Integrative analysis of Iso-Seq and RNA-seq data reveals transcriptome complexity and differential isoform in skin tissues of different hair length Yak.

BACKGROUND: The hair follicle development process is regulated by sophisticated genes and signaling networks, and the hair grows from the hair follicle. The Tianzhu white yak population exhibits differences in hair length, especially on the forehead and shoulder region. However, the genetic mechanism is still unclear. Isoform sequencing (Iso-seq) technology with advantages in long reads sequencing. Hence, we combined the Iso-seq and RNA-seq methods to investigate the transcript complexity and difference between long-haired yak (LHY) and normal-haired yak (NHY). RESULTS: The hair length measurement result showed a significant difference between LHY and NHY on the forehead and the shoulder (P-value < 0.001). The skin samples from the forehead and the shoulder of LHY and NHY were pooled for isoform sequencing (Iso-seq). We obtained numerous long transcripts, including novel isoforms, long non-coding RNA, alternative splicing events, and alternative polyadenylation events. Combined with RNA-seq data, we performed differential isoforms (DEIs) analysis between LHY and NHY. We found that some hair follicle and skin development-related DEIs, like BMP4, KRT2, IGF2R, and COL1A2 in the forehead skin; BMP1, KRT1, FGF5, COL2A1, and IGFBP5 in the shoulder skin. Enrichment analysis revealed that DEIs in both two comparable groups significantly participated in skin and hair follicle development-related pathways, like ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling pathways. The results indicated that the hair follicle development of Tianzhu white yak may influence the hair length difference. Besides, the protein-protein interaction (PPI) network of DEIs showed COL2A1 and COL3A1 exhibited a high degree of centrality, and these two genes were suggested as potential candidates for the hair length growth of Tianzhu white yak. CONCLUSIONS: The results provided a comprehensive analysis of the transcriptome complexity and identified differential transcripts that enhance our understanding of the molecular mechanisms underlying the variation in hair length growth in Tianzhu white yak.

Dissecting hair breakage in alopecia areata: the central role of dysregulated cysteine homeostasis.

In the initial stages of Alopecia Areata (AA), the predominance of hair breakage or exclamation mark hairs serves as vital indicators of disease activity. These signs are non-invasive and are commonly employed in dermatoscopic examinations. Despite their clinical salience, the underlying etiology precipitating this hair breakage remains largely uncharted territory. Our exhaustive review of the existing literature points to a pivotal role for cysteine-a key amino acid central to hair growth-in these mechanisms. This review will probe and deliberate upon the implications of aberrant cysteine metabolism in the pathogenesis of AA. It will examine the potential intersections of cysteine metabolism with autophagy, ferroptosis, immunity, and psychiatric manifestations associated with AA. Such exploration could illuminate new facets of the disease's pathophysiology, potentially paving the way for innovative therapeutic strategies.

Biotransformation of Cacumen platycladi Extract by Lactiplantibacillus plantarum CCFM1348 Promotes Hair Growth in Mice.

Cacumen platycladi (CP) is a frequently used traditional Chinese medicine to treat hair loss. In this study, CP fermented by Lactiplantibacillus plantarum CCFM1348 increased the proliferation of human dermal papilla cells. In an in vivo assay, compared to nonfermented CP, postbiotics (fermented CP) and synbiotics (live bacteria with nonfermented CP) promoted hair growth in mice. The Wnt/ß-catenin signaling pathway plays crucial roles in the development of hair follicles, including growth cycle restart and maintenance. Both postbiotics and synbiotics upregulated ß-catenin, a major factor of the Wnt/ß-catenin signaling pathway. Postbiotics and synbiotics also increased the vascular endothelial growth factor expression and decreased the BAX/Bcl2 ratio in the dorsal skin of mice. These results suggest that fermented CP by L. plantarum CCFM1348 may promote hair growth through regulating the Wnt/ß-catenin signaling pathway, promoting the expression of growth factors and reducing apoptosis.

[Research progress in regulation of hair growth by dermal adipose tissue].

Objective: To summarize the dynamic and synchronized changes between the hair cycle and dermal adipose tissue as well as the impact of dermal adipose tissue on hair growth, and to provide a new research idea for the clinical treatment of hair loss. Methods: An extensive review of relevant literature both domestic and international was conducted, analyzing and summarizing the impact of dermal adipose precursor cells, mature dermal adipocytes, and the processes of adipogenesis in dermal adipose tissue on the transition of hair cycle phases. Results: Dermal adipose tissue is anatomically adjacent to hair follicles and closely related to the changes in the hair cycle. The proliferation and differentiation of dermal adipose precursor cells promote the transition of hair cycle from telogen to anagen, while mature adipocytes can accelerate the transition from anagen to catagen of the hair cycle by expressing signaling molecules, with adipogenesis in dermal adipose tissue and hair cycle transition signaling coexistence. Conclusion: Dermal adipose tissue affects the transition of the hair cycle and regulates hair growth by secreting various signaling molecules. However, the quantity and depth of existing literature are far from sufficient to fully elucidate its prominent role in regulating the hair cycle, and the specific regulatory mechanisms needs to be further studied.

White horses - non-coding sequences drive premature hair greying and predisposition to melanoma.

The Grey allele in horses is causing premature hair greying and susceptibility to melanoma. The causal mutation is a 4.6 kb tandem duplication in intron 6 of the Syntaxin 17 gene. A recent study demonstrated that the most common allele at the Grey locus (G3) involves three tandem copies of this sequence, whilst a more rare allele (G2) has two tandem copies and the wild-type allele (G1) only one copy. The G3 allele is causing fast greying and high incidence of skin melanoma, whereas the G2 allele is causing slow greying and no obvious increase in melanoma incidence. Further somatic copy number expansion has been documented in melanoma tissue from Grey horses. Functional studies showed that this intronic sequence acts as a weak melanocyte-specific enhancer that becomes substantially stronger by the copy number expansion. The Grey mutation is associated with upregulated expression of both Syntaxin 17 and the neighbouring NR4A3 gene in Grey horse melanomas. It is still an open question which of these genes is most important for the phenotypic effects or if causality is due to the combined effect of upregulation of both genes. Interestingly, RNAseq data in the Human Protein Atlas give support for a possible role of NR4A3 because it is particularly upregulated in human skin cancer, and it belongs to a cluster of genes associated with skin cancer and melanin biosynthesis. The Grey mutation and its association with melanoma provide a possibility to study the path to tumour development in numerous Grey horses carrying exactly the same predisposing mutation.

Stability and inter-family associations of hair endocannabinoid and N-acylethanolamines across the perinatal period in mothers, fathers, and children.

Analysis of endocannabinoids (ECs) and N-acylethanolamines (NAEs) in hair is assumed to retrospectively assess long-term EC/NAE concentrations. To inform their use, this study investigated stability of EC/NAE hair concentrations in mothers, fathers, and their children across the perinatal period as well as associations between family members. In a prospective cohort study, EC (AEA, 1-AG/2-AG) and NAE (SEA, PEA, OEA) levels were quantified in hair samples taken four times in mothers (n = 336) and their partners (n = 225) from pregnancy to two years postpartum and in offspring (n = 319) from shortly after birth to two years postpartum. Across the perinatal period, maternal and paternal hair ECs/NAEs showed poor multiple-test consistency (16-36%) and variable relative stability, as well as inconsistent absolute stability for mothers. Regarding children, hair ECs/NAEs evidenced poor multiple-test consistency (4-19%), no absolute stability, and either no or variable relative stability. Hair ECs/NAEs showed small to medium significant associations across the perinatal period within couples and parent-child dyads. Findings suggest hair ECs/NAEs during the perinatal period possess variable stability in adults, albeit more stability in fathers than mothers in this time. This highlights the need to further investigate factors associated with changes in hair ECs/NAEs across time. The first two years of life may be a dynamic phase for the endocannabinoid system in children, potentially characterized by complex within-family correspondence that requires further systematic investigation.

Methionine Dependence of Hair Maintenance in C57BL/6 Mice.

BACKGROUND/AIM: Hair-follicle keratinocytes contain high levels of cysteine, which is derived from methionine, rapidly proliferate, and form the hair shaft. The high proliferation rate of hair-follicle keratinocytes resembles that of aggressive cancer cells. In the present study, we determined the effect of a methionine-deficient diet on hair loss (alopecia) in mice with or without homocysteine supplementation. MATERIALS AND METHODS: Mice were fed a normal rodent diet (2020X, ENVIGO) (Group 1); a methionine-choline-deficient diet (TD.90262, ENVIGO) (Group 2); a methionine-choline-deficient diet with a 10 mg/kg/day supply of homocysteine administered by intra-peritoneal (i.p.) injection for 2 weeks (Group 3). In Group 2, mice were fed a methionine-choline-deficient diet for an additional 2 weeks but with 10 mg/kg/day of i.p. l-homocysteine and the mice were observed for two additional weeks. Subsequently, the mice were fed a standard diet that included methionine. Hair loss was monitored by photography. RESULTS: After 14 days, hair loss was observed in Group 2 mice on a methionine-restricted diet but not in Group 3 mice on the methionine-restricted diet which received i.p. homocysteine. In Group 2, at 2 weeks after methionine restriction, hair loss was not rescued by homocysteine supplementation. However, after restoration of methionine in the diet, hair growth resumed. Thus, after 2 weeks of methionine restriction, only methionine restored hair loss, not homocysteine. CONCLUSION: Hair maintenance requires methionine in the diet. Future experiments will determine the effects of methionine restriction on hair-follicle stem cells.

Hair cortisol and changes in cortisol dynamics in chronic kidney disease.

Objective: We compared hair cortisol (HC) with classic tests of the hypothalamic-pituitary-adrenal (HPA) axis in chronic kidney disease (CKD) and assessed its association with kidney and cardiometabolic status. Design and methods: A cross-sectional study of 48 patients with CKD stages I-IV, matched by age, sex, and BMI with 24 healthy controls (CTR) was performed. Metabolic comorbidities, body composition, and HPA axis function were studied. Results: A total of 72 subjects (age 52.9 ± 12.2 years, 50% women, BMI 26.2 ± 4.1 kg/m2) were included. Metabolic syndrome features (hypertension, dyslipidaemia, glucose, HOMA-IR, triglycerides, waist circumference) and 24-h urinary proteins increased progressively with worsening kidney function (p < 0.05 for all). Reduced cortisol suppression after 1-mg dexamethasone suppression (DST) (p < 0.001), a higher noon (12:00 h pm) salivary cortisol (p = 0.042), and salivary cortisol AUC (p = 0.008) were seen in CKD. 24-h urinary-free cortisol (24-h UFC) decreased in CKD stages III-IV compared with I-II (p < 0.001); higher midnight salivary cortisol (p = 0.015) and lower suppressibility after 1-mg DST were observed with declining kidney function (p < 0.001). Cortisol-after-DST cortisol was >2 mcg/dL in 23% of CKD patients (12.5% in stage III and 56.3% in stage IV); 45% of them had cortisol >2 mcg/dL after low-dose 2-day DST, all in stage IV (p < 0.001 for all). Cortisol-after-DST was lineally inversely correlated with eGFR (p < 0.001). Cortisol-after-DST (OR 14.9, 95% CI 1.7-103, p = 0.015) and glucose (OR 1.3, 95% CI 1.1-1.5, p = 0.003) were independently associated with eGFR <30 mL/min/m2). HC was independently correlated with visceral adipose tissue (VAT) (p = 0.016). Cortisol-after-DST (p = 0.032) and VAT (p < 0.001) were independently correlated with BMI. Conclusion: Cortisol-after-DST and salivary cortisol rhythm present progressive alterations in CKD patients. Changes in cortisol excretion and HPA dynamics in CKD are not accompanied by significant changes in long-term exposure to cortisol evaluated by HC. The clinical significance and pathophysiological mechanisms explaining the associations between HPA parameters, body composition, and kidney damage warrant further study.

Hair cortisol levels are associated with overweight and obesity in the ELSA-Brasil cohort.

Introduction: Hair cortisol level has recently been identified as a promising marker for detecting long-term cortisol levels and a marker of hypothalamic-pituitary-adrenal cortex (HPA) axis activity. However, research on the association between obesity and an altered cortisol metabolism remains controversial. Objective: This study aimed to investigate the relationship between hair cortisol levels and overweight and obesity in participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Methods: This was a cross-sectional study involving 2,499 participants from the second follow-up (visit 3, 2017-2019) attending research centers in Rio de Janeiro and Rio Grande do Sul states. Hair samples were collected, and cortisol levels were analyzed using enzyme-linked immunosorbent assay (ELISA) kits. Cortisol levels were classified as low (< 40 pg/mg), medium (40-128 pg/mg), or high (> 128 pg/mg). The participants were classified as eutrophic, overweight, or obese according to their weight (kg) and height (m2). Odds ratios (ORs) with 95% confidence intervals (95%CI) were estimated. Results: Of the 2499 individuals, 30% had eutrophic weight, 40% were overweight, and 30% were obese. Notably, cortisol levels gradually increased with increasing body weight. Among participants with high hair cortisol levels, 41.2% were classified as overweight and 34.2% as obese. Multinomial logistic regression analysis indicated that participants with high cortisol levels were 43% (OR =1.43; 95%CI: 1.02-2.03) more likely to be overweight and 72% (OR =1.72; 95%CI:1.20-2.47) more likely to be obese than participants with low hair cortisol levels. After adjustment for all covariates, high cortisol levels remained associated with obesity (OR = 1.54; 95%CI:1.02-2.31) and overweight (OR =1.33; 95%CI:0.91-1.94). Conclusion: In the ELSA-Brazil cohort, hair stress were positively associated with overweight and obesity. These results underscore the importance of considering stress and cortisol as potential factors in obesity prevention and intervention efforts, and highlight a novel aspect of the complex relationship between stress and obesity in the Brazilian population.

First Insight into Fetal Exposure to Legacy and Emerging Plasticizers Revealed by Infant Hair and Meconium: Occurrence, Biotransformation, and Accumulation.

Epidemiological studies have demonstrated the embryonic and developmental toxicity of plasticizers. Thus, understanding the in utero biotransformation and accumulation of plasticizers is essential to assessing their fate and potential toxicity in early life. In the present study, 311 infant hair samples and 271 paired meconium samples were collected at birth in Guangzhou, China, to characterize fetal exposure to legacy and emerging plasticizers and their metabolites. Results showed that most of the target plasticizers were detected in infant hair, with medians of 9.30, 27.6, and 0.145 ng/g for phthalate esters (PAEs), organic phosphate ester (OPEs), and alternative plasticizers (APs), and 1.44, 0.313, and 0.066 ng/g for the metabolites of PAEs, OPEs, and APs, respectively. Positive correlations between plasticizers and their corresponding primary metabolites, as well as correlations among the oxidative metabolites of bis(2-ethylhexyl) phthalate (DEHP) and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH), were observed, indicating that infant hair retained the major phase-I metabolism of the target plasticizers. While no positive correlations were found in parent compounds or their primary metabolites between paired infant hair and meconium, significant positive correlations were observed among secondary oxidative metabolites of DEHP and DINCH in hair and meconium, suggesting that the primary metabolites in meconium come from hydrolysis of plasticizers in the fetus but most of the oxidative metabolites come from maternal-fetal transmission. The parent compound/metabolite ratios in infant hair showed a decreasing trend across pregnancy, suggesting in utero accumulation and deposition of plasticizers. To the best of our knowledge, this study is the first to report in utero exposure to both parent compounds and metabolites of plasticizers by using paired infant hair and meconium as noninvasive biomonitoring matrices and provides novel insights into the fetal biotransformation and accumulation of plasticizers across pregnancy.

Evolutionary origin of Hoxc13-dependent skin appendages in amphibians.

Cornified skin appendages, such as hair and nails, are major evolutionary innovations of terrestrial vertebrates. Human hair and nails consist largely of special intermediate filament proteins, known as hair keratins, which are expressed under the control of the transcription factor Hoxc13. Here, we show that the cornified claws of Xenopus frogs contain homologs of hair keratins and the genes encoding these keratins are flanked by promoters in which binding sites of Hoxc13 are conserved. Furthermore, these keratins and Hoxc13 are co-expressed in the claw-forming epithelium of frog toe tips. Upon deletion of hoxc13, the expression of hair keratin homologs is abolished and the development of cornified claws is abrogated in X. tropicalis. These results indicate that Hoxc13-dependent expression of hair keratin homologs evolved already in stem tetrapods, presumably as a mechanism for protecting toe tips, and that this ancestral genetic program was coopted to the growth of hair in mammals.

Keratin Microspheres as Promising Tool for Targeting Follicular Growth.

Skin is the body barrier that constrains the infiltration of particles and exogenous aggression, in which the hair follicle plays an important role. Recent studies have shown that small particles can penetrate the skin barrier and reach the hair follicle, making them a potential avenue for delivering hair growth-related substances. Interestingly, keratin-based microspheres are widely used as drug delivery carriers in various fields. In this current study, we pursue the effect of newly synthesized 3D spherical keratin particles on inducing hair growth in C57BL/6 male mice and in human hair follicle dermal papilla cells. The microspheres were created from partially sulfonated, water-soluble keratin. The keratin microspheres swelled in water to form spherical gels, which were used for further experiments. Following topical application for a period of 20 days, we observed a regrowth of hair in the previously depleted area on the dorsal part of the mice in the keratin microsphere group. This observation was accompanied by the regulation of hair-growth-related pathways as well as changes in markers associated with epidermal cells, keratin, and collagen. Interestingly, microsphere keratin treatment enhanced the cell proliferation and the expression of hair growth markers in dermal papilla cells. Based on our data, we propose that 3D spherical keratin has the potential to specifically target hair follicle growth and can be employed as a carrier for promoting hair growth-related agents.

Nutraceuticals known to promote hair growth do not interfere with the inhibitory action of tamoxifen in MCF7, T47D and BT483 breast cancer cell lines.

BACKGROUND: Hair loss/thinning is a common side effect of tamoxifen in estrogen receptor (ER) positive breast cancer therapy. Some nutraceuticals known to promote hair growth are avoided during breast cancer therapy for fear of phytoestrogenic activity. However, not all botanical ingredients have similarities to estrogens, and in fact, no information exists as to the true interaction of these ingredients with tamoxifen. Therefore, this study sought to ascertain the effect of nutraceuticals (+/- estrogen/tamoxifen), on proliferation of breast cancer cells and the relative expression of ERα/ß. METHODS: Kelp, Astaxanthin, Saw Palmetto, Tocotrienols, Maca, Horsetail, Resveratrol, Curcumin and Ashwagandha were assessed on proliferation of MCF7, T47D and BT483 breast cancer cell lines +/- 17ß-estradiol and tamoxifen. Each extract was analysed by high performance liquid chromatography (HPLC) prior to use. Cellular ERα and ERß expression was assessed by qRT-PCR and western blot. Changes in the cellular localisation of ERα:ERß and their ratio following incubation with the nutraceuticals was confirmed by immunocytochemistry. RESULTS: Estradiol stimulated DNA synthesis in three different breast cancer cell lines: MCF7, T47D and BT483, which was inhibited by tamoxifen; this was mirrored by a specific ERa agonist in T47D and BT483 cells. Overall, nutraceuticals did not interfere with tamoxifen inhibition of estrogen; some even induced further inhibition when combined with tamoxifen. The ERα:ERß ratio was higher at mRNA and protein level in all cell lines. However, incubation with nutraceuticals induced a shift to higher ERß expression and a localization of ERs around the nuclear periphery. CONCLUSIONS: As ERα is the key driver of estrogen-dependent breast cancer, if nutraceuticals have a higher affinity for ERß they may offer a protective effect, particularly if they synergize and augment the actions of tamoxifen. Since ERß is the predominant ER in the hair follicle, further studies confirming whether nutraceuticals can shift the ratio towards ERß in hair follicle cells would support a role for them in hair growth. Although more research is needed to assess safety and efficacy, this promising data suggests the potential of nutraceuticals as adjuvant therapy for hair loss in breast cancer patients receiving endocrine therapy.

Xanthohumol, a prenylated flavonoid from hops (Humulus lupulus L.) exerts multidirectional pro-healing properties towards damaged zebrafish hair cells by regulating the innate immune response.

Xanthohumol (XN) is a prominent prenylated flavonoid present in the hop plant (Humulus lupulus L.). Despite undoubted pro-healing properties of hop plant, there is still a need for clinical investigations confirming these effects as well as the underlying molecular mechanisms. The present study was designed to (1) establish the role of XN in non-invasive inflammation induced by chemical damage to zebrafish hair cells, (2) clarify if it influences cell injury severity, neutrophil migration, macrophage activation, cell regeneration, and (3) find out whether it modulates the gene expression profile of chosen immune and stress response markers. All experiments were performed on 3 dpf zebrafish larvae. After fertilization the embryos were transferred to appropriate XN solutions (0.1 µM, 0.3 µM and 0.5 µM). The 40 min 10 µM CuSO4 exposure evoked severe damage to posterior lateral line hair cells triggering a robust acute inflammatory response. Four readouts were selected as the indicators of XN role in the process of inflammation: 1) hair cell death, 2) neutrophil migration towards damaged hair cells, 3) macrophage activation and recruitment to damaged hair cells, 4) hair cell regeneration. The assessments involved in vivo confocal microscopy imaging and qPCR based molecular analysis. It was demonstrated that XN (1) influences death pathway of damaged hair cells by redirecting their severe necrotic phenotype into apoptotic one, (2) impacts the immune response via regulating neutrophil migration, macrophage recruitment and activation (3) modulates gene expression of immune system markers and (4) accelerates hair cell regeneration.

A pH imbalance is linked to autophagic dysregulation of inner ear hair cells in Atp6v1ba-deficient zebrafish.

V-ATPase is an ATP hydrolysis-driven proton pump involved in the acidification of intracellular organelles and systemic acid-base homeostasis through H+ secretion in the renal collecting ducts. V-ATPase dysfunction is associated with hereditary distal renal tubular acidosis (dRTA). ATP6V1B1 encodes the B1 subunit of V-ATPase that is integral to ATP hydrolysis and subsequent H+ transport. Patients with pathogenic ATP6V1B1 mutations often exhibit an early onset of sensorineural hearing loss. However, the mechanisms underlying this association remain unclear. We employed morpholino oligonucleotide-mediated knockdown and CRISPR/Cas9 gene editing to generate Atp6v1ba-deficient (atp6v1ba-/-) zebrafish as an ortholog model for ATP6V1B1. The atp6v1ba-/- zebrafish exhibited systemic acidosis and significantly smaller otoliths compared to wild-type siblings. Moreover, deficiency in Atp6v1ba led to degeneration of inner ear hair cells, with ultrastructural changes indicative of autophagy. Our findings indicate a critical role of ATP6V1B1 in regulating lysosomal pH and autophagy in hair cells, and the results provide insights into the pathophysiology of sensorineural hearing loss in dRTA. Furthermore, this study demonstrates that the atp6v1ba-/- zebrafish model is a valuable tool for further investigation into disease mechanisms and potential therapies for acidosis-related hearing impairment.

Traditional Scraping (Gua Sha) Combined with Copper-Curcumin Nanoparticle Oleogel for Accurate and Multi-Effective Therapy of Androgenic Alopecia.

Androgenetic alopecia (AGA) is a prevalent systemic disease caused by diverse factors, for which effective treatments are currently limited. Herein, the oleogel (OG) containing copper-curcumin (CuR) nanoparticles is developed, designated as CuRG, which is also combined with traditional naturopathic scraping (Gua Sha, SCR) as a multifunctional therapy for AGA. With the assistance of lipophilic OG and SCR, CuR can efficaciously penetrate the epidermal and dermal regions where most hair follicles (HFs) reside, thereby releasing curcumin (CR) and copper ions (Cu2+) subcutaneously to facilitate hair regeneration. Concomitantly, the mechanical stimulation induced by SCR promotes the formation of new blood vessels, which is conducive to reshaping the microenvironment of HFs. This study validates that the combination of CuRG and SCR is capable of systematically interfering with different pathological processes, ranging from improvement of perifollicular microenvironment (oxidative stress and insufficient vascularization), regulation of inflammatory responses to degradation of androgen receptor, thus potentiating hair growth. Compared with minoxidil, a widely used clinical drug for AGA therapy, the designed synergistic system displays augmented hair regeneration in the AGA mouse model.

Neurotensin counteracts hair growth inhibition induced by chronic restraint stress.

Stress has been considered as a potential trigger for hair loss through the neuroendocrine-hair follicle (HF) axis. Neurotensin (NTS), a neuropeptide, is known to be dysregulated in the inflammatory-associated skin diseases. However, the precise role of NTS in stress-induced hair loss is unclear. To investigate the function and potential mechanisms of NTS in stress-induced hair growth inhibition, we initially detected the expression of neurotensin receptor (Ntsr) and NTS in the skin tissues of stressed mice by RNA-sequencing and ELISA. We found chronic restraint stress (CRS) significantly decreased the expression of both NTS and Ntsr in the skin tissues of mice. Intracutaneous injection of NTS effectively counteracted CRS-induced inhibition of hair growth in mice. Furthermore, NTS regulated a total of 1093 genes expression in human dermal papilla cells (HDPC), with 591 genes being up-regulated and 502 genes being down-regulated. GO analysis showed DNA replication, cell cycle, integral component of plasma membrane and angiogenesis-associated genes were significantly regulated by NTS. KEGG enrichment demonstrated that NTS also regulated genes related to the Hippo signalling pathway, axon guidance, cytokine-cytokine receptor interaction and Wnt signalling pathway in HDPC. Our results not only uncovered the potential effects of NTS on stress-induced hair growth inhibition but also provided an understanding of the mechanisms at the gene transcriptional level.

Disruption of TUFT1, a Desmosome-Associated Protein, Causes Skin Fragility, Woolly Hair, and Palmoplantar Keratoderma.

Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss-of-function variants in desmosomal genes leads to a variety of skin- and heart-related phenotypes. In this study, we report TUFT1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma but without a cardiac phenotype, we identified a homozygous splice-site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of TUFT1 protein. Patients' skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that TUFT1 is positioned within the desmosome and that its location is dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1-knockout mouse model mimicked the patients' phenotypes. Altogether, this study reveals TUFT1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair, and palmoplantar keratoderma.

Hair cortisol and endocannabinoid measurement in patients with adrenal incidentalomas: a case-control study.

PURPOSE: The role of endocannabinoids (ECs) in the regulation of the hypothalamic-pituitary-adrenocortical axis has already been studied; however, data are scarce in humans. The aim of our study was to analyze EC [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)] and cortisol (F) levels in hair samples of patients with adrenal incidentalomas (AIs) in comparison with those found in controls and assess their association with the hormone profile. METHODS: Forty-four patients with AIs [32 with non-functioning AIs (NFAIs) and 12 with possible autonomous secretion (PACS)] and 44 controls were recruited. Basal and post-1 mg overnight dexamethasone suppression test (ODST) F, adrenocorticotropic hormone, dehydroepiandrosterone sulfate, and 24-h urinary free cortisol were analyzed. After hair collection, EC and F levels were measured by liquid chromatography tandem-mass spectrometry. RESULTS: There was no difference between the groups regarding age, sex, and metabolic status. Significantly decreased hair AEA and 2-AG levels were found in patients with AIs compared to controls (p < 0.001 and p = 0.002, respectively) as well as between NFAI or PACS and controls (p < 0.001 or p = 0.002 and p = 0.038 or p = 0.02, respectively). Among the AI patients, EC levels tended to be lower in the PACS group. AEA hair levels were negatively correlated with F levels post-1 mg ODST (rs = -0.257, p = 0.033). We found no significant difference comparing hair F between the groups. CONCLUSION: Our findings suggest that hair EC measurement could be a potential biomarker in the evaluation of patients with AIs, whereas hair F analysis is not a useful diagnostic test for mild hypercortisolemia.