GDNF Therapy: Can We Make It Work?

2021 ◽  
pp. 1-4
Author(s):  
Anders Björklund

In two recent postmortem studies, Jeffrey Kordower and colleagues report new findings that open up for an interesting discussion on the status of GDNF/NRTN signaling in patients with Parkinson’s disease (PD), adding an interesting perspective on the, admittedly very limited, signs of restorative effects previously seen in GDNF/NRTN-treated patients. Their new findings show that the level of the GDNF signaling receptor Ret is overall reduced by about 65% relative to non-PD controls, and most severely, up to 80%, in nigral neurons containing α-synuclein inclusions, accompanied by impaired signaling downstream of the Ret receptor. Notably, however, the vast majority of the remaining nigral neurons retained a low level of Ret expression, and hence a threshold level of signaling. Further observations made in two patients who had received AAV-NRTN gene therapy 8–10 years earlier suggest the intriguing possibility that NRTN is able to restore Ret expression and upregulate its own signaling pathway. This “wind-up” mechanism, which is likely to depend on an interaction with dopaminergic transcription factor Nurr1, has therapeutic potential and should encourage renewed efforts to turn GDNF/NRTN therapy into success, once the recurring problem of under-dosing is resolved.

2021 ◽  
Vol 32 (19-20) ◽  
pp. 987-996
Author(s):  
Hildegard Büning ◽  
Boris Fehse ◽  
Zoltán Ivics ◽  
Stefan Kochanek ◽  
Ulrike Koehl ◽  
...  

2020 ◽  
Vol 11 ◽  
Author(s):  
Shihai Jia ◽  
Jeremie D. Oliver ◽  
Emma C. Turner ◽  
Maranda Renouard ◽  
Marianna Bei ◽  
...  

In these studies, we explored for the first time the molecular relationship between the paired-domain-containing transcription factor, Pax9, and the ectodysplasin (Eda) signaling pathway during mouse incisor formation. Mice that were deficient in both Pax9 and Eda were generated, and the status of dentition analyzed in all progeny using gross evaluation and histomorphometric means. When compared to wildtype controls, Pax9+/–Eda–/– mice lack mandibular incisors. Interestingly, Fgf and Shh signaling are down-regulated while Bmp4 and Lef1 appear unaffected. These findings suggest that Pax9-dependent signaling involves the Eda pathway and that this genetic relationship is important for mandibular incisor development. Studies of records of humans affected by mutations in PAX9 lead to the congenital absence of posterior dentition but interestingly involve agenesis of mandibular central incisors. The latter phenotype is exhibited by individuals with EDA or EDAR mutations. Thus, it is likely that PAX9, in addition to playing a role in the formation of more complex dentition, is also involved with EDA signaling in the initiation of odontogenesis within the incisal domain.


2004 ◽  
Vol 21 (4) ◽  
pp. 131-133
Author(s):  
Mohammed Rustom

An Introduction to Islam by David Waines consists of three parts:“Foundations,” “Islamic Teaching and Practice,” and “Islam in the ModernWorld.” The author begins by characteristically painting the picture of pre-Islamic pagan Arabia on the eve of Islam’s advent. He discusses the role andsignificance the pre-Islamic Arabs accorded their pantheon of deities, as wellas the (largely inherited) moral codes that governed their conduct in tribalsociety. Waines neatly ties this into what follows, where he discusses thebirth of Prophet Muhammad, the event of the Qur’an’s revelation, and theopposition he encountered from his fellow tribesmen in Makkah. This is followedby an analysis of the Qur’an’s significance, its conception of divinity,and the content and importance of the Hadith as a source of guidance forMuslims. The section is rounded off with examinations of such topics as the first period of civil strife (fitnah) after the Prophet’s death and the interestingbody of literature devoted to Muslim-Christian polemics in earlymedieval Islam.The transition from the first part of the book to the second part is ratherfluid, for the second part is essentially an elaboration of the themes discussedin the first. With remarkable ease and accuracy, the author elucidatesthe historical development and main features of Islamic law in both its theoryand practice. Returning to his earlier discussion on the Hadith, here hebriefly outlines how its corpus came to be collected. Readers unfamiliar withthe main theological controversies that confronted Islam in its formativeyears (e.g., the problem of free will and the status of the grave sinner) willfind the section devoted to Islamic theology fairly useful.Waines goes on to explain some of the principle Mu`tazilite andAsh`arite doctrines, and outlines some of the ideas of Neoplatonic Islamicphilosophy, albeit through the lenses of al-Ghazali’s famous refutation.Surprisingly, the author does not address any of the major developments inIslamic philosophy post-Ibn Rushd, such as the important work of theIshraqi (Illuminationist) school (incidentally, the founder of this school,Shihab al-Din Suhrawardi, was a contemporary of Ibn Rushd). The last twochapters are devoted to Sufism and Shi`ism, respectively. Although Wainesdoes misrepresent Ibn al-`Arabi’s metaphysics of Being by calling it a “system”(pp. 153 and 192), on the whole he presents the Islamic mystical traditionin a refreshing and informed manner. His section on Shi`ism is splendid.It is written with considerable care, and he effectively isolates the mainthemes characteristic of Twelver Shi`ite thought and practice.In the third and longest part of this work, Waines incorporates IbnBattutah’s travel accounts into the book’s narrative. This works very well, asit gives readers a sense of the diverse and rich cultural patterns that wereintricately woven into the fabric of fourteenth-century Islamic civilization.After reading through the section, this present reviewer could not help butmarvel at how the observations of a fourteenth-century traveler and legaljudge from Tangiers could so effectively contribute to a twenty-first centuryintroductory textbook on Islam. Additionally, Waines takes readers throughsome of the essential features of the three important “gunpowder” Muslimdynasties, devotes an interesting discussion to the role played by the mosquein a Muslim’s daily life, and outlines some of its different architectural andartistic expressions throughout Islamic history ...


Author(s):  
Chris Armstrong

The status quo within international politics is that individual nation-states enjoy extensive and for the most part exclusive rights over the resources falling within their borders. Egalitarians have often assumed that such a situation cannot be defended, but perhaps some sophisticated defences of state or national rights over natural resources which have been made in recent years prove otherwise. This chapter critically assesses these various arguments, and shows that they are not sufficient to justify the institution of ‘permanent sovereignty’ over resources. Even insofar as those arguments have some weight, they are compatible with a significant dispersal of resource rights away from individual nation-states, both downwards towards local communities, and upwards towards transnational and global agencies.


2020 ◽  
Vol 11 (1) ◽  
pp. 241-250
Author(s):  
Zhenyu Li ◽  
Guangqian Ding ◽  
Yudi Wang ◽  
Zelong Zheng ◽  
Jianping Lv

AbstractTranscription factor EB (TFEB)-based gene therapy is a promising therapeutic strategy in treating neurodegenerative diseases by promoting autophagy/lysosome-mediated degradation and clearance of misfolded proteins that contribute to the pathogenesis of these diseases. However, recent findings have shown that TFEB has proinflammatory properties, raising the safety concerns about its clinical application. To investigate whether TFEB induces significant inflammatory responses in the brain, male C57BL/6 mice were injected with phosphate-buffered saline (PBS), adeno-associated virus serotype 8 (AAV8) vectors overexpressing mouse TFEB (pAAV8-CMV-mTFEB), or AAV8 vectors expressing green fluorescent proteins (GFPs) in the barrel cortex. The brain tissue samples were collected at 2 months after injection. Western blotting and immunofluorescence staining showed that mTFEB protein levels were significantly increased in the brain tissue samples of mice injected with mTFEB-overexpressing vectors compared with those injected with PBS or GFP-overexpressing vectors. pAAV8-CMV-mTFEB injection resulted in significant elevations in the mRNA and protein levels of lysosomal biogenesis indicators in the brain tissue samples. No significant changes were observed in the expressions of GFAP, Iba1, and proinflammation mediators in the pAAV8-CMV-mTFEB-injected brain compared with those in the control groups. Collectively, our results suggest that AAV8 successfully mediates mTFEB overexpression in the mouse brain without inducing apparent local inflammation, supporting the safety of TFEB-based gene therapy in treating neurodegenerative diseases.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hajer Tlili ◽  
Anca Macovei ◽  
Daniela Buonocore ◽  
Manuela Lanzafame ◽  
Hanen Najjaa ◽  
...  

Abstract Background Hyperactivation of mechanistic target of rapamycin (mTOR) signaling pathway is involved in the regulation of cellular growth, proliferation, and more in general, is a common phenomenon in most types of cancers. Thus, natural substances targeting this pathway can be of great therapeutic potential in supporting the treatment of tumor patients. Rhus tripartita (Ucria) Grande is a plant growing in desertic areas which is traditionally used for the treatment of several diseases in Tunisia. In the present work, the biochemical profile of the main compounds present in the plant leaf extract was determined and the anti-leukemic potential of the plant extracts against acute monocytic leukaemia (AML) THP-1 cells was investigated. Methods After HPLC identification of some phenolic compounds present in the plant extract and the quantification of saponin content, the cytotoxic effect of Rhus tripartita extracts on THP-1 cell culture was evaluated using the colorimetric MTT assay for cell viability. THP-1 cells were incubated with medium containing the relative IC50 concentrations of total plant extract, saponin extract and some standard compounds (rutin (R); kaempferol (K); mixture of catechin, epicatechin, and epicatechin-gallate (CEEG); ellagic acid (EA). Finally, qRT-PCR and western blotting analysis were used to evaluate the effect of some flavonoids present in a crude extract of polyphenols and the total extract of saponins on cell survival and apoptosis. Results Analysis of expression level of some gene (PIK3CA, PTEN, AKT1, mTOR, EIF4E, RPS6KB1, and TSC1) involved in the mTOR pathway and the phosphorylation of S6 and AKT proteins allowed to observe that a total Rhus tripartita extract and some of the compounds found in the extract controls THP-1 cell proliferation and apoptosis via regulation of the PI3K-Akt-mTOR signaling pathway. Conclusion Rhus tripartita-induced inhibition of cell cycle and induction of apoptosis may involve the mTOR pathway. Therefore, Rhus tripartita extract may be a useful candidate as a natural anti-cancer drug to support the treatment of AML.


Economies ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 80
Author(s):  
Rosmah Nizam ◽  
Zulkefly Abdul Karim ◽  
Tamat Sarmidi ◽  
Aisyah Abdul Rahman

This paper examines the effect of financial inclusion on the firm growth of the manufacturing sector (513 firms) in selected ASEAN countries (Malaysia, Philippines, and Vietnam) using a cross-section threshold estimation technique. The levels of financial inclusion across firms were measured based on the distribution of financial services (access to credit). The main findings revealed that there is a non-monotonic effect of financial inclusion on the firm’s growth. These findings show that the impact of financial inclusion on firm growth in the manufacturing sector is significantly positive below a threshold point, and turns to significantly negative after a certain threshold point has been reached. These new findings suggest that manufacturing firm owners and banking institutions should deepen their financial inclusion efforts, and limit the distribution of credit access within the optimum value or threshold level in promoting the growth of the firm.


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