Metabolism-related biomarkers, molecular classification, and immune infiltration in diabetic ulcers with validation

Xiao-Xuan Ma1,2| Ying Zhang1,2 | Jing-Si Jiang3 | Yi Ru1,2 | Ying Luo1,2 |Yue Luo3| Xiao-Ya Fei 3 | Jian-Kun Song3 | Xin Ma1,2,3 | Bin Li 2,3 |Yi-Mei Tan3| Le Kuai 1,2

1 Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

2 Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, shanghai, China

3 Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China

Correspondence

Yi-Mei Tan, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China.

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Le Kuai, Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.

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Funding information

National Natural Science Foundation of China, Grant/Award Numbers: 81973860, 82174383, 82204954, 82004235; National Key Research and Development Program of China, Grant/Award Number: 2018YFC1705305; Shanghai Clinical Key Specialty Construction Project, Grant/Award Number: shslczdzk05001; Shanghai Development Office of TCM, Grant/Award Numbers: ZY(2018-2020)-FWTX-1008, ZY(2021-2023)-0302; Shanghai Science and Technology Committee, Grant/Award Numbers: 21Y21920101, 21Y21920102; Youth Talent Promotion Project of China Association of Traditional Chinese Medicine (2021-2023) Category A, Grant/Award Number: CACM-2021-QNRC2-A10; Health Young Talents of Shanghai Municipal Health Commission, Grant/Award Number: 2022YQ026; Xinglin Youth Scholar of Shanghai University of Traditional Chinese Medicine, Grant/Award Number: RY411.33.10; Shanghai Sailing Program, Grant/Award Numbers: 21YF1448100, 22YF1450000, 22YF1441300, 23YF1439800;  Clinical transformation incubation program in hospital, Grant/Award Number: lczh2021-05; “Chen Guang” project supported byShanghai Municipal Education Commission and Shanghai Education Development Foundation, Grant/Award

Number: 22CGA50

Abbreviations: BP, biological pathways; CC, cellular components; CFB, complement factor B; DU, diabetic ulcer; DM, diabetes mellitus; DE, differentially expressed; DFUs, diabetic foot ulcers; EMT, epithelial-mesenchymal transformation; FDR, false discovery rate; GALNT6, polypeptide Nacetylgalactosaminyltransferase 6; GEO, gene expression omnibus; GLDC, glycine decarboxylase; GO, gene ontology; GTP, guanosine triphosphate; KEGG, Kyoto encyclopedia of genes and genomes; KLK6, Kallikrein-related peptidase 6; LC–MS/MS, liquid chromatography–tandem mass spectrometry; LYN, LYN proto-oncogene, Src family tyrosine kinase; MF, molecular function; MMP, member of the metalloproteinase; MMP12, matrix metallopeptidase 12; MRGs, metabolomic-regulated genes; NC, negative control; PCA, principal component analysis; qRT-PCR, quantitative real-time polymerase chain reaction; RHOH, Ras homologue family member H; ROC, receiver operating characteristic; SD, standard deviation; SPF, specific pathogen free; STZ, streptozotocin; TGF-β, the transforming growth factor beta; TH1, type 1 helper; XDH, Xanthine dehydrogenase. Xiao-Xuan Ma, Ying Zhang and Jing-Si Jiang are contributed equally to this study.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

© 2023 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Abstract

Diabetes mellitus (DM) can lead to diabetic ulcers (DUs), which are the most severe complications. Due to the need for more accurate patient classifications and diagnostic models, treatment and management strategies for DU patients still need improvement. The difficulty of diabetic wound healing is caused closely related to biological metabolism and immune chemotaxis reaction dysfunction. Therefore, the purpose of our study is to identify metabolic biomarkers in patients with DU and construct a molecular subtype-specific prognostic model that is highly accurate and robust. RNA-sequencing data for DU samples were obtained from the Gene Expression Omnibus (GEO) database. DU patients and normal individuals were compared regarding the expression of metabolism-related genes (MRGs). Then, a novel diagnostic model based on MRGs was constructed with the random forest algorithm, and classification performance was evaluated utilizing receiver operating characteristic (ROC) analysis. The biological functions of MRGs-based subtypes were investigated using consensus clustering analysis. A principal component analysis (PCA) was conducted to determine whether MRGs could distinguish between subtypes. We also examined the correlation between MRGs and immune infiltration. Lastly, qRT-PCR was utilized to validate the expression of the hub MRGs with clinical validations and animal experimentations. Firstly, 8 metabolism-related hub genes were obtained by random forest algorithm, which could distinguish the DUs from normal samples validated by the ROC curves. Secondly, DU samples could be consensus clustered into three molecular classifications by MRGs, verified by PCA analysis. Thirdly, associations between MRGs and immune infiltration were confirmed, with LYN and Type 1 helper cell significantly positively correlated; RHOH and TGF-β family remarkably negatively correlated. Finally, clinical validations and animal experiments of DU skin tissue samples showed that the expressions of metabolic hub genes in the DU groups were considerably upregulated, including GLDC, GALNT6, RHOH, XDH, MMP12, KLK6, LYN, and CFB. The current study proposed an auxiliary MRGs-based DUs model while proposing MRGs-based molecular clustering and confirmed the association with immune infiltration, facilitating the diagnosis and management of DU patients and designing individualized treatment plans.

KEYWORDS

diabetic ulcers, immune infiltration, machine learning, metabolic, random forest algorithm

Key Messages

• the current study systematically investigated the interactions between MRGs and immune responses

• the study explored the role of MRGs in DUs through random forest models and experimental validation

• eight MRGs obtained in the random forest were verified in clinical validations and animal experiments, and inhibiting these targets could be targeted to promote DUs healing

• it is worthwhile to classify three diabetic ulcer subtypes based on MRGs, encouraging the implementation of precise diagnostic and treatment strategies

• the study provides a reference for delving into the function and significance of MRGs in other sicknesses

TGF-β Signaling in Cellular Senescence and Aging-Related Pathology

The Facial Aging Process From the “Inside Out”

Arthur Swift, MD; Steven Liew, MD; Susan Weinkle, MD; Julie K. Garcia, PhD; and Michael B. Silberberg, MD, MBA

Dr Swift is director at the Westmount Institute of Plastic Surgery in Montréal, QC, Canada. Dr Liew is a specialist plastic surgeon and medical director at the Shape Clinic in Darlinghurst, NSW, Australia. Dr Weinkle is an affiliate clinical professor of Dermatology at the University of South Florida, Tampa, FL, USA. Dr Garcia is manager of Health Economics Outcomes Research at Allergan plc, an AbbVie Company, Irvine, CA, USA. Dr Silberberg is executive medical director at Allergan Ltd, an AbbVie Company, Parkway, Marlow Buckinghamshire, United Kingdom.

Aesthetic Surgery Journal

2021, Vol 41(10) 1107–1119

© 2020 The Aesthetic Society.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, providedthe original work is properly cited. For commercial re-use, please contact 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。

DOI: 10.1093/asj/sjaa339

www.aestheticsurgeryjournal.com

Corresponding Author:

Dr Arthur Swift, Westmount Institute of Plastic Surgery, 4141 Sherbrooke Street West, Suite 420, Montreal, Canada H3Z 1B7.

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近十年面部年轻化治疗进展

冉维志，高崧瀛

黑龙江省医院整形颌面外科（哈尔滨  150030）

冉维志：主任医师，二级教授岗位，黑龙江省医院整形颌面外科前主任。黑龙江省整形外科领军人才梯队学科带头人，曾在日本新泻大学研修。任中国康复医学会修复重建外科专业委员会常委、美容学组组长，黑龙江省康复医学会修复重建外科学会主任委员，任《中华整形外科杂志》等编委。近年来完成课题近 10 项，并获奖。发表国家级论文 30 余篇。专业方向：面部年轻化。

【摘要】   面部老化由皮肤、其深方软组织（包括脂肪、肌肉、筋膜韧带等）及骨骼等因素导致。在皮肤方面主要表现为皱纹加深，皮肤干燥、粗糙、颜色加深等；深方软组织表现为容积丢失和重力所致松垂；骨骼方面主要表现为骨质的选择性吸收。目前，对抗不同原因所致的面部老化，应采取针对原因的综合治疗方法，如手术、埋线提升（线雕）、自体脂肪移植、透明质酸、肉毒素注射及光-电技术等。

【关键词】 面部老化；面部年轻化；治疗进展

Advances in treatment of facial rejuvenation in the past ten years

RAN Weizhi, GAO Songying

Department of Plastic Surgery, Heilongjiang Provincial Hospital, Harbin Heilongjiang, 150030, P.R.China Corresponding author: RAN Weizhi, Email: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。

【Abstract】 Facial aging is caused by several aspects involving skin, its deep soft tissue (fat, muscles, fascia ligaments, etc), and bones. The skin presents deepen wrinkles, darker, drying, and roughness. Volume loss and sag caused by gravity can be seen in deep soft tissue. And selective absorption can be seen in bones. At present, to combat facial aging caused by different causes, we have adopted comprehensive treatment methods such as facial rhytidectomy, embedded wire ascension, autogenous fat graft, hyaluronic acid or botulinum toxin injection, and optoelectronic techniques, etc.

【Key words】 Facial aging; facial rejuvenation; treatment progress

Methods for the Improvement of Acne Scars Used in Dermatology and Cosmetology: A Review

Karolina Chilicka 1,* , Monika Rusztowicz 1 , Renata Szyguła 1 and Danuta Nowicka 2 ID

1 Department of Health Sciences, Institute of Health Sciences, University of Opole, 45-040 Opole, Poland; 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (M.R.); 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (R.S.)

2 Department of Dermatology, Venereology and Allergology, Wrocław Medical University, 50-368 Wrocław, Poland; 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 * Correspondence: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。; Tel.: +48-665-43-94-43

Abstract: Acne vulgaris is a chronic skin disease that, depending on its course, is characterized by the occurrence of various skin eruptions such as open and closed comedones, pustules, papules, and cysts. Incorrectly selected treatment or the presence of severe acne vulgaris can lead to the formation of atrophic scars. In this review, we summarize current knowledge on acne scars and methods for their improvement. There are three types of atrophic scars: icepick, rolling, and boxcar. They are of different depths and widths and have different cross-sections. Scars can combine to form clusters. If acne scars are located on the face, they can reduce the patient’s quality of life, leading to isolation and depression. There are multiple effective modalities to treat acne scars. Ablative lasers, radiofrequency, micro-needling, and pilings with trichloroacetic acid have very good treatment results. Contemporary dermatology and cosmetology use treatments that cause minimal side effects, so the patient can return to daily functioning shortly after treatment. Proper dermatological treatment and skincare, as well as the rapid implementation of cosmetological treatments, will certainly achieve satisfactory results in reducing atrophic scars.

Keywords: acne vulgaris; atrophic scars; dermatology; scar improvement

Citation: Chilicka, K.; Rusztowicz, M.; Szyguła, R.; Nowicka, D. Methods for the Improvement of Acne Scars Used in Dermatology and Cosmetology: A Review. J. Clin. Med. 2022, 11, 2744. https://doi.org/ 10.3390/jcm11102744

Academic Editors: Hei Sung Kim and Stamatis Gregoriou

Received: 19 April 2022

Accepted: 11 May 2022

Published: 12 May 2022

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Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Diverse Roles of Cellular Senescence in Skeletal Muscle Inflammation, Regeneration, and Therapeutics

Yuki Saito1† and Takako S. Chikenji 1,2 * †1

Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo, Japan, 2 Department of Health Sciences, School of Medicine, Hokkaido University, Sapporo, Japan

Skeletal muscle undergoes vigorous tissue remodeling after injury. However, aging, chronic inflammatory diseases, sarcopenia, and neuromuscular disorders cause muscle loss and degeneration, resulting in muscular dysfunction. Cellular senescence, a state of irreversible cell cycle arrest, acts during normal embryonic development and remodeling after tissue damage; when these processes are complete, the senescent cells are eliminated. However, the accumulation of senescent cells is a hallmark of aging tissues or pathological contexts and may lead to progressive tissue degeneration. The mechanisms responsible for the effects of senescent cells have not been fully elucidated. Here, we review current knowledge about the beneficial and detrimental effects of senescent cells in tissue repair, regeneration, aging, and age-related disease, especially in skeletal muscle. We also discuss how senescence of muscle stem cells and muscle-resident fibro-adipogenic progenitors affects muscle pathologies or regeneration, and consider the possibility that immunosenescence leads to muscle pathogenesis. Finally, we explore senotherapy, the therapeutic targeting of senescence to treat agerelated disease, from the standpoint of improving muscle regeneration.

Keywords: senescence, skeletal muscle, chronic inflammation, aging, muscle regeneration, muscle stem cells, FAPs, fibrosis

Edited by:

Barbara St. Pierre Schneider, University of Nevada, Las Vegas, United States

Reviewed by: Keitaro Yamanouchi, The University of Tokyo, Japan Antoneta Granic, Newcastle University, United Kingdom

*Correspondence: Takako S. Chikenji 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。†

ORCID: Yuki Saito orcid.org/0000-0002-7949-1628 Takako S. Chikenji orcid.org/0000-0003-2832-3656

Specialty section: This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology

Received: 11 July 2021

Accepted: 23 August 2021

Published: 06 September 2021

Citation: Saito Y and Chikenji TS (2021) Diverse Roles of Cellular Senescence in Skeletal Muscle Inflammation, Regeneration, and Therapeutics. Front. Pharmacol. 12:739510.

doi: 10.3389/fphar.2021.739510