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Article: Immodulin peptides influence musculoskeletal homeostasis by linking extracellular cues to macrophage and myoblast nuclear receptors.

Mascarenhas, Desmond D

European journal of translational myology

2022

Abstract: Immodulins are synthetic peptides derived from the C-terminal domains of insulin-like growth factor binding proteins (IGFBPs). Immodulins from the 3/5/6 (but not 1/2/4) IGFBP evolutionary clade transduce extracellular matrix (ECM) signals to RXR, NR4A1 ... ...

Abstract	Immodulins are synthetic peptides derived from the C-terminal domains of insulin-like growth factor binding proteins (IGFBPs). Immodulins from the 3/5/6 (but not 1/2/4) IGFBP evolutionary clade transduce extracellular matrix (ECM) signals to RXR, NR4A1 and PPAR-alpha nuclear receptors (NRs) to stimulate novel macrophage lineages. The rationale of this study was to reconcile physical associations of immodulins with ECM and NRs, effects of siRNAs and chemical inhibitors in vivo, and immodulin-driven pro-differentiation effects in cell culture. When added to THP1D cells, immodulins stimulate CD169+ Clec9a+ and Clec12a+ macrophage lineages via a EP300/RXRγ/Nur77 transcriptional mechanism. This phenomenon is accompanied by the secretion of CCL22, IL-10 and TGFbeta and the ability to stimulate FoxP3+ T-cells in co-culture. ECM ligands of 3/5/6 immodulins include iron, zinc, glycosaminoglycans, transferrin and phosphatidylinositol-4,5,-biphosphate (PIP2), which can influence their pro-differentiation effects. Remarkably, immodulins also stimulate myogenesis in C2C12 myoblasts, thereby revealing a novel link between immune and musculoskeletal homeostasis. Distinct NR agonists stimulate these companion differentiation processes. Using solution NMR to guide design, immodulins with a tripeptide extension near the iron-binding pocket demonstrated higher iron-binding and improved pro-differentiation activities. Transferrin-bound immodulin shows binding preference for both high-molecular-weight hyaluronan (HMWHA) and HMWHA:CD44 complexes at endosomal pH, and interacts with PIP2 at normal physiological pH, offering intriguing mechanistic insights.
Language	English
Publishing date	2022-09-19
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2545577-1
ISSN	2037-7460 ; 2037-7452
ISSN (online)	2037-7460
ISSN	2037-7452
DOI	10.4081/ejtm.2022.10695
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Transcriptional re-programming in rat central nervous system two weeks after burn trauma: the impact of nephrilin treatment on the expression of oxidative stress-related genes.

Mascarenhas, Desmond D

Scars, burns & healing

2020 Volume 6, Page(s) 2059513120939443

Abstract: Introduction: Survivors of severe burns suffer lifetime neuroinflammatory consequences manifested by higher incidence of major depression and neurodegenerative disease. In a scald model, nephrilin peptide has previously been shown to protect rats from ... ...

Abstract	Introduction: Survivors of severe burns suffer lifetime neuroinflammatory consequences manifested by higher incidence of major depression and neurodegenerative disease. In a scald model, nephrilin peptide has previously been shown to protect rats from loss of lean body mass, kidney function and glycaemic control, complications that have also been shown to endure in burn patient populations. Nephrilin's mechanism of action has been suggested to involve protection from excessive oxidative stress. Methods: Using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) amplification of transcripts in total RNA extracted from dorsal root ganglia of male rats 14 days after exposure to thermal insult, we query the relative levels of expression of 34 genes believed to be associated with oxidative stress biology in the central nervous system (CNS). We use these data to explore the central role of oxidative stress in astrogliosis, immunosuppression and mitochondrial homeostasis. Results and discussion: Rats that received nephrilin treatment (4 mg/kg by subcutaneous bolus injection once daily for seven days after scald injury) showed significantly reduced elevations in gene expression of some key genes such as NOX2, GFAP, AQP4 and RAC1, but not of others such as NOX4, STEAP4, ARG1 and CCL2. Conclusion: The implications of these data with reference to nephrilin's potential clinical utility for mitigating the enduring effects of burn trauma on the CNS are discussed. Nephrilin reduces the expression of some genes implicated in neurodegeneration after burn insult. Lay summary: Nephrilin peptide is a novel treatment for short- and long-term systemic effects of burn trauma. This study measures the capability of nephrilin to address post-traumatic neurodegenerative disease by looking at the expression of genes in the central nervous system, in a rat scald model. Nephrilin appears to have beneficial effects by reducing the expression of some key genes known to be relevant in neurodegenerative processes, but not others.
Language	English
Publishing date	2020-08-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	2837910-X
ISSN	2059-5131 ; 2059-5131
ISSN (online)	2059-5131
ISSN	2059-5131
DOI	10.1177/2059513120939443
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Article ; Online: Covalent modification of nephrilin peptide with valproic acid increases its efficacy as a therapeutic in burn trauma.

Mascarenhas, Desmond D / Ravikumar, Puja / Amento, Edward P

Burns open : an international open access journal for burn injuries

2020 Volume 4, Issue 3, Page(s) 85–89

Abstract: Introduction: Nephrilin peptide, a designed inhibitor of Rictor complex, modulates systemic responses to trauma, alleviating clinically relevant variables in a rat scald model and sepsis mortality in a mouse model. This study explores the possibility ... ...

Abstract	Introduction: Nephrilin peptide, a designed inhibitor of Rictor complex, modulates systemic responses to trauma, alleviating clinically relevant variables in a rat scald model and sepsis mortality in a mouse model. This study explores the possibility that chemical conjugation of small molecules to the aminoterminus of nephrilin can modify its biological activity in the rat scald model. Methods: One of four molecules (valproic acid, decanoic acid, fenofibric acid and ibuprofen) was chemically attached to the amino terminus of nephrilin during synthesis. Animals were treated with each modified nephrilin by subcutaneous bolus injection on days 1-7 post-burn. Results: Compared to nephrilin, valproic acid-modified nephrilin showed significantly (all p < 0.05) improved systemic effects on kidney function (creatinine 0.17 ± 0.03 vs 0.31 ± 0.09 mg/dL), glycemic control (AUC 57.5 ± 40 vs 136.4 ± 69.2 mg.dL.hr), inflammation (IL-6 24 ± 9 vs 39 ± 8 pg/ml), pathological angiogenesis (1.46 ± 0.87 vs 6.53 ± 3.16 pct pixels) and weight gain (3.74 ± 0.31 vs 2.99 ± 0.53 slope), all variables previously shown to bear upon clinically relevant burn injury outcomes. Conclusion: Modification of nephrilin with valproic acid increases the efficacy of nephrilin peptide in burns.
Language	English
Publishing date	2020-06-11
Publishing country	England
Document type	Journal Article
ISSN	2468-9122
ISSN (online)	2468-9122
DOI	10.1016/j.burnso.2020.06.002
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Article: Epigenetic memory of oxidative stress: does nephrilin exert its protective effects via Rac1?

Mascarenhas, Desmond D / Herndon, David N / Arany, Istvan

Biologics : targets & therapy

2017 Volume 11, Page(s) 97–106

Abstract: Aim: Nephrilin peptide, a designed inhibitor of Rictor complex (mTORC2), exerts pleiotropic protective effects in metabolic, xenobiotic and traumatic stress models. Stress can generate enduring epigenetic changes in gene function. In this work we ... ...

Abstract	Aim: Nephrilin peptide, a designed inhibitor of Rictor complex (mTORC2), exerts pleiotropic protective effects in metabolic, xenobiotic and traumatic stress models. Stress can generate enduring epigenetic changes in gene function. In this work we examine the possibility that nephrilin treatment protects against acute and enduring global changes in oxidative metabolism, with a focus on the Rictor-complex-mediated activation of Rac1, a subunit of NADPH oxidase (Nox) via PKCs, Prex1 and p66shc. Methods: Given the wide range of animal models in which nephrilin peptide has previously demonstrated effectiveness in vivo, we chose three different experimental systems for this investigation: dermal fibroblasts, renal proximal tubule epithelial cells (PTECs), and kidney tissue and urine from an animal model of burn trauma in which nephrilin was previously shown to prevent loss of kidney function. Results: (1) Nephrilin protects dermal fibroblasts from loss of viability and collagen synthesis after ultraviolet A (UV-A) or H Conclusion: Nephrilin protects against oxidative stress, possibly by modulating the activation of Rac1.
Language	English
Publishing date	2017-07-17
Publishing country	New Zealand
Document type	Journal Article
ISSN	1177-5475
ISSN	1177-5475
DOI	10.2147/BTT.S136188
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Article ; Online: Women, innovation, and literature

Mascarenhas, Desmond D / Veer, Sally

Journal of innovation and entrepreneurship : JIE Vol. 3 , p. 1-5

2014 Volume 3, Page(s) 1–5

Abstract: Background: Avant-garde literature may influence the evolution of social attitudes and meanings. Women purchase the bulk of literary fiction products in the USA and may thereby play a hitherto undescribed role in business innovation by influencing this ... ...

Author's details	Desmond D. Mascarenhas and Sally Veer
Abstract	Background: Avant-garde literature may influence the evolution of social attitudes and meanings. Women purchase the bulk of literary fiction products in the USA and may thereby play a hitherto undescribed role in business innovation by influencing this type of cultural production. Innovation output in the USA is regionalized and linked to certain psychological traits in local populations. It is reasonable, therefore, to ask whether some of those same psychological traits in women correlate with the consumption of avant-garde literature. Findings: In a large female cohort, RD scores derived from the eSAIL correlated with geographic regions previously associated with economic innovation. RD values also show significant differences among quartiles of a female cohort scored for innovation based on submissions to an online competition that allowed subjective definitions of ‘innovation.’ Using online virtual book clubs, RD scores were shown to be significantly closer among pairs of women who had self-selected for similarities in reading taste. Finally, using 724 ratings derived from reader-book pairs, we showed that RD values were significantly different between women who preferred avant-garde literature (11 novels) and those who preferred other long fiction (21 novels), even though average ratings from the reading population at large were nearly identical for both groups of books. Conclusions: RD values in women correlated with indices of innovation activity and content. These findings may have implications for our understanding of the influence of psychological traits upon the production of cultural attitudes in innovation-dependent economies.
Keywords	eSAIL ; Innovation ; Avant-garde literature
Language	English
Size	Online-Ressource, graph. Darst.
Publisher	SpringerOpen
Publishing place	Heidelberg
Document type	Article ; Online
ZDB-ID	2679760-4
ISSN	2192-5372
ISSN	2192-5372
DOI	10.1186/2192-5372-3-7
Database	ECONomics Information System

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Article ; Online: Positive effects of ferric iron on the systemic efficacy of nephrilin peptide in burn trauma.

Mascarenhas, Desmond D / El Ayadi, Amina / Ravikumar, Puja / Kang, Gyeong Jin / Langer, Tammy / Moreno, Carlos / Amento, Edward P

Scars, burns & healing

2020 Volume 6, Page(s) 2059513120928494

Abstract: Introduction: Nephrilin peptide is a designed inhibitor of Rictor complex (also known as mTORC2), an evolutionarily conserved assembly believed to modulate responses to cellular stress. We previously demonstrated the ability of nephrilin peptide to ... ...

Abstract	Introduction: Nephrilin peptide is a designed inhibitor of Rictor complex (also known as mTORC2), an evolutionarily conserved assembly believed to modulate responses to cellular stress. We previously demonstrated the ability of nephrilin peptide to suppress neuroinflammation, loss of body mass, glycaemic control and kidney function in a rat scald model, as well as sepsis mortality in a mouse model. The present study explores the effect of nephrilin plus iron formulations on clinically relevant outcomes in the rat scald model. Methods: Animals were treated with nephrilin by subcutaneous bolus injection on post-burn days 1-7. Equimolar ferric iron in the formulation improved the positive systemic effects of nephrilin on kidney function, glycaemic control, oxidative stress, early hyperinflammation, late inflammasome activation, hyperangiogenesis and body mass, all variables previously shown to bear upon clinically relevant burn injury outcomes. The sparing effects of nephrilin-iron were demonstrated in both sexes. Discussion: Surprisingly, optimum daily treatment doses were in the range of 2-4 mg/kg, while 8 mg/kg was less effective, suggesting the possibility of marginal pro-oxidant effects from the 'free' iron fraction. Thus, although ferric iron in the nephrilin formulation is clearly helpful, care must be exercised to select an optimum treatment dose. Conclusion: Iron increases the efficacy of nephrilin peptide in burns.
Language	English
Publishing date	2020-06-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2837910-X
ISSN	2059-5131 ; 2059-5131
ISSN (online)	2059-5131
ISSN	2059-5131
DOI	10.1177/2059513120928494
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Article ; Online: Genetic and Cultural Reconstruction of the Migration of an Ancient Lineage.

Mascarenhas, Desmond D / Raina, Anupuma / Aston, Christopher E / Sanghera, Dharambir K

BioMed research international

2015 Volume 2015, Page(s) 651415

Abstract: A rare R1a1 Y-haplogroup (Y-HG) L657 clade subtype designated as LPKSTR is found in most male members of a clan of "founder" families within the Goud Saraswat Brahmin community in Lotli town in Western India. TMRCA calculations using pairwise comparisons ...

Abstract	A rare R1a1 Y-haplogroup (Y-HG) L657 clade subtype designated as LPKSTR is found in most male members of a clan of "founder" families within the Goud Saraswat Brahmin community in Lotli town in Western India. TMRCA calculations using pairwise comparisons to control cohorts suggested a probable migration history distinct from the canonical narrative for medieval migration of orthodox Brahmin families to South India. Using Y-HG centroid analysis, chi-square analysis of TMRCA distributions and archeological find-spots, and discriminant function analysis we show that the parental Z93 L342.2 subclade in which LPKSTR occurs originated in West Asia and that LPKSTR individuals migrated toward the southeast by a Bolan Pass route distinct from the traditionally presumed route of Brahmin ingress into the Indian subcontinent. The proposed migration route is supported by archeological, toponymic, numismatic, linguistic, iconographic, and literary data. Lastly, we present cultural metrics demonstrating that these LPKSTR lineages retained distinct family practices with respect to literacy, religious practice, and emigration not shared with orthodox Brahmins of canonical geographic origin within the same community, despite centuries of intermarriage. Long-term transmission of differentiated family practices within a patrilineal endogamous community has rarely been documented.
MeSH term(s)	Emigration and Immigration/history ; Genetics, Medical ; Haplotypes/genetics ; History, 21st Century ; History, Medieval ; Humans ; India ; Male ; Religion
Language	English
Publishing date	2015-09-30
Publishing country	United States
Document type	Clinical Trial ; Historical Article ; Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2698540-8
ISSN	2314-6141 ; 2314-6133
ISSN (online)	2314-6141
ISSN	2314-6133
DOI	10.1155/2015/651415
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Article ; Online: Bioactive peptides control receptor for advanced glycated end product-induced elevation of kidney insulin receptor substrate 2 and reduce albuminuria in diabetic mice.

Singh, Baljit K / Mascarenhas, Desmond D

American journal of nephrology

2008 Volume 28, Issue 6, Page(s) 890–899

Abstract: Background/aims: Sixteen-week-old db/db mice exhibit significantly elevated blood glucose and albuminuria. Kidney mesangial cell matrix expansion and collagen IV synthesis correlate with disease progression, but the underlying mechanism is unclear.: ... ...

Abstract	Background/aims: Sixteen-week-old db/db mice exhibit significantly elevated blood glucose and albuminuria. Kidney mesangial cell matrix expansion and collagen IV synthesis correlate with disease progression, but the underlying mechanism is unclear. Methods: Adaptive biochemical datasets were generated in cultured 293 kidney cells and in db/db mice. Results: In animals receiving daily subcutaneous bolus injections (weeks 8-13) of 20 microg/day humanin or 40 microg/day protein kinase C (NPKC) (a PKC-beta2 inhibitor peptide), there was a significant reduction in albuminuria, insulin receptor substrate 2 (IRS-2) and phospho-Akt (Ser473) levels in kidney tissue extracts (p < 0.05 in all cases). Elevated IRS-2 (not IRS-1), altered Akt1 and selective phosphorylation of p-Akt/Ser473 and p-IRS-1/Ser307 (but not p-Akt/Thr308 or p-IRS-2/Ser731) are correlates of the receptor for advanced glycated end product activation and are linked to albuminuria in vivo, whereas in P38 peptide-treated animals, collagen IV synthesis can be uncoupled from albuminuria altogether. Conclusion: Taken together, our results suggest that elevated IRS-2 and altered Akt phosphorylation may be more closely tied to the cause of diabetic kidney disease in db/db mice than mesangial matrix expansion per se, though both may originate from elevated circulatory glucose, and mesangial matrix expansion may independently exacerbate kidney dysfunction.
MeSH term(s)	Albuminuria/metabolism ; Animals ; Collagen Type IV/metabolism ; Diabetes Mellitus/metabolism ; Disease Models, Animal ; Glycation End Products, Advanced/metabolism ; Hemoglobins/metabolism ; Humans ; Insulin Receptor Substrate Proteins/metabolism ; Kidney/metabolism ; Mice ; Models, Biological ; Peptides/chemistry ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism
Chemical Substances	Collagen Type IV ; Glycation End Products, Advanced ; Hemoglobins ; Insulin Receptor Substrate Proteins ; Peptides ; Akt1 protein, mouse (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2008
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	604540-6
ISSN	1421-9670 ; 0250-8095
ISSN (online)	1421-9670
ISSN	0250-8095
DOI	10.1159/000141042
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Article ; Online: Genetic and Cultural Reconstruction of the Migration of an Ancient Lineage

Desmond D. Mascarenhas / Anupuma Raina / Christopher E. Aston / Dharambir K. Sanghera

BioMed Research International, Vol

2015 Volume 2015

Abstract: A rare R1a1 Y-haplogroup (Y-HG) L657 clade subtype designated as LPKSTR is found in most male members of a clan of “founder” families within the Goud Saraswat Brahmin community in Lotli town in Western India. TMRCA calculations using pairwise comparisons ...

Abstract	A rare R1a1 Y-haplogroup (Y-HG) L657 clade subtype designated as LPKSTR is found in most male members of a clan of “founder” families within the Goud Saraswat Brahmin community in Lotli town in Western India. TMRCA calculations using pairwise comparisons to control cohorts suggested a probable migration history distinct from the canonical narrative for medieval migration of orthodox Brahmin families to South India. Using Y-HG centroid analysis, chi-square analysis of TMRCA distributions and archeological find-spots, and discriminant function analysis we show that the parental Z93 L342.2 subclade in which LPKSTR occurs originated in West Asia and that LPKSTR individuals migrated toward the southeast by a Bolan Pass route distinct from the traditionally presumed route of Brahmin ingress into the Indian subcontinent. The proposed migration route is supported by archeological, toponymic, numismatic, linguistic, iconographic, and literary data. Lastly, we present cultural metrics demonstrating that these LPKSTR lineages retained distinct family practices with respect to literacy, religious practice, and emigration not shared with orthodox Brahmins of canonical geographic origin within the same community, despite centuries of intermarriage. Long-term transmission of differentiated family practices within a patrilineal endogamous community has rarely been documented.
Keywords	Medicine ; R
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Hindawi Limited
Document type	Article ; Online
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Article ; Online: A nuclear complex of rictor and insulin receptor substrate-2 is associated with albuminuria in diabetic mice.

Singh, Baljit K / Singh, Amoolya / Mascarenhas, Desmond D

Metabolic syndrome and related disorders

2010 Volume 8, Issue 4, Page(s) 355–363

Abstract: Background: Signaling events associated with diabetic nephropathy are not well understood. Triangulation of events triggered by unrelated bioactive peptides nephrilin and anephril, both of which inhibit albuminuria in diabetic mice, could reveal a ... ...

Abstract	Background: Signaling events associated with diabetic nephropathy are not well understood. Triangulation of events triggered by unrelated bioactive peptides nephrilin and anephril, both of which inhibit albuminuria in diabetic mice, could reveal a common subset of events associated with albuminuria. Methods: db/db mice received 20 microg/day anephril or nephrilin for 7 weeks. Streptozotocin (STZ)-treated DBA/2J mice received 2 mg/kg nephrilin for 26 days. In both studies, urine albumin and creatinine, plasma glucose, and tissue proteins were measured by enzyme-linked immunosorbent assay (ELISA). In a safety study, DBA/2J mice received 20 mg/kg nephrilin for 26 days, and tissues from these mice were fixed in formalin for histological analysis. HEK293 human kidney cells were treated with glycated hemoglobin plus 20 microg/mL nephrilin or anephril for 24 h. Results: Both peptides reduced albuminuria in db/db mice compared to saline-treated animals without affecting plasma glucose or insulin. In kidney tissues, the immunoreactivities of insulin receptor substrate-2 (IRS2), phosphorylated protein kinase C (p-PKC), and serum- and glucocortocoid-inducible kinase (SGK1) were reduced. Nephrilin, but not anephril, lowered elevated SGK1 in spleens of db/db mice. In STZ-pretreated DBA/2J mice, nephrilin reduced albuminuria and the accumulation of nuclear Rictor, IRS2, and p-PKC in the kidney. In cultured kidney cells, nephrilin disrupted the association of Rictor with IRS2 and nuclear compartmentalization. Histopathological examination of tissues from mice treated with 20 mg/kg nephrilin daily for 26 days showed no significant pathology compared to saline-treated controls. Conclusions: We define a subset of signaling markers closely associated with albuminuria. Mammalian target of rapamycin complex 2 (mTORC2)::IRS complexes may play a role in the nuclear accumulation, and possible downstream transcriptional effects, of p-PKC. The activity and apparent safety of nephrilin in rodents suggest a novel intervention strategy for diabetic kidney disease.
MeSH term(s)	Albuminuria/physiopathology ; Amino Acid Sequence ; Animals ; Blood Glucose/metabolism ; Carrier Proteins/metabolism ; Cell Line ; Cell Nucleus/metabolism ; Creatinine/blood ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/physiopathology ; Diabetes Mellitus, Experimental/urine ; Enzyme-Linked Immunosorbent Assay ; Humans ; Immunoprecipitation ; Indicators and Reagents ; Insulin/blood ; Insulin Receptor Substrate Proteins/physiology ; Mesangial Cells/pathology ; Mice ; Mice, Inbred DBA ; Molecular Sequence Data ; Rapamycin-Insensitive Companion of mTOR Protein ; Signal Transduction/physiology ; Trans-Activators/physiology ; Transcription Factors
Chemical Substances	Blood Glucose ; Carrier Proteins ; Crtc2 protein, mouse ; Indicators and Reagents ; Insulin ; Insulin Receptor Substrate Proteins ; Rapamycin-Insensitive Companion of mTOR Protein ; Trans-Activators ; Transcription Factors ; rictor protein, mouse ; Creatinine (AYI8EX34EU)
Language	English
Publishing date	2010-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2151220-6
ISSN	1557-8518 ; 1540-4196
ISSN (online)	1557-8518
ISSN	1540-4196
DOI	10.1089/met.2010.0011
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