are altered during inflammatory pathologies, among which neurodegenerative and bowel diseases stand out. Therapeutic assays with melatonin indicate that it has a beneficial therapeutic value in the treatment of several inflammatory diseases, such as Alzheimer, Amiotrophic Lateral, Multiple Sclerosis and Huntigton´s disease as well as ulcerative colitis. However, contradictory effects have been demonstrated in Parkinson´s and Chron´s diseases, which, in some cases, the reported effects were beneficial while in others the pathology was exacerbated. These various results may be related to several factors. In the first place, it should be taken into account that at the beginning of the inflammation phase there is a production of reactive oxygen species (ROS) that should not be blocked by exclusively antioxidant molecules, since, on the one hand, it would be interfering with the action of neutrophils and macrophages and, on the other, with the apoptotic signals activated by ROS. It is also important to keep in mind that the end result of an anti-inflammatory molecule will depend on the degree of inflammation or whether or not it has been resolved and has therefore become chronic. In this review we present the use of melatonin in the control of inflammation underlying the above mentioned diseases. These actions are mediated through their receptors but also with their direct antioxidant action and melatonin's ability to break the vicious cycle of ROSinflammation. This review is aimed at evaluating the effect of melatonin on activity of the inflammatory process and at its immunomodulator effects.

Cell tracking, survival, and differentiation capacity of adipose-derived stem cells after engraftment in rat tissue.

Adipose tissue is an important source of adipose derived stem cells (ADSCs). These cells have the potential of being used for certain therapies, in which the main objective is to recover the function of a tissue/organ affected by a disease. In order to contribute to repair of the tissue, these cells should be able to survive and carry out their functions in unfavorable conditions after being transplanted. This process requires a better understanding of the biology involved: such as the time cells remain in the implant site, how long they stay there, and whether or not they differentiate into host tissue cells. This report focuses on these questions. ADSC were injected into three different tissues (substantia nigra, ventricle, liver) and they were tracked in vivo with a dual GFP-Luc reporter system. The results show that ADSCs were able to survive up to 4 months after the engraftment and some of them started showing resident cell tissue phenotype. These results demonstrate their long-term capacity of survival and differentiation when injected in vivo.

Deep Brain Stimulation in Patients with Parkinson's Disease: Effect on Psychiatric Symptoms and Quality of Life.

BACKGROUND AND STUDY AIMS: To determine the effect on psychiatric symptoms and quality of life in 30 patients with Parkinson's disease (PD) treated with deep brain stimulation (DBS) of both subthalamic nuclei (STN) after 1 year of follow-up. MATERIAL AND METHOD: We conducted a prospective 1-year follow-up study with a baseline assessment before and 6 and 12 months after surgery. The following were used as assessment instruments: the Bech-Rafaelsen Melancholia Scale (MES), the Bech-Rafaelsen Mania Scale (MAS), the Beck Scale for Suicidal Ideation (SSI), the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Oviedo Sleep Questionnaire (OSQ), the 36-Item Short Form Health Survey (SF-36), the Unified Parkinson's Disease Rating Scale (UPDRS), the dose of levodopa, and the active contact stereotactic coordinates. RESULTS: We recorded a clinical improvement between baseline with medication use (ON medication) and the results obtained at 6 and 12 months with medication use and stimulation (ON stimulation, ON medication) in MES and OSQ (p < 0.0001) and in SF-36 (p < 0.005). No changes were observed in MAS and SSI. There was a clinical improvement between baseline with ON medication and the results obtained at 12 months with ON stimulation, ON medication in Y-BOCS (p < 0.04). Also, there was a 53.3% reduction in levodopa at 6 months and a 54.7% reduction at 12 months after surgery (p < 0.0001). There was an improvement between baseline with OFF medication and the results obtained at 6 and 12 months OFF medication, ON stimulation (p < 0.0001) in UPDRS-III. There were no statistically significant differences between the initial and final active contact coordinates, or between stimulation parameters. CONCLUSIONS: DBS of the STN in patients with PD is associated with an improvement in psychiatric (affective and sleep-wake cycle) symptoms, clinical motor symptoms, and quality of life at 1 year after surgery.

Application of Kinase Inhibitors for Anti-aging Intervention.

Protein phosphorylation, mediated by protein kinases, has important physiological and pathological implications in our lives. Targeting kinase is one of the most interesting of the emerging topics in the pharmaceutical industry, especially since there is a focus on cancer therapy. Given that kinases may be involved in the aging process the focus will be on using the kinase inhibitor for anti-aging intervention to enhance healthspan and increase longevity. In this review, we will summarize: (i) the impact of the phosphoproteomic approach to elucidate molecular mechanisms of diseases; (ii) importance of the drug discovery approach for targeting kinases; (iii) the dysregulation of Janus kinase (JAK) / signal-transducing adapter molecules (STAT) and p70 ribosomal protein S6 kinase (S6Ks) pathway in aging and the age-related process; (iv) the epidemiological studies available in order to see whether a correlation between JAK/STAT and S6Ks mRNA expression levels exist in cancer and in patient outcome; (v) finally, we will show selected inhibitors of these kinases approved by the US Food and Drug Administration (FDA).

Effect of VBC-1814/7J, a poly-phytocompound, on a non-infectious model of pharyngitis.

Pharyngitis presents as an inflammation of the oropharynx, and clinical examination often shows evidence of nasopharyngitis. In numerous cases the condition occurs as a self-limiting illness of non-infectious aetiology, whose clinical management remains a matter for debate given the inappropriateness of antibiotics, the reported worsening following steroid use and the recent discouragement of the use of Chinese herbal medicine. The aim of the present study was thus to test VBC-1814/7J, a poly-phytocompound with known anti-inflammatory and immune-response enhancing properties, in an experimental model of non-infectious pharyngitis. Experimental non-infectious pharyngitis was induced by applying a pyridine solution to the surface of the pharyngeal mucosa in rats that were either normally fed (group A) or fed VBC-1814/7J three days prior to and three days subsequent to the induction of pharyngitis (group B). Healthy rats treated with topical saline were used as a control (group C). At time-points of 0, one hour, one day and three days sacrifices were carried out and microscopic examination, Evans blue (EB) dye extravasation and tissue concentrations of tumour necrosis factor (TNF)-α, interleukin (IL)-6 and mRNA of α- and ß-defensins were studied. As compared with group C, group A showed significant microscopic damage, EB extravasation, and increases in the levels of TNF-α and IL-6, as well as in the mRNA of three defensins (P<0.001) on the third day of observation. VBC-1814/7J significantly mitigated these microscopic and inflammatory markers while allowing a prompter and wider defensin reaction (P<0.05 vs. group A). These data suggest that VBC-1814/7J, as demonstrated in earlier studies, has the potential to address non-infectious pharyngitis in clinical practice.

Immunolocalization of Substance P and NK-1 Receptor in ADIPOSE Stem Cells.

Substance P (SP) is a neuropeptide belonging to the thachykinin peptide family. SP, after binding to its receptor, the neurokinin 1 receptor (NK1R), controls several transcription factors such as NF-κB, hypoxia inducible factor (HIF-1α), c-myc, c-fos, c-jun, and AP-1. SP and NK1R have a widespread distribution in both the central and peripheral nervous systems. They are also present in cells not belonging to the nervous system (immune cells, placenta, etc.). SP is located in all body fluids, that is, blood, cerebrospinal fluid, etc., making it ubiquitous throughout the human body. SP and NK1R genes are expressed in the stem cell line TF-1 and in primary stem cells derived from human placental cord blood. However, to our knowledge, the presence of SP and the NK1R receptor in adipose stem cells (ADSC) is unknown. We demonstrated by immunofluorescence the localization of SP and NK1R in human and rat ADSC. SP and NK1R are located in both the cytoplasm and the nucleus of these cells. The NK1R is higher in the nucleus than in the cytoplasm of ADSCs. By Western blot we demonstrated the presence of different isoforms of NK1R that have different subcellular locations in the ADSC. SP induces proliferation and mitogenesis through NK1R in ADSCs. These findings reported here for the first time suggest an important role for a SP/NK1R system, either as genetic and/or epigenetic factor, in both the cytoplasm and nucleus functions of the ADSCs. J. Cell. Biochem. 118: 4686-4696, 2017. © 2017 Wiley Periodicals, Inc.

Aging and Oxidative Stress Decrease Pineal Elongation Factor 2: In Vivo Protective Effect of Melatonin in Young Rats Treated With Cumene Hydroperoxide.

We studied the alterations of Elongation Factor 2 (eEF2) in the pineal gland of aged rats as well as the possible protective role of exogenous melatonin on these changes in young rats treated with cumene hydroperoxide (CH), a compound that promotes lipid peroxidation and inhibits protein synthesis. The study was performed using male Wistar rats of 3 (control), 12, and 24 months and 3-month-old rats treated with CH, melatonin, and CH plus melatonin. We found that pineal eEF-2 is affected by aging and CH, these changes being prevented by exogenous melatonin in the case of CH-treated rats. The proteomic studies show that many other proteins are affected by aging and oxidative stress in the pineal gland. The results suggest that one of the possible mechanisms underlying pineal gland dysfunction during aging is the effect of lipid peroxidation on eEF-2, which is a key component of protein synthesis machinery. J. Cell. Biochem. 118: 182-190, 2017. © 2016 Wiley Periodicals, Inc.

Immunophenotypic features of dedifferentiated skull base chordoma: An insight into the intratumoural heterogeneity.

Chordomas are rare and low-grade malignant solid tumours, despite their histologically benign appearance, that arise in the bone from embryonic notochordal vestiges of the axial skeleton, a mesoderm-derived structure that is involved in the process of neurulation and embryonic development. Chordomas occurring in the skull base tend to arise in the basiocciput along the clivus. Three major morphological variants have been described (classical, chondroid, and atypical/dedifferentiated). The pathogenesis and molecular mechanisms involved in chordoma development remain uncertain. From a pathological standpoint, the microenvironment of a chordoma is heterogeneous, showing a dual epithelial-mesenchymal differentiation. These tumours are characterised by slow modality of biologic growth, local recurrence, low incidence of metastasis rates, and cancer stem cell (CSC) phenotype. The main molecular findings are connected with brachyury immunoexpression and activation of the downstream Akt and mTOR signalling pathways. The differentiation between typical and atypical chordomas is relevant because the tumoural microenvironment and prognosis are partially different. This review provides an insight into the recent and relevant concepts and histochemical markers expressed in chordomas, with special emphasis on dedifferentiated chordomas and their prognostic implications.

Cavernous sinus thrombosis during pregnancy.

Cavernous sinus thrombosis (CST) represents a rare but devastating disease process that may be associated with significant long-term patient morbidity or mortality. Rapid diagnosis and aggressive medical and surgical management are imperative for patients with CST. We present the case of a 24-year-old pregnant woman with intraorbital abscess and CST secondary to Streptococcus milleri. Surgical intervention included orbital abscess drainage and dental extraction, medical therapy included intravenous antibiotic, heparin, and methylprednisolone and an elective cesarean section was performed. The latter was the key point to resolution the disease.