The skin of the naked mole-rat and its resilience against aging and cancer.

The naked mole-rat (NMR) Heterocephalus glaber (from the Greek/latin words ἕτερος, heteros = divergent, κεφαλή, kephale = head and glabra = hairless) was first described by Rüppell (Fig. 1) and belongs to the Hystricognath (from the Greek words ὕστριξ, hystrix = porcupine and γνάθος, gnathos = jaw) as a suborder of rodents. NMR are characterized by the highest longevity among rodents and reveal a profound cancer resistance. Details of its skin-specific protective and resistance mechanisms against aging and carcinogenesis have so far not been adequately characterized. Recently, our knowledge of NMR skin biology was complemented and expanded by published data using state-of-the art histological and molecular techniques. Here we review and integrate novel published data regarding skin morphology and histology of the aging NMR and the underlying mechanisms at the cellular and molecular level. We relate this data to the longevity of the NMR and its resistance to neoplastic transformation and discuss further open questions to understand its extraordinary longevity. In addition, we will address the exposome, defined as "the total of all non-genetic, endogenous and exogenous environmental influences" on the skin, respiratory tract, stomach, and intestine. Finally, we will discuss in perspective further intriguing possibilities arising from the interaction of skin with other organs.

[Skin aging-cellular senescence : What is the future?] / Hautalterung ­ zelluläre Seneszenz : Wohin geht die Reise?

BACKGROUND: Cellular senescence is the main cause of skin and organ aging and is associated with a wide range of aging-related diseases. OBJECTIVES: To understand which senolytics, senomorphics, and cell-based therapies have been developed to alleviate and even rejuvenate skin aging and reduce cellular senescence. METHODS: Basic literature for the mode of action of senolytics and senomorphics and their clinical perspectives in daily routine are discussed. RESULTS: Various causes lead to mitochondrial dysfunction and the activation of pro-aging signaling pathways, which eventually lead to cellular senescence with degradation of structural proteins of the dermal connective tissue and severe suppression of regenerative stem cell niches of the skin. CONCLUSIONS: Depletion of senescent cells suppress skin aging and enforce rejuvenation of skin and other organs and their function. The removal of senescent cells by cells of the native immune system is severely disturbed during aging. Selected senolytics and senomorphics are approved and are already on the market.

Ribosomal Dysfunction Is a Common Pathomechanism in Different Forms of Trichothiodystrophy.

Mutations in a broad variety of genes can provoke the severe childhood disorder trichothiodystrophy (TTD) that is classified as a DNA repair disease or a transcription syndrome of RNA polymerase II. In an attempt to identify the common underlying pathomechanism of TTD we performed a knockout/knockdown of the two unrelated TTD factors TTDN1 and RNF113A and investigated the consequences on ribosomal biogenesis and performance. Interestingly, interference with these TTD factors created a nearly uniform impact on RNA polymerase I transcription with downregulation of UBF, disturbed rRNA processing and reduction of the backbone of the small ribosomal subunit rRNA 18S. This was accompanied by a reduced quality of decoding in protein translation and the accumulation of misfolded and carbonylated proteins, indicating a loss of protein homeostasis (proteostasis). As the loss of proteostasis by the ribosome has been identified in the other forms of TTD, here we postulate that ribosomal dysfunction is a common underlying pathomechanism of TTD.

TFIIH mutations can impact on translational fidelity of the ribosome.

TFIIH is a complex essential for transcription of protein-coding genes by RNA polymerase II, DNA repair of UV-lesions and transcription of rRNA by RNA polymerase I. Mutations in TFIIH cause the cancer prone DNA-repair disorder xeroderma pigmentosum (XP) and the developmental and premature aging disorders trichothiodystrophy (TTD) and Cockayne syndrome. A total of 50% of the TTD cases are caused by TFIIH mutations. Using TFIIH mutant patient cells from TTD and XP subjects we can show that the stress-sensitivity of the proteome is reduced in TTD, but not in XP. Using three different methods to investigate the accuracy of protein synthesis by the ribosome, we demonstrate that translational fidelity of the ribosomes of TTD, but not XP cells, is decreased. The process of ribosomal synthesis and maturation is affected in TTD cells and can lead to instable ribosomes. Isolated ribosomes from TTD patients show an elevated error rate when challenged with oxidized mRNA, explaining the oxidative hypersensitivity of TTD cells. Treatment of TTD cells with N-acetyl cysteine normalized the increased translational error-rate and restored translational fidelity. Here we describe a pathomechanism that might be relevant for our understanding of impaired development and aging-associated neurodegeneration.

An Updated Checklist of Free-living Marine Nematodes from Coastal India.

The present study provides an updated species list of free-living marine nematodes reported from coastal India (Coasts and Islands) based on the thorough consultation of literature published from 1956 to 2022. This exercise resulted in a total of 617 valid species belonging to 266 genera, 48 families, 21 superfamilies and 9 orders. Class Chromadorea comprises 487 species represented by 205 genera, while class Enoplea includes 130 species belonging to 61 genera. The most common family was Xyalidae, with 76 species and the least common families having a single species each were represented by Aegialoalaimidae, Rhadinematidae, Aphanolaimidae, Rhabditidae, Pandolaimidae and Rhabdodemaniidae. The checklist provides a robust framework for the distribution and biogeography of free-living marine nematodes from the Indian waters and could be used to relate with marine ecosystems of other countries.

Morphological and Molecular Description of a New Species Haematoloechus dehradunensis sp. nov. (Plagiorchiidae: Haematoloechinae) from the Lungs of Euphlyctis cyanophlyctis (Anura, Dicroglossidae) from Dehradun, along with a Note on H. singaporensis Yuen, 1962, a New Record to India.

PURPOSE: Morphological and molecular description of a new species of Haematoloechus dehradunensis sp. nov. collected from the lungs of Euphlyctis cyanophlyctis (Schneider 1799) from Dehradun (Uttarakhand), India and reporting first record of H. singaporensis from India. METHODS: Digeneans were fixed in AFA (alcohol-formalin-acetic acid), stained with Borax's carmine, studied and photomicrographed with a BX53 DIC/BF Olympus research microscope. Molecular studies were done by DNA isolation using Qiagen, DNeasy® Blood and Tissue Kit and PCR amplification using r-DNA ITS-1 marker situated between 18S and 1.58S gene. RESULTS AND CONCLUSION: The new species is differentiated from other known species of Haematoloechus in having larger oral sucker, kidney-shaped ovary and oval-lobed testes. H. singaporensis collected from E. cyanophlyctis represents a first record for India and a new host record. ITS sequences submitted and compared at NCBI GenBank support the uniqueness of the new species.

Angiogenin Released from ABCB5+ Stromal Precursors Improves Healing of Diabetic Wounds by Promoting Angiogenesis.

Severe angiopathy is a major driver for diabetes-associated secondary complications. Knowledge on the underlying mechanisms essential for advanced therapies to attenuate these pathologies is limited. Injection of ABCB5+ stromal precursors at the edge of nonhealing diabetic wounds in a murine db/db model, closely mirroring human type 2 diabetes, profoundly accelerates wound closure. Strikingly, enhanced angiogenesis was substantially enforced by the release of the ribonuclease angiogenin from ABCB5+ stromal precursors. This compensates for the profoundly reduced angiogenin expression in nontreated murine chronic diabetic wounds. Silencing of angiogenin in ABCB5+ stromal precursors before injection significantly reduced angiogenesis and delayed wound closure in diabetic db/db mice, implying an unprecedented key role for angiogenin in tissue regeneration in diabetes. These data hold significant promise for further refining stromal precursors-based therapies of nonhealing diabetic foot ulcers and other pathologies with impaired angiogenesis.

Nucleolar TFIIE plays a role in ribosomal biogenesis and performance.

Ribosome biogenesis is a highly energy-demanding process in eukaryotes which requires the concerted action of all three RNA polymerases. In RNA polymerase II transcription, the general transcription factor TFIIH is recruited by TFIIE to the initiation site of protein-coding genes. Distinct mutations in TFIIH and TFIIE give rise to the degenerative disorder trichothiodystrophy (TTD). Here, we uncovered an unexpected role of TFIIE in ribosomal RNA synthesis by RNA polymerase I. With high resolution microscopy we detected TFIIE in the nucleolus where TFIIE binds to actively transcribed rDNA. Mutations in TFIIE affects gene-occupancy of RNA polymerase I, rRNA maturation, ribosomal assembly and performance. In consequence, the elevated translational error rate with imbalanced protein synthesis and turnover results in an increase in heat-sensitive proteins. Collectively, mutations in TFIIE-due to impaired ribosomal biogenesis and translational accuracy-lead to a loss of protein homeostasis (proteostasis) which can partly explain the clinical phenotype in TTD.

Persistent JunB activation in fibroblasts disrupts stem cell niche interactions enforcing skin aging.

Fibroblasts residing in the connective tissues constitute the stem cell niche, particularly in organs such as skin. Although the effect of fibroblasts on stem cell niches and organ aging is an emerging concept, the underlying mechanisms are largely unresolved. We report a mechanism of redox-dependent activation of transcription factor JunB, which, through concomitant upregulation of p16INK4A and repression of insulin growth factor-1 (IGF-1), initiates the installment of fibroblast senescence. Fibroblast senescence profoundly disrupts the metabolic and structural niche, and its essential interactions with different stem cells thus enforces depletion of stem cells pools and skin tissue decline. In fact, silencing of JunB in a fibroblast-niche-specific manner-by reinstatement of IGF-1 and p16 levels-restores skin stem cell pools and overall skin tissue integrity. Here, we report a role of JunB in the control of connective tissue niche and identified targets to combat skin aging and associated pathologies.

Connective Tissue and Fibroblast Senescence in Skin Aging.

There is increasing evidence that skin aging is significantly enforced by the accumulation of senescent dermal fibroblasts. Various stressors damaging macromolecules inside and outside fibroblasts are responsible. In addition, NK cells fail to adequately remove senescent (SEN) fibroblasts from tissues. SEN fibroblasts by the release of the proinflammatory, tissue degrading senescent-associated secretory phenotype factors and vesicles with distinct cargo impact on their endogenous niche and spread senescence and skin aging. In this review, we will further discuss less noticed facets, including the plasticity of distinct dermal fibroblast phenotypes, the underestimated impact of the extracellular matrix itself, and the depletion of fibroblast subsets on skin homeostasis and aging.

TLR4-dependent shaping of the wound site by MSCs accelerates wound healing.

We here address the question whether the unique capacity of mesenchymal stem cells to re-establish tissue homeostasis depends on their potential to sense pathogen-associated molecular pattern and, in consequence, mount an adaptive response in the interest of tissue repair. After injection of MSCs primed with the bacterial wall component LPS into murine wounds, an unexpected acceleration of healing occurs, clearly exceeding that of non-primed MSCs. This correlates with a fundamental reprogramming of the transcriptome in LPS-treated MSCs as deduced from RNAseq analysis and its validation. A network of genes mediating the adaptive response through the Toll-like receptor 4 (TLR4) pathway responsible for neutrophil and macrophage recruitment and their activation profoundly contributes to enhanced wound healing. In fact, injection of LPS-primed MSCs silenced for TLR4 fails to accelerate wound healing. These unprecedented findings hold substantial promise to refine current MSC-based therapies for difficult-to-treat wounds.

First Report on the Genus Gyrinicola Yamaguti, 1938 from India with a Description of a New Species.

INTRODUCTION: Gyrinicola dehradunensis sp. nov. from the intestine of tadpoles of the small paa frog, Nanorana minica, from Dehradun (Uttarakhand), India is described and illustrated. Gyrinicola dehradunensis is the first species of the genus recorded from India and the second species recorded from Asia. METHODS: Light microscopy was used for the identification of nematodes using BX53 DIC/BF Olympus research microscope with an attached DP27 digital camera. Drawings for the description of the new species were made from photomicrographs. For molecular studies, DNA was isolated using Qiagen, DNeasy® Blood and Tissue Kit and amplified using r-DNA ITS-18S, and ITS-1.58S primers. RESULTS: The new species is differentiated from the known species by the absence of larvated eggs and the presence of a tooth-like projection in the buccal region. N. minica is a new host record for the genus. Four r-DNA ITS1 sequences of the new species have been submitted to the NCBI Genbank.

Indomethacin impairs mitochondrial dynamics by activating the PKCζ-p38-DRP1 pathway and inducing apoptosis in gastric cancer and normal mucosal cells.

The subcellular mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in gastric cancer and normal mucosal cells is elusive because of the diverse cyclooxygenase-independent effects of these drugs. Using human gastric carcinoma cells (AGSs) and a rat gastric injury model, here we report that the NSAID indomethacin activates the protein kinase Cζ (PKCζ)-p38 MAPK (p38)-dynamin-related protein 1 (DRP1) pathway and thereby disrupts the physiological balance of mitochondrial dynamics by promoting mitochondrial hyper-fission and dysfunction leading to apoptosis. Notably, DRP1 knockdown or SB203580-induced p38 inhibition reduced indomethacin-induced damage to AGSs. Indomethacin impaired mitochondrial dynamics by promoting fissogenic activation and mitochondrial recruitment of DRP1 and down-regulating fusogenic optic atrophy 1 (OPA1) and mitofusins in rat gastric mucosa. Consistent with OPA1 maintaining cristae architecture, its down-regulation resulted in EM-detectable cristae deformity. Deregulated mitochondrial dynamics resulting in defective mitochondria were evident from enhanced Parkin expression and mitochondrial proteome ubiquitination. Indomethacin ultimately induced mitochondrial metabolic and bioenergetic crises in the rat stomach, indicated by compromised fatty acid oxidation, reduced complex I- associated electron transport chain activity, and ATP depletion. Interestingly, Mdivi-1, a fission-preventing mito-protective drug, reversed indomethacin-induced DRP1 phosphorylation on Ser-616, mitochondrial proteome ubiquitination, and mitochondrial metabolic crisis. Mdivi-1 also prevented indomethacin-induced mitochondrial macromolecular damage, caspase activation, mucosal inflammation, and gastric mucosal injury. Our results identify mitochondrial hyper-fission as a critical and common subcellular event triggered by indomethacin that promotes apoptosis in both gastric cancer and normal mucosal cells, thereby contributing to mucosal injury.

Newly Defined ATP-Binding Cassette Subfamily B Member 5 Positive Dermal Mesenchymal Stem Cells Promote Healing of Chronic Iron-Overload Wounds via Secretion of Interleukin-1 Receptor Antagonist.

In this study, we report the beneficial effects of a newly identified dermal cell subpopulation expressing the ATP-binding cassette subfamily B member 5 (ABCB5) for the therapy of nonhealing wounds. Local administration of dermal ABCB5+ -derived mesenchymal stem cells (MSCs) attenuated macrophage-dominated inflammation and thereby accelerated healing of full-thickness excisional wounds in the iron-overload mouse model mimicking the nonhealing state of human venous leg ulcers. The observed beneficial effects were due to interleukin-1 receptor antagonist (IL-1RA) secreted by ABCB5+ -derived MSCs, which dampened inflammation and shifted the prevalence of unrestrained proinflammatory M1 macrophages toward repair promoting anti-inflammatory M2 macrophages at the wound site. The beneficial anti-inflammatory effect of IL-1RA released from ABCB5+ -derived MSCs on human wound macrophages was conserved in humanized NOD-scid IL2rγ null mice. In conclusion, human dermal ABCB5+ cells represent a novel, easily accessible, and marker-enriched source of MSCs, which holds substantial promise to successfully treat chronic nonhealing wounds in humans. Stem Cells 2019;37:1057-1074.

Description of a new species of Rhabdias Stiles and Hassall, 1905 (Nematoda: Rhabdiasidae) from Western Himalayan foothills (Uttarakhand), India.

Rhabdias garhwalensis sp. nov. from the lungs of Duttaphrynus himalayanus (Günther, 1864) collected in Kimoi Tehsil, district Tehri Garhwal (Uttarakhand), India is described and illustrated. Rhabdias garhwalensis sp. nov. represents the 15th species described from the Oriental zoogeographical zone and the 9th species from India. The new species is differentiated from the closely related Oriental species in having 6 lips, cup-shaped buccal cavity with muscular striations in the posterior region and smaller esophagus to body length ratio. In addition to the new species, a second species, Cosmocercoides bufonis Karve, 1944, was found in the large intestine of D. himalayanus.

JunB defines functional and structural integrity of the epidermo-pilosebaceous unit in the skin.

Transcription factors ensure skin homeostasis via tight regulation of distinct resident stem cells. Here we report that JunB, a member of the AP-1 transcription factor family, regulates epidermal stem cells and sebaceous glands through balancing proliferation and differentiation of progenitors and by suppressing lineage infidelity. JunB deficiency in basal progenitors results in a dermatitis-like syndrome resembling seborrheic dermatitis harboring structurally and functionally impaired sebaceous glands with a globally altered lipid profile. A fate switch occurs in a subset of JunB deficient epidermal progenitors during wound healing resulting in de novo formation of sebaceous glands. Dysregulated Notch signaling is identified to be causal for this phenotype. In fact, pharmacological inhibition of Notch signaling can efficiently restore the lineage drift, impaired epidermal differentiation and disrupted barrier function in JunB conditional knockout mice. These findings define an unprecedented role for JunB in epidermal-pilosebaceous stem cell homeostasis and its pathology.

Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome.

Retarded growth and neurodegeneration are hallmarks of the premature aging disease Cockayne syndrome (CS). Cockayne syndrome proteins take part in the key step of ribosomal biogenesis, transcription of RNA polymerase I. Here, we identify a mechanism originating from a disturbed RNA polymerase I transcription that impacts translational fidelity of the ribosomes and consequently produces misfolded proteins. In cells from CS patients, the misfolded proteins are oxidized by the elevated reactive oxygen species (ROS) and provoke an unfolded protein response that represses RNA polymerase I transcription. This pathomechanism can be disrupted by the addition of pharmacological chaperones, suggesting a treatment strategy for CS. Additionally, this loss of proteostasis was not observed in mouse models of CS.

Nematode parasites of Duttaphrynus stomaticus (Lutken, 1864) (Amphibia: Anura) with description of a new species of Rhabdias Stiles and Hassall, 1905 (Nematoda: Rhabdiasidae) from Dehradun (Uttarakhand), India.

Rhabdias stomatica sp. nov. from the lungs of Duttaphrynus stomaticus (Lutken, 1864) from Dehradun, Uttarakhand, India is described and illustrated. Rhabdias stomatica sp. nov. is the 16th species described from the Oriental biogeographical region and the 8th species from India. The new species is differentiated from the closely related Oriental species in having 4 weakly developed lips, a trapezoidal shaped buccal cavity, different position of nerve ring and in the esophagus/body length ratio. In addition, to the new species found in the lungs, mature specimens of Aplectana macintoshii (Stewart, 1914) Travassos, 1931 and larvae representing two unidentified species of nematode were found in the large intestine of the D. stomaticus.