Abstract Background Major depressive disorder (MDD) is a highly prevalent mental health disorder with females experiencing higher rates of depression (11.6%), anxiety (15.7%) and physiological ...distress (14.5%) than males. Recently, the Endocannabinoid system (ECS) has been proposed to be a key contributing factor in the pathogenesis and symptom severity of MDD due to its role in neurotransmitter production, inflammatory response and even regulation of the female reproductive cycle. This review critically evaluates evidence regarding ECS levels in female-sexed individuals with depressive disorders to further understand ECS role. Materials and methods A systematic literature review of available research published prior to April 2022 was identified using PubMed (U.S. National Library of Medicine), CINAHL (EBSCO), Web of Science, AMED and Scopus (Elsevier). Studies were included if they reported ECS analysis of female-sexed individuals with depression and were excluded if they did not differentiate results between sexes, assessed mental health conditions other than depression, tested efficacy of endocannabinoid/n-acylethanolamine/cannabis or marijuana administration and that were unable to be translated. Critical appraisal of each included study was undertaken using the Joanna Briggs Institute Critical Appraisal Tool for Systematic Reviews. Results The 894 located citations were screened for duplicates ( n = 357) and eligibility by title and abstract ( n = 501). The full text of 33 studies were reviewed, and 7 studies were determined eligible for inclusion. These studies indicated that depressed female-sexed individuals have altered levels of ECS however no significant pattern was identified due to variability of study outcomes and measures, limiting overall interpretation. Discussion This review suggests potential involvement of ECS in underlying mechanisms of MDD in female sexed-individuals, however no pattern was able to be determined. A major contributor to the inability to attain reliable and valid understanding of the ECS levels in female-sexed individuals with depression was the inconsistency of depression screening tools, inclusion criteria’s and analysis methods used to measure eCBs. Future studies need to implement more standardised methodology to gain a deeper understanding of ECS in female-sexed individuals with depressive disorders. Trial registration This review was submitted to PROSPERO for approval in April 2022 (Registration #CRD42022324212).
Phox homology (PX) domains are membrane interacting domains that bind to phosphatidylinositol phospholipids or phosphoinositides, markers of organelle identity in the endocytic system. Although many ...PX domains bind the canonical endosome-enriched lipid PtdIns3P, others interact with alternative phosphoinositides, and a precise understanding of how these specificities arise has remained elusive. Here we systematically screen all human PX domains for their phospholipid preferences using liposome binding assays, biolayer interferometry and isothermal titration calorimetry. These analyses define four distinct classes of human PX domains that either bind specifically to PtdIns3P, non-specifically to various di- and tri-phosphorylated phosphoinositides, bind both PtdIns3P and other phosphoinositides, or associate with none of the lipids tested. A comprehensive evaluation of PX domain structures reveals two distinct binding sites that explain these specificities, providing a basis for defining and predicting the functional membrane interactions of the entire PX domain protein family.
A genetic mutation in the Vps35 subunit of retromer has recently been linked to late onset Parkinson's disease. We observed that the distribution and maturation of Vps35 D620N positive endosomes are ...altered. While Vps35 D620N containing retromer still binds CI‐M6PR, its trafficking is perturbed as shown by secretion of its ligand cathepsin D. As cathepsin D is involved in processing of α‐synuclein, a well‐established causative agent of Parkinson's disease, its altered trafficking may therefore represent the underlying cause of disease.
The retromer is a trimeric cargo‐recognition protein complex composed of Vps26, Vps29 and Vps35 associated with protein trafficking within endosomes. Recently, a pathogenic point mutation within the Vps35 subunit (D620N) was linked to the manifestation of Parkinson's disease (PD). Here, we investigated details underlying the molecular mechanism by which the D620N mutation in Vps35 modulates retromer function, including examination of retromer's subcellular localization and its capacity to sort cargo. We show that expression of the PD‐linked Vps35 D620N mutant redistributes retromer‐positive endosomes to a perinuclear subcellular localization and that these endosomes are enlarged in both model cell lines and fibroblasts isolated from a PD patient. Vps35 D620N is correctly folded and binds Vps29 and Vps26A with the same affinity as wild‐type Vps35. While PD‐linked point mutant Vps35 D620N interacts with the cation‐independent mannose‐6‐phosphate receptor (CI‐M6PR), a known retromer cargo, we find that its expression disrupts the trafficking of cathepsin D, a CI‐M6PR ligand and protease responsible for degradation of α‐synuclein, a causative agent of PD. In summary, we find that the expression of Vps35 D620N leads to endosomal alterations and trafficking defects that may partly explain its action in PD.
Transit of proteins through the endosomal organelle following endocytosis is critical for regulating the homeostasis of cell-surface proteins and controlling signal transduction pathways. However, ...the mechanisms that control these membrane-transport processes are poorly understood. The Phox-homology (PX) domain-containing proteins sorting nexin (SNX) 17, SNX27, and SNX31 have emerged recently as key regulators of endosomal recycling and bind conserved Asn-Pro-Xaa-Tyr–sorting signals in transmembrane cargos via an atypical band, 4.1/ezrin/radixin/moesin (FERM) domain. Here we present the crystal structure of the SNX17 FERM domain bound to the sorting motif of the P-selectin adhesion protein, revealing both the architecture of the atypical FERM domain and the molecular basis for recognition of these essential sorting sequences. We further show that the PX-FERM proteins share a promiscuous ability to bind a wide array of putative cargo molecules, including receptor tyrosine kinases, and propose a model for their coordinated molecular interactions with membrane, cargo, and regulatory proteins.
Feedback is known to have a large influence on student learning gains, and the emergence of online tools has greatly enhanced the opportunity for delivering timely, expressive, digital feedback and ...for investigating its learning impacts. However, to date there have been no large quantitative investigations of the feedback provided by large teams of markers, feedback use by large cohorts of students, nor its impact on students' academic performance across successive assessment tasks. We have developed an innovative online system to collect large-scale data on digital feedback provision and use. Our markers (n = 38) used both audio and typed feedback modalities extensively, providing 388 ± 4 and 1126 ± 37 words per report for first- and second-year students, respectively. Furthermore, 92% of first year and 85% of second-year students accessed their feedback, with 58% accessing their feedback for over an hour. Lastly, the amount of time students spent interacting with feedback is significantly related to the rate of improvement in subsequent assessment tasks. This study challenges assertions that many students do not collect, or use, their feedback. More importantly, we offer novel insights into the relationships between feedback provision, feedback use and successful academic outcomes.
Ayurvedic formulations: Potential COVID-19 therapeutics? Mahaboob Ali, Anees Ahmed; Bugarcic, Andrea; Naumovski, Nenad ...
Phytomedicine Plus : International journal of phytotherapy and phytopharmacology,
08/2022, Volume:
2, Issue:
3
Journal Article
Peer reviewed
Open access
•The interest in anti-COVID-19 properties of Ayurvedic formulations has been reviewed.•The Ayurvedic formulations appear to have prophylactic and/or therapeutic properties.•The use of Ayurvedic ...formulations is justified in all COVID-19 stages.•Ayurvedic formulations can be beneficial in reducing recovery time from COVID-19.•The use of Ayurvedic formulations as an “add-on” treatment can be beneficial.
Background: While Molnupiravir and Paxlovid have recently been approved for use in some countries, there are no widely available treatments for COVID-19, the disease caused by SARS-CoV-2 infection. Herbal extracts have been used to treat respiratory clinical indications by Ayurvedic medicine practitioners with minimal adverse reactions and intense research efforts are currently under way to develop some of these formulations for COVID-19 treatment.
Methods: Literature search for in silico, in vitro, in vivo, and clinical studies on the topic of Ayurvedic formulations for potential COVID-19 treatment, in order to present the current state of current knowledge by integrating information across all systems.
Results: The search yielded 20 peer reviewed articles on in silico studies examining the interaction of phytoconstituents of popular Ayurvedic formulations with SARS-CoV-2 components and its receptors; five articles on preclinical investigations of the ability of selected Ayurvedic formulations to inhibit functions of SARS-CoV-2 proteins; and 51 completed clinical trials on the efficacy of using Ayurvedic formulations for treatment of mild to moderate COVID-19. Clinical data was available from 17 of the 51 trials. There was a considerable overlap between formulations used in the in silico studies and the clinical trials. This finding was unexpected as there is no clearly stated alignment between studies and the traditional pathway to drug discovery– basic discovery leading to in vitro and in vivo proof of concept, followed by validation in clinical trials. This was further demonstrated in the majority of the in silico studies where focus was on potential antiviral mechanisms, while the clinical trials were focused on patient recovery using oral treatments. In all 17 clinical trials where data was available, Ayurvedic treatments lead to a shorter period to recovery in participants with COVID-19.
Conclusion: The most commonly used Ayurvedic treatments for management of respiratory symptoms associated with SARS-CoV-2 infection appear to have prophylactic and/or therapeutic properties. It would be of particular interest to assess synergistic and concomitant systemic effects and antiviral activities of individual phytoconstituents and their combinations in the Ayurvedic treatments.
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The trimeric Vps29–Vps35–Vps26 sub‐complex of retromer mediates retrograde transport of transmembrane proteins from endosomes to the trans‐Golgi network. Our group has recently identified a Vps26 ...paralogue, Vps26B, which is able to suppress the expression of Vps26A when exogenously expressed in mammalian cells and defines a distinct retromer complex (Vps26B‐retromer) in vivo and in vitro. In this study, we use HEK293 cells stably expressing either Vps26A‐myc or Vps26B‐myc to address the role of retromer cargo transport and subcellular localization of the two core retromer complexes as defined by the two mammalian‐specific Vps26 paralogues. Vps26B‐retromer, like Vps26A‐retromer, associates with TBC1D5 and GOLPH3. In contrast, no interaction between Vps26B‐retromer and cation‐independent mannose 6‐phosphate receptor (CI‐M6PR) was detected, leading to a degradation of this receptor and an increase in cathepsin D secretion. Colocalization of Vps26 paralogues with different endosomally located Rab proteins shows prolonged association of Vps26B‐retromer with maturing endosomes relative to Vps26A‐retromer. Interestingly, the cycling of CI‐M6PR is restored upon deletion of the variable Vps26B C‐terminal region indicating that this region is directly responsible for the differential function of the two paralogues. In summary, we show that the two distinct retromer complexes defined by different Vps26 paralogues are not functionally equivalent and that the Vps26B C‐terminal region can control cargo selection of the Vps26B‐retromer.
Abstract
Parkinson’s disease (PD) is an irreversible neurodegenerative disorder clinically manifesting in uncontrolled motor symptoms. There are two primary hallmark features of Parkinson’s ...disease—an irreversible loss of dopaminergic neurons of the substantia nigra pars compacta and formation of intracellular insoluble aggregates called Lewy bodies mostly composed of alpha-synuclein. Using a clinical improvements-first approach, we identified several clinical trials involving consumption of a specific diet or nutritional supplementation that improved motor and nonmotor functions. Here, we aimed to investigate if and how pyrroloquinoline quinone (PQQ) compound disrupts preformed alpha-synuclein deposits using SH-SY5Y cells, widely used Parkinson’s disease cellular model. SH-SY5Y neuroblastoma cells, incubated in presence of potassium chloride (KCl) to induce alpha-synuclein protein aggregation, were treated with PQQ for up to 48 hr. Resulting aggregates were examined and quantified using confocal microscopy. Overall, nutritional compound PQQ reduced the average number and overall size of intracellular cytoplasmic alpha-synuclein aggregates in a PD cellular model.
Following endocytosis, the fates of receptors, channels, and other transmembrane proteins are decided via specific endosomal sorting pathways, including recycling to the cell surface for continued ...activity. Two distinct phox-homology (PX)-domain-containing proteins, sorting nexin (SNX) 17 and SNX27, are critical regulators of recycling from endosomes to the cell surface. In this study we demonstrate that SNX17, SNX27, and SNX31 all possess a novel 4.1/ezrin/radixin/moesin (FERM)-like domain. SNX17 has been shown to bind to Asn-Pro-Xaa-Tyr (NPxY) sequences in the cytoplasmic tails of cargo such as LDL receptors and the amyloid precursor protein, and we find that both SNX17 and SNX27 display similar affinities for NPxY sorting motifs, suggesting conserved functions in endosomal recycling. Furthermore, we show for the first time that all three proteins are able to bind the Ras GTPase through their FERM-like domains. These interactions place the PX-FERM-like proteins at a hub of endosomal sorting and signaling processes. Studies of the SNX17 PX domain coupled with cellular localization experiments reveal the mechanistic basis for endosomal localization of the PX-FERM-like proteins, and structures of SNX17 and SNX27 determined by small angle X-ray scattering show that they adopt non-self-assembling, modular structures in solution. In summary, this work defines a novel family of proteins that participate in a network of interactions that will impact on both endosomal protein trafficking and compartment specific Ras signaling cascades.
To ensure clinical competency, and to facilitate the delivery of safe and effective care, it is important that continuing professional development (CPD) offerings for health professionals are ...relevant, appropriate and accessible. In the field of naturopathic medicine, there has been no research seeking to understand the educational needs and preferences of this workforce. This cross-sectional study aims to address this knowledge gap.
Australian adults holding a formal qualification in naturopathy were invited to complete a novel 29-item online questionnaire, comprising items on knowledge/skill gaps, knowledge/skill development, education delivery preferences and education barriers.
One-hundred-ten naturopaths completed the survey. The most frequently reported knowledge and skills gaps of undergraduate naturopathic training were pathology test interpretation and business development/administration, respectively. Across the four broad areas of professional/clinical skills, clinical specialities, populations and clinical settings, respondents rated, respectively, effective patient education, mental health, care of adult populations, and working in integrative health care settings as high value or important areas for further education. Respondents indicated a preference for CPD to be delivered via seminars/workshops, webinars, journals and conferences, with a penchant for blended or online delivery. Correspondingly, most respondents reported cost and distance as major/moderate barriers to further education.
This study has identified several important knowledge/skills deficits in Australian undergraduate naturopathic medicine education. An important next step of this work is the translation of findings into future naturopathic medicine curricula and CPD offerings.
•NM practitioners have an obligation to ensure their knowledge and skills are current.•There has been no investigation of the educational needs of the NM workforce.•This study identified important knowledge and skills deficits in Australian NM education.•These findings have important implications for future NM education and practice.
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