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Research articles about the effects of rumen-protected choline (RPC) supplementation on metabolic response, and reproductive and productive performances in transitional dairy cows were reviewed and presented. Analysis was conducted on 32 research papers that were published. The papers examined treatments without RPC supplementation and RPC supplementation levels varying from 10 to 100 gm/day. The feeding duration of RPC started from 40 to 140 days prepartum and continued until 20 to 140 days postpartum in multiparous dairy cows. Studies indicated that adding herbal choline (Cho) to the diet of transition dairy cows resulted in increased milk production and improved milk quality, leading to enhanced energy balance and reduced oxidative stress. The concentration and yield of IgG in colostrum provide passive immunity to dairy newborns and can be enhanced by dietary Cho supplementation. The inconsistent effects of RPC supplementation on reproduction may be due to several factors such as heat stress, genetics, and management. RPC supplementation improved the transition dairy cows' milk yield and quality, but dosage response was not observed as in the prior publication. Remarkably, the length of RPC supplementation had a positive correlation with an increase in milk yield. Based on this review, 45-50 gm/day dietary RPC supplementation between 3 weeks pre-calving to 8 weeks post-calving is suggested to increase at least 10% milk yield in dairy cows., Competing Interests: The authors declare that they have no conflicts of interest., (© The authors.)

This review explores the complex relationship between social determinants of health and the biology of chronic wounds associated with diabetes mellitus, with an emphasis on racial/ethnic disparities. Chronic wounds pose significant healthcare challenges, often leading to severe complications for millions of people in the United States, and disproportionally affect African American, Hispanic, and Native American individuals. Social determinants of health, including economic stability, access to healthcare, education, and environmental conditions, likely influence stress, weathering, and nutrition, collectively shaping vulnerability to chronic diseases, such as obesity and DM, and an elevated risk of chronic wounds and subsequent lower extremity amputations. Here, we review these issues and discuss the urgent need for further research focusing on understanding the mechanisms underlying racial/ethnic disparities in chronic wounds, particularly social deprivation, weathering, and nutrition, to inform interventions to address these disparities., (© 2024 The Author(s). Wound Repair and Regeneration published by Wiley Periodicals LLC on behalf of The Wound Healing Society.)

Monocytes and macrophages (Mos/Mϕs) play diverse roles in wound healing by adopting a spectrum of functional phenotypes; however, the regulation of such heterogeneity remains poorly defined. We enhanced our previously published Bayesian inference TF activity model, incorporating both single-cell RNA sequencing and single-cell ATAC sequencing data to infer transcription factor (TF) activity in Mos/Mϕs during skin wound healing. We found that wound Mos/Mϕs clustered into early-stage Mos/Mϕs, late-stage Mϕs, and APCs, and that each cluster showed differential chromatin accessibility and differential predicted TF activity that did not always correlate with mRNA or protein expression. Network analysis revealed two highly connected large communities involving a total of 19 TFs, highlighting TF cooperation in regulating wound Mos/Mϕs. This analysis also revealed a small community populated by NR4A1 and NFKB1, supporting a proinflammatory link between these TFs. Importantly, we validated a proinflammatory role for NR4A1 activity during wound healing, showing that Nr4a1 knockout mice exhibit decreased inflammatory gene expression in early-stage wound Mos/Mϕs, along with delayed wound re-epithelialization and impaired granulation tissue formation. In summary, our study provides insight into TF activity that regulates Mo/Mϕ heterogeneity during wound healing and provides a rational basis for targeting Mo/Mϕ TF networks to alter phenotypes and improve healing., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Background: (1)Sarcopenia, or low skeletal mass index (SMI), contributes to higher lung cancer mortality. The SMI at third lumbar vertebrae (L3) is the reference standard for body composition analysis. However, there is a need to explore the validity of alternative landmarks in this population. We compared the agreement of sarcopenia identification at the first lumbar (L1) and second lumbar (L2) to L3 in non-Hispanic Black (NHB) and White (NHW) individuals with lung cancer., Methods: (2)This retrospective, cross-sectional study included 214 NHB and NHW adults with lung cancer. CT scans were analyzed to calculate the SMI at L1, L2, and L3. T-tests, chi-square, Pearson's correlation, Cohen's kappa, sensitivity, and specificity analysis were used., Results: (3)Subjects presented with a mean age of 68.4 ± 9.9 years and BMI of 26.3 ± 6.0 kg/m 2 . Sarcopenia prevalence varied from 19.6% at L1 to 39.7% at L3. Cohen's kappa coefficient was 0.46 for L1 and 0.64 for L2, indicating weak and moderate agreement for the identification of sarcopenia compared to L3., Conclusions: (4)Sarcopenia prevalence varied greatly depending on the vertebral landmark used for assessment. Using L2 or L1 alone resulted in a 16.8% and 23.8% misclassification of sarcopenia in this cohort of individuals with lung cancer., Competing Interests: Conflicts of Interest: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Obesity is associated with low-grade chronic inflammation and impaired glucose metabolism, both of which are detrimental to wound healing. C-C motif chemokine receptor 2 (CCR2) plays an important role in cell recruitment during healing, and our recent studies revealed the significance of CCR2-CCL2 signaling in promoting the proliferation of pro-inflammatory monocytes/macrophages in wounds. Therefore, we sought to determine whether diet-induced obesity increases monocyte/macrophage proliferation and their accumulation in skin wounds. We first confirmed that wound closure was delayed in obese CCR2 RFP/+ mice fed with a high-fat diet (HFD) compared to mice fed with a normal diet (ND). Using in vivo imaging and flow cytometry analysis, we found that HFD mice had significantly increased accumulation of CCR2+ monocytes/macrophages, particularly pro-inflammatory CCR2+Ly6C+ cells in wounds compared to their ND counterparts. Importantly, HFD mice exhibited an increased proliferation of wound CCR2+Ly6C+ compared to ND mice. Together, our data suggest that obesity leads to an increased proliferation and accumulation of pro-inflammatory CCR2+Ly6C+ monocytes/macrophages in skin wounds, which may contribute to delayed healing.

Monocytes (Mo) and macrophages (Mφ) play important roles in the function of tissues, organs, and systems of all animals during homeostasis, infection, injury, and disease. For decades, conventional wisdom has dictated that Mo and Mφ are end-stage cells that do not proliferate and that Mφ accumulation in tissues is the result of infiltration of Mo from the blood and subsequent differentiation to Mφ. However, reports from the early 1900s to the present describe evidence of Mo and Mφ proliferation in different tissues and contexts. The purpose of this review is to summarize both historical and current evidence for the contribution of Mφ proliferation to their accumulation in different tissues during homeostasis, infection, injury, and disease. Mφ proliferate in different organs and tissues, including skin, peritoneum, lung, heart, aorta, kidney, liver, pancreas, brain, spinal cord, eye, adipose tissue, and uterus, and in different species including mouse, rat, rabbit, and human. Mφ can proliferate at different stages of differentiation with infiltrating Mo-like cells proliferating in certain inflammatory contexts (e.g. skin wounding, kidney injury, bladder and liver infection) and mature resident Mφ proliferating in other inflammatory contexts (e.g. nematode infection, acetaminophen liver injury) and during homeostasis. The pathways involved in stimulating Mφ proliferation also may be context dependent, with different cytokines and transcription factors implicated in different studies. Although Mφ are known to proliferate in health, injury, and disease, much remains to be learned about the regulation of Mφ proliferation in different contexts and its impact on the homeostasis, injury, and repair of different organs and tissues., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Significance: Chronic skin wounds are a significant health problem around the world, often leading to amputation and even death. Although persistent inflammation is a hallmark of these poorly healing wounds, few available therapies have been designed to target inflammation. In this review, we summarize available evidence of the role of the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome in impaired wound healing and describe strategies to inhibit the inflammasome to improve wound healing. Recent Advances: The NLRP3 inflammasome plays an important physiological role in skin wound healing, during which transient inflammasome activity contributes to both epidermal and dermal healing. In contrast, sustained activity of the NLRP3 inflammasome leads to impaired epidermal and dermal healing associated with diabetes. Of importance, preclinical studies have demonstrated that inhibiting the NLRP3 inflammasome-induced resolution of inflammation, increased granulation tissue formation and collagen deposition, and accelerated reepithelialization and wound closure. Critical Issues: NLRP3 inflammasome inhibitors have appealing potential for translation into therapies for chronic wounds. Although preclinical studies have shown promising results, there is a need for human/clinical studies to evaluate dosing formulations, potential therapeutic effects, dose-response relationships, and possible side effects. Future Directions: Among strategies to inhibit the NLRP3 inflammasome, glyburide, metformin, peroxisome proliferator-activated receptor agonists, and the dipeptidyl peptidase 4 inhibitor saxagliptin appear to be closest to clinical translation, as these drugs are already Food and Drug Administration approved for other indications. Future clinical studies are needed to develop topical formulations of these drugs, and to assess the safety and efficacy of these inhibitors, to improve healing of chronic wounds.

Many factors regulate scar formation, which yields a modified extracellular matrix (ECM). Among ECM components, microfibril-associated proteins have been minimally explored in the context of skin wound repair. Microfibril-associated protein 5 (MFAP5), a small 25 kD serine and threonine rich microfibril-associated protein, influences microfibril function and modulates major extracellular signaling pathways. Though known to be associated with fibrosis and angiogenesis in certain pathologies, MFAP5's role in wound healing is unknown. Using a murine model of skin wound repair, we found that MFAP5 is significantly expressed during the proliferative and remodeling phases of healing. Analysis of existing single-cell RNA-sequencing data from mouse skin wounds identified two fibroblast subpopulations as the main expressors of MFAP5 during wound healing. Furthermore, neutralization of MFAP5 in healing mouse wounds decreased collagen deposition and refined angiogenesis without altering wound closure. In vitro, recombinant MFAP5 significantly enhanced dermal fibroblast migration, collagen contractility, and expression of pro-fibrotic genes. Additionally, TGF-ß1 increased MFAP5 expression and production in dermal fibroblasts. Our findings suggest that MFAP5 regulates fibroblast function and influences scar formation in healing wounds. Our work demonstrates a previously undescribed role for MFAP5 and suggests that microfibril-associated proteins may be significant modulators of wound healing outcomes and scarring., (© 2023. The Author(s).)

Chronic wounds in diabetic patients are associated with significant morbidity and mortality; however, few therapies are available to improve healing of diabetic wounds. Our group previously reported that low-intensity vibration (LIV) could improve angiogenesis and wound healing in diabetic mice. The purpose of this study was to begin to elucidate the mechanisms underlying LIV-enhanced healing. We first demonstrate that LIV-enhanced wound healing in db/db mice is associated with increased IGF1 protein levels in liver, blood, and wounds. The increase in insulin-like growth factor (IGF) 1 protein in wounds is associated with increased Igf1 mRNA expression both in liver and wounds, but the increase in protein levels preceded the increase in mRNA expression in wounds. Since our previous study demonstrated that liver was a primary source of IGF1 in skin wounds, we used inducible ablation of IGF1 in the liver of high-fat diet (HFD)-fed mice to determine whether liver IGF1 mediated the effects of LIV on wound healing. We demonstrate that knockdown of IGF1 in liver blunts LIV-induced improvements in wound healing in HFD-fed mice, particularly increased angiogenesis and granulation tissue formation, and inhibits the resolution of inflammation. This and our previous studies indicate that LIV may promote skin wound healing at least in part via crosstalk between the liver and wound. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

NK cells are best known for their killing of virus-infected cells and tumor cells via release of cytotoxic factors. However, NK cells can also produce growth factors and cytokines, and thus have the potential to influence physiological processes such as wound healing. In this study, we test the hypothesis that NK cells play a physiological role in skin wound healing of C57BL/6J mice. Immunohistochemical and flow cytometry assays showed that NK cells accumulate in excisional skin wounds, peaking on day 5 postinjury. We also found that NK cells proliferate locally in wounds, and blocking IL-15 activity locally reduces NK cell proliferation and accumulation in wounds. Wound NK cells exhibit primarily a mature CD11b+CD27- and NKG2A+NKG2D- phenotype and express LY49I and proinflammatory cytokines such as IFN-γ, Tnf-a, and Il-1β. Systemic depletion of NK cells resulted in enhanced re-epithelization and collagen deposition, suggesting a negative role for these cells in skin wound healing. Depletion of NK cells did not influence accumulation of neutrophils or monocytes/macrophages in wounds but did reduce expression of IFN-γ, Tnf-a, and Il-1β, indicating that NK cells contribute to proinflammatory cytokine expression in wounds. In short, NK cells may impede physiological wound healing via production of proinflammatory cytokines., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Introduction: Chronic, non-healing skin wounds such as diabetic foot ulcers (DFUs) are common in patients with type 2 diabetes mellitus (T2DM) and often result in limb amputation and even death. However, mechanisms by which T2DM and inflammation negatively impact skin wound healing remains poorly understood. Here we investigate a mechanism by which an excessive level of chemokine CCL28, through its receptor CCR10, impairs wound healing in patients and mice with T2DM. Methods & Results: Firstly, a higher level of CCL28 was observed in skin and plasma in both patients with T2DM, and in obesity-induced type 2 diabetic db/db mice. Compared with WT mice, adipose tissue from db/db mice released 50% more CCL28, as well as 2- to 3-fold more IL-1β, IL-6, and TNF-α, and less VEGF, as determined by ELISA measurements. Secondly, overexpression of CCL28 with adenovirus (Adv-CCL28) caused elevation of proinflammatory cytokines as well as CCR10 expression and also reduced eNOS expression in the dorsal skin of WT mice as compared with control Adv. Thirdly, topical application of neutralizing anti-CCL28 Ab dose-dependently accelerated wound closure and eNOS expression, and decreased IL-6 level, with an optimal dose of 1 μg/wound. In addition, mRNA levels of eNOS and anti-inflammatory cytokine IL-4 were increased as shown by real-time RT-PCR. The interaction between eNOS and CCR10 was significantly reduced in diabetic mouse wounds following application of the optimal dose of anti-CCL28 Ab, and eNOS expression increased. Finally, enhanced VEGF production and increased subdermal vessel density as indicated by CD31 immunostaining were also observed with anti-CCL28 Ab. Discussion: Taken together, topical application of neutralizing anti-CCL28 Ab improved dorsal skin wound healing by reducing CCR10 activation and inflammation in part by preventing eNOS downregulation, increasing VEGF production, and restoring angiogenesis. These results indicate anti-CCL28 Ab has significant potential as a therapeutic strategy for treatment of chronic non-healing diabetic skin wounds such as DFUs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Haus, DiPietro, Koh and Minshall.)

Background: Lung cancer incidence and mortality rates are higher in Non-Hispanic Black (NHB) compared to Non-Hispanic White (NHW) individuals in the Chicago metropolitan area, which may be related to exposure to chronic stress which may increase inflammation., Specific Aim: We investigated disparities in inflammation as measured by neutrophil to lymphocyte ratio (NLR) in individuals with lung cancer by race and by neighborhood concentrated disadvantage index (CDI)., Methods: This retrospective, cross-sectional study included 263 NHB and NHW adults with lung cancer. We analyzed NLR as a continuous and categorical variable to determine degree and prevalence of inflammation. We used Mann Whitney U, t-tests, Chi square tests, linear and logistic regression models as appropriate., Results: More than 60% of subjects had inflammation (NLR ≥ 3) at lung cancer diagnosis. The degree of inflammation was significantly lower in NHB (NLR 5.50 +/- 7.45) compared to NHW individuals (NLR 6.53 +/- 6.53; p=0.01) but did not differ by neighborhood CDI. The prevalence of inflammation (NLR ≥ 3) was significantly lower in NHB (55.07%) compared to NHW individuals (71.20%; p<0.01) and in those from the most disadvantaged (54.07%) compared to the least disadvantaged (71.88%; p<0.01) neighborhoods., Conclusion: At lung cancer diagnosis, there is a lower degree and prevalence of inflammation in NHB compared to NHW individuals, and lower prevalence in those residing in the most disadvantaged neighborhoods. Further research is needed to determine mechanisms of inflammation that may be contributing to lung cancer disparities as well as whether NLR is an appropriate biomarker when examining racial differences in inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Byrne, Gomez, Kim, Oddo, Koh and Fantuzzi.)

People with spinal cord injury (SCI) are at high risk of developing a pressure injury. It is unclear why some people with SCI develop pressure injury while others with similar predisposing risk factors do not during acute hospitalisation. This may hinder healthcare utilisation to prevent pressure injuries. The purpose of the study was to examine the proof-of-concept objective bedside skin blood flow measurements before a pressure injury develops in spinal cord injured patients during acute hospitalisation. This was an observational study. All participants had acute traumatic SCI and were pressure injury-free upon enrollment. Skin blood flow patterns were collected at both heels under two circumstances: localised pressure for reactive hyperemia, and localised heating for heat hyperemia. Our results showed that reactive and heat hyperemia were successfully induced in all eleven participants. Two participants developed pressure injury and nine did not have pressure injury at discharge. Heat hyperemia was smaller in participants with pressure injury. No difference was observed in reactive hyperemia between the groups. In conclusion, skin blood flow measurements could be obtained at bedside during acute hospitalisation of SCI for the purpose of research. Further examination of a larger group is warranted to determine clinical use of heat hyperemia pattern as predictor for pressure injury development., (© 2022 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

Monocytes (Mos)/macrophages (Mϕs) orchestrate biological processes critical for efficient skin wound healing. However, current understanding of skin wound Mo/Mϕ heterogeneity is limited by traditional experimental approaches such as flow cytometry and immunohistochemistry. Therefore, we sought to more fully explore Mo/Mϕ heterogeneity and associated state transitions during the course of excisional skin wound healing in mice using single-cell RNA sequencing. The live CD45+CD11b+Ly6G- cells were isolated from skin wounds of C57BL/6 mice on days 3, 6, and 10 postinjury and captured using the 10x Genomics Chromium platform. A total of 2813 high-quality cells were embedded into a uniform manifold approximation and projection space, and eight clusters of distinctive cell populations were identified. Cluster dissimilarity and differentially expressed gene analysis categorized those clusters into three groups: early-stage/proinflammatory, late-stage/prohealing, and Ag-presenting phenotypes. Signature gene and Gene Ontology analysis of each cluster provided clues about the different functions of the Mo/Mϕ subsets, including inflammation, chemotaxis, biosynthesis, angiogenesis, proliferation, and cell death. Quantitative PCR assays validated characteristics of early- versus late-stage Mos/Mϕs inferred from our single-cell RNA sequencing dataset. Additionally, cell trajectory analysis by pseudotime and RNA velocity and adoptive transfer experiments indicated state transitions between early- and late-state Mos/Mϕs as healing progressed. Finally, we show that the chemokine Ccl7, which was a signature gene for early-stage Mos/Mϕs, preferentially induced the accumulation of proinflammatory Ly6C+F4/80lo/- Mos/Mϕs in mouse skin wounds. In summary, our data demonstrate the complexity of Mo/Mϕ phenotypes, their dynamic behavior, and diverse functions during normal skin wound healing., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Chronic, nonhealing skin wounds, such as diabetic foot ulcers (DFUs), are common in patients with type 2 diabetes. Here, we investigated the role of chemokine (C-C motif) ligand 28 (CCL28) and its receptor C-C chemokine receptor type 10 (CCR10) in downregulation of endothelial nitric (NO) oxide synthase (eNOS) in association with delayed skin wound healing in the db/db mouse model of type 2 diabetes. We observed reduced eNOS expression and elevated CCL28/CCR10 levels in dorsal skin of db/db mice and subdermal leg biopsy specimens from human subjects with type 2 diabetes. Further interrogation revealed that overexpression of CCR10 reduced eNOS expression, NO bioavailability, and tube formation of human dermal microvascular endothelial cells (HDMVECs) in vitro, which was recapitulated in mouse dorsal skin. In addition, incubation of HDMVECs with CCL28 led to internalization of the CCR10/eNOS complex and colocalization with lysosome-associated membrane protein 1. Finally, topical application of myristoylated CCR10 binding domain 7 amino acid (Myr-CBD7) peptide prevented CCR10-eNOS interaction and subsequent eNOS downregulation, enhanced eNOS/NO levels, eNOS/VEGF-R2+ microvessel density, and blood perfusion, reduced inflammatory cytokine levels, and importantly, decreased wound healing time in db/db mice. Thus, endothelial cell CCR10 activation in genetically obese mice with type 2 diabetes promotes eNOS depletion and endothelial dysfunction, and targeted disruption of CCR10/eNOS interaction improves wound healing., (© 2022 by the American Diabetes Association.)