Background
Protein disulfide isomerase A3 (PDIA3, also named GRP58, ER-60, ERp57) is conserved across species and mediates protein folding in the endoplasmic reticulum. PDIA3 is, reportedly, a chaperone for STAT3. However, the role of PDIA3 in regulating mitochondrial bioenergetics and STAT3 phosphorylation at serine 727 (S727) has not been described.
Methods
Mitochondrial respiration was compared in immortalized human cerebral microvascular cells (CMEC) wild type or null for PDIA3 and in whole organism C. Elegans WT or null for pdi-3 (worm homologue). Mitochondrial morphology and cell signaling pathways in PDIA3-/- and WT cells were assessed. PDIA3-/- cells were subjected to oxygen–glucose deprivation (OGD) to determine the effects of PDIA3 on cell survival after injury.
Results
We show that PDIA3 gene deletion using CRISPR-Cas9 in cultured CMECs leads to an increase in mitochondrial bioenergetic function. In C. elegans, gene deletion or RNAi knockdown of pdi-3 also increased respiratory rates, confirming a conserved role for this gene in regulating mitochondrial bioenergetics. The PDIA3-/- bioenergetic phenotype was reversed by overexpression of WT PDIA3 in cultured PDIA3-/- CMECs. PDIA3-/- and siRNA knockdown caused an increase in phosphorylation of the S727 residue of STAT3, which is known to promote mitochondrial bioenergetic function. Increased respiration in PDIA3-/- CMECs was reversed by a STAT3 inhibitor. In PDIA3-/- CMECs, mitochondrial membrane potential and reactive oxygen species production, but not mitochondrial mass, was increased, suggesting an increased mitochondrial bioenergetic capacity. Finally, PDIA3-/- CMECs were more resistant to oxygen–glucose deprivation, while STAT3 inhibition reduced the protective effect.
Conclusions
We have discovered a novel role for PDIA3 in suppressing mitochondrial bioenergetic function by inhibiting STAT3 S727 phosphorylation.
Hidradenitis suppurativa (HS) is a chronic relapsing, remitting disease which results in the formation of inflammatory nodules and pustules in intertriginous areas. HS is a complex disease with known psychosocial impact. Adalimumab is a biologic, used for treatment resistant HS, which working by inactivating TNF‐alpha. Our primary objective was to determine the effects of adalimumab on HS‐PGA and DLQI scores in patients with HS that had been on the treatment for at least 6 months. Our secondary objective was to note and assess the significance of adverse effects and impacts on wider health, namely occupational and social. A retrospective cross‐sectional study was performed using clinic notes from routine follow ups in biologic clinics in three specialist HS centers. About 77% (n = 78/101) patients demonstrated improvements in their HS‐PGA scores. Significant improvements in the DLQI scores of the patient cohort (P = .0001, 95% CI −12.8 to −5.9) have also been demonstrated. A total of 31.7% (32/101) patients experienced adverse effects spanning multiple organ systems, with 27.7% (28/101) requiring treatment cessation. Three of these patients stopped due to the worsening of preexisting mental health symptoms. Adalimumab is effective in reducing HS‐PGA and DLQI scores, but patients still complain of systemic effects necessitating drug cessation in some instances. A holistic and multisystemic approach to follow up is required, and there is scope for further studies examining temporal causality in the context of adalimumab and its multisystemic physical and psychological effects.
Objective To systematically review and summarize the available literature regarding the effectiveness and safety of biologics in the treatment of juvenile-onset systemic lupus erythematosus. Methods PubMed was systematically searched for relevant literature (2012–2017 inclusive) using the following criteria: (1) patients diagnosed with juvenile-onset systemic lupus erythematosus (≤18 years at diagnosis); (2) treatment with any biological agent; and (3) outcome measures assessing effectiveness and safety. Systematic literature reviews, meta-analyses, randomized controlled trials, cohort studies, case control studies, cross sectional surveys and case-series with ≥3 patients were included. Independent extraction of articles by two authors using predefined criteria was performed. The quality of each study was assessed using CASP tools and Oxford CEBM Levels of Evidence. Results Nine articles met inclusion criteria: six cohort studies, two case series and one pilot study, totalling 230 patients. All but one article reported the effects of rituximab, the other those of belimumab. Overall, patients had active disease refractory to standard of care regimens using corticosteroids and immunosuppressants. Available evidence for rituximab demonstrated improvements in disease activity, complement levels and anti-dsDNA titres accompanying a steroid-sparing effect. Conclusion Rituximab can be considered an effective treatment in juvenile-onset systemic lupus erythematosus patients with severe disease manifestations and/or refractory disease. Based on current evidence, use of belimumab in juvenile-onset systemic lupus erythematosus patients cannot be recommended. The long-term safety of these biological agents remains uncertain. Further prospective studies, ideally robust randomized controlled trials, are urgently needed to obtain more accurate data on the effectiveness and long-term safety of rituximab, belimumab and other biologics in juvenile-onset systemic lupus erythematosus.
Aggressive angiomyxoma is a rare mesenchymal tumour, primarily arising in the soft tissue of the pelvis and perineum in women of reproductive age. There is a paucity of evidence on optimal management because of the rarity of these tumours, but the consensus has been for surgical excision. We present the case of a 65-year-old woman who was admitted with left-sided buttock pain and initially diagnosed with a perianal abscess. She underwent examination under anaesthesia rectum with surgical excision of the lesion, subsequent histopathological and immunochemical analysis was suggestive of aggressive angiomyxoma. To complement our case report, we also present a literature review focusing on aggressive angiomyxoma in the ischioanal fossa (also known as the ischiorectal fossa) with only eight cases of primary aggressive angiomyxoma involving the ischioanal fossa documented to date. The primary aims of this case report and literature review are to familiarise clinicians with the clinical, histopathological and immunochemical features of these tumours, and to increase appreciation that despite the rarity of aggressive angiomyxoma, it might be considered in the differential diagnosis of ischioanal lesions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.