Delayed Ulcer Healing Research Articles

Effect of Quercetin With Oral Hypoglycemics in Streptozotocin‐Induced Diabetes, and Its Effect on Ulcerogenic Activity

AbstractA diabetic‐induced ulcer is a complication of diabetes in which the formation of an ulcer increases and also causes a delay in ulcer healing. Diabetes adds a bonus to various factors like starvation and stress, imbalanced acid‐pepsin secretions, impaired mucosal resistance, acid‐back diffusion, and neuronal dysfunction. Feeding a high‐fat diet for 15 days after induction of STZ in rats develops diabetes mellitus simultaneously with growth, resulting in an acceleration of ulcers for any of the above reasons. The OGTT investigation included both normal and diabetic rats, and the researchers establish a consistently low dosage of conventional oral hypoglycemic agents for the treatment. Clinical studies in the literature highlight that effectively treating patients with diabetes complications has been demonstrated through glycemic control. Hence, effective palliative hypoglycemic agents are employed. Long‐term usage has revealed that they exert a drastic negative effect. Hence, herbal drug combinations with these standard drugs have proved to be effective in minimizing the side effects. QE, which has hypoglycemic, dyslipidemia, and antioxidant properties, has been effective when administered with Glipizide (5 mg kg−1). The monotherapy of this Glipizide and QE has not shown a beneficial effect in protecting the stomach from ulcers. The combination (G + QE) showed effective control of glucose without any hypoglycemia. QE as a single adjunct with Glipizide has proven promising in preventing and treating diabetic ulcers.

Impact of great saphenous vein ablation on healing and recurrence of venous leg ulcers in patients with post-thrombotic syndrome: A retrospective comparative study

BackgroundThe optimal treatment approach for patients with active venous leg ulcers (VLUs) and post-thrombotic syndrome (PTS) associated with great saphenous vein (GSV) reflux remains unclear. To address this gap, we retrospectively compared the outcomes of patients with post-thrombotic VLU with an intact GSV vs those with a stripped or ablated GSV. MethodsWe retrospectively analyzed data from 48 patients with active VLUs and documented PTS, who were treated at a single center between January 2018 and December 2022. Clinical information, including ulcer photographs, was recorded in a prospectively maintained digital database at the initial and follow-up visits. Two patient groups—group A (with an intact GSV) and group B (with a stripped or ablated GSV)—were compared in terms of time to complete healing, proportion of ulcers achieving complete healing, and ulcer recurrence during the follow-up period. ResultsThere were no significant differences in age, gender, initial ulcer size, or ulcer duration between the two groups. All included patients had femoropopliteal post-thrombotic changes. Group A had significantly more completely healed ulcers (33 of 34 ulcers, 97%) compared with group B (10 of 14 ulcers, 71%) (P = .008). Group A also exhibited a significantly shorter time to complete ulcer healing (median: 42.5 days, interquartile range [IQR]: 65) compared with group B (median: 161 days, IQR: 530.5) (P = .0177), with a greater probability of ulcer healing (P = .0084). Long-term follow-up data were available for 45 of 48 patients (93.7%), with a mean duration of 39.6 months (range: 5.7-67.4 months). The proportion of ulcers that failed to heal or recurred during the follow-up period was significantly lower in group A (9 of 32 ulcers, 27%) compared with group B (11 of 13 ulcers, 85%) (P = .0009). In addition, in a subgroup analysis, patients with an intact but refluxing GSV (12 of 34) had a significantly shorter time to heal (median: 34 days, IQR: 57.25) (P = .0242), with a greater probability of ulcer healing (P = .0091) and significantly fewer recurrences (2 of 12, 16%) (P = .006) compared with group B. ConclusionsOur findings suggest that removal of the GSV through stripping or ablation in patients with post-thrombotic deep venous systems affecting the femoropopliteal segment may result in delayed ulcer healing and increased ulcer recurrence. Patients with an intact GSV had better outcomes, even when the refluxing GSV was left untreated. These findings emphasize the potential impact of GSV treatment on the management of VLUs in individuals with PTS. Further investigation is needed to validate these results and explore alternative therapeutic strategies to optimize outcomes for this patient population.

Analysis of the Influence of Diabetic Nephropathy in Patients with Diabetic Foot Osteomyelitis.

This study analyzed the influence of diabetic nephropathy on the healing prognosis after conservative surgery in diabetic foot osteomyelitis (DFO). A retrospective observational study was carried out between January 2021 and December 2022 and involved 278 outpatients with a diagnosis of DFO at a specialized diabetic foot unit, including 74 (26.62%) patients with DN (group 2) and 204 (73.38%) patients without DN (group 1). There were 266 (95.70%) ulcers on the forefoot, 8 (2.90%) on the midfoot, and 4 (1.45%) on the hindfoot (p = 0.992). The healing rates were 85.1% (n = 63) for group 2 and 81.3% (n = 165) for group 1 (p = 0.457). When exploring the influence of DN on the risk of delayed ulcer healing, the results did not show a significant effect [12 (6; 28) weeks among patients with DN vs. 12 (6; 21) weeks among patients without DN; p = 0.576]. No significant differences were observed in complications, with one (2.59%) death occurring in group 1 (p = 0.296) and three minor amputations being performed in both groups [two (5.13%) amputations in group 1 vs. one amputation (9.09%) in group 2; p = 0.217]. Bone cultures were performed for a total of 190 patients (133 in group 1 and 57 in group 2). Of these, 176 positive bone cultures were isolated: 71 positive bone cultures (57.7%) were monomicrobial cultures in group 1, with 30 (56.6%) in group 2. There were 52 (42.3%) that had at least two microorganisms in group 1, and 23 (43.4%) in group 2 (p = 0.890). The most frequently prescribed oral antibiotic was amoxicillin/clavulanate (43.89%), followed by levofloxacin (28.4%), and trimethoprim/sulfamethoxazole (14.7%). This study shows that DN does not have a significant influence on the healing prognosis of patients with DFO after conservative surgery.

Comorbidities as prognostic factors in the healing of venous ulcers

Background: The problem of venous ulcers and chronic venous insufficiency is quite common in dermatological clinics. Every day, we face challenges regarding treatment and prognosis. As the patients are more often over fifty years of age, with more comorbidities, and at the very beginning of treatment, we already have an idea of how the entire process of epithelization of the ulcers may take place. Materials and Methods: A total of 105 patients with chronic venous insufficiency and venous ulcers were included in the study. Each was followed for more than twelve weeks. Patients with hypertension, diabetes mellitus, and thrombophlebitis were analyzed separately. Results: Patients with an ulcer closure time of twelve weeks and longer had a high blood pressure more often. Diabetics with venous ulcers on the lower extremities more often had delayed ulcer healing. A statistically significant difference was confirmed in the distribution of the patients with and without thrombophlebitis. Conclusion: The existence of comorbidities, such as hypertension, diabetes mellitus, and thrombosis, may affect the healing process of venous ulcers, yet thrombosis proved to be the most important factor. Key words: Venous Ulcers; Diabetes Mellitus; Thrombosis; Hypertension

Patient-centered Outcomes for Individuals with a Venous Leg Ulcer: A Scoping Review

To summarize randomized clinical trials addressing patient-centered outcomes of individuals with a venous leg ulcer. This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. After participating in this educational activity, the participant will:1. Summarize the results of the review of randomized controlled trials addressing patient-centered outcomes of individuals with a venous leg ulcer.2. Identify the limitations of the research analyzed for the review.

Anti-Ulcer Potentials of Aqueous Extract of Triticum aestivum on Delayed Healing of Experimentally Induced/Gastric Ulcer

Background: Ulcer reoccurrence and delay of healing caused by certain factors is now a major problem with the treatment of peptic ulcer. This study sought to unravel the role of Triticum aestivum in delayed ulcer healing in Wistar rats. Materials and Methods: Twenty five (25) Experimental animals (male Wistar rats) weighing 120g – 150g were randomly divided into five groups (N = 5) viz; I (Control), II (20% acetic acid ulceration + 2 mg/kg of indomethacin), III, IV, and V received 50 mg/kg, 100 mg/kg and 200 mg/kg of T. aestivum + 20% acetic acid ulceration + 2 mg/kg of indomethacin. Ulcer was induced by serosa application of 20% acetic acid and was delayed by subcutaneous administration of 2 mg/kg of indomethacin for 14 days. Results: Findings from this study showed that the relative body weight changes decreased substantially in delayed untreated group juxtaposed to control which was improved in T. aestivum extract (TAE) groups. Total gastric acidity, ulcer area, and relative stomach weight were substantially (P < 0.05) increased in delayed ulcer group juxtaposed to control group. These changes were substantially reversed in TAE-treated groups. A substantial decrease was observed in the catalase level and expression of nitric oxide accompanied by an increase in malondialdehyde was noted in delayed ulcer group juxtaposed to control which were ameliorated in all TAE treated groups. Histological and macroscopic evaluations revealed that there was a substantial decrease in inflammation and erosion of the gastric mucosa in groups treated with T. aestivum juxtaposed to delayed ulcer group. Conclusion: It can thus be said that aqueous extract of T. aestivum attenuates delayed gastric ulcer healing due to antioxidants and anti-inflammatory properties. The highest concentration (200 mg/kg) in this proved to be the most beneficial.

Weight-bearing physical activity in people with diabetes-related foot disease: A systematic review.

IntroductionWeight‐bearing physical activity is important for people with diabetes‐related foot disease but may also contribute to ulceration or delayed ulcer healing. No overview of weight‐bearing activity of people at different stages of foot disease is available. We aimed to summarise quantitatively measured daily activity levels in people with diabetes‐related foot disease.MethodsWe systematically searched peer‐reviewed literature for studies reporting objectively measured weight‐bearing activity in people with diabetes‐related foot disease. We calculated daily step counts' means (over studies) and weighted means (over participants). International Working Group on the Diabetic Foot (IWGDF) risk strata, different climates, and activity indoors versus outdoors were compared.ResultsFrom 1247 publications, 27 were included. Mean steps/day in people with IWGDF risk 1/2: 6125 (12 studies; 345 participants; weighted mean: 5384). In IWGDF risk 3: 6167 (8 studies; 291 participants; weighted mean: 6239). In those with a foot ulcer: 4248 (6 studies; 186 participants; weighted mean: 4484). People living in temperate oceanic climates are more active compared to those in hotter or more humid climates (mean steps/day for no ulcer: 7712 vs. 5224 [18 studies]; for ulcer: 6819 vs. 2945 [6 studies]). People are more active indoors than outdoors (mean 4047 vs. 2514 [3 studies]).ConclusionLevels of weight‐bearing physical activity are similar between people with diabetes at various risk levels for foot ulceration but lower for those with a foot ulcer. Weight‐bearing activity differs depending on the climatological environment and is higher indoors than outdoors. These findings provide reference for intervention studies or for clinicians aiming to provide mobility advice in this population.

Efficacy of a Chitosan-curcumin Mixture in Treating Indomethacininduced Acute Gastric Ulcer in Rats.

Curcumin is claimed as a potent protectant against Gastric Ulcer (GU) induced by strong necrotizing agents, including NSAIDs through its antioxidant, anti-inflammatory and gastroprotective activities. However, it was found to exert opposite effects to either delay ulcer healing or exacerbate ulcer inflammation through some curative mechanisms differently modified by curcumin dosage. Its ability to inhibit the expression of COX-2 may also delay the healing of NSAIDs-induced GU. Recently, a topical chitosan-curcumin solution has been found to be a safe and potential alternative agent in treating oral ulcer. Therefore, an oral chitosan-curcumin mixture was developed and determined for its efficacy in treating NSAIDs-induced GU in the rat. A chitosan (150 mg)-curcumin (20 mg) mixture with optimal gastric pH was developed. Indomethacin (30 mg/kg) was given orally to the rat and test preparations were administered orally at 5 h later and then every 24 h for two consecutive days. The sum of all gastric ulcerated areas (mm2) for each stomach was used as ulcer index. Gastric pro-inflammatory mediators and cytoprotective factors were determined. An oral administration of a chitosan-curcumin mixture exerted a superior efficacy than curcumin, chitosan or lansoprazole (a standard antiulcer agent) in healing indomethacin-induced GU. It was revealed that the mixture exhibited the highest anti-oxidant, anti-inflammatory and gastric mucus producing activities including the high potency in down-regulating pro-inflammatory COX-2 and iNOS expression but up-regulating cytoprotective COX-1, nNOS and eNOS expression. The present findings indicated the benefit of a chitosan-curcumin mixture as a potential alternative agent in treating NSAIDs-induced gastric ulcers.

Deferoxamine-loaded transfersomes accelerates healing of pressure ulcers in streptozotocin-induced diabetic rats

Diabetic nonhealing ulcers are the leading cause of nontraumatic amputations. An increased cancer risk has been found in patients treated with current therapies such as becaplermin gel. Therefore, an urgent need exists for novel approaches to control delayed ulcer healing. HIF-1α mediates adaptive responses to hypoxia by regulating angiogenesis, proliferation, migration, and cell survival. However, its function is impaired by hyperglycemia. Deferoxamine (DFO) might be an effective HIF-1α stabilizer by inhibiting PHD enzyme through the prevention of iron release in diabetic tissue. Herein, transfersomes were used as nanocarriers for DFO. The system depends on the ability of transfersomes to enhance the penetration of the large hydrophilic drug, DFO through the skin and sustain its release by applying a two-factor, three-level full factorial design to optimize entrapment efficiency, particle size, zeta potential and in vitro drug release. The soybean phosphatidylcholine (SPC) amount and the ratio of surfactant to SPC were selected as independent variables. The formulations had an entrapment efficiency range of 54.46–91.56%, particle size range of 109.2–265.6 nm, polydispersity index values less than one and negative zeta potential range of −17.53 to −29.03 mV. In vitro study revealed that the DFO-loaded transfersomal gel has uniform distribution of DFO, applicable pH, and suitable viscosity and found effective in sustaining DFO release. Moreover, in-vivo study of the optimized formulation demonstrated cutaneous wound healing potential in rats’ diabetic pressure ulcers. Overall, DFO-loaded transfersomal gel shows promise as a potential therapy for the treatment of human diabetic ulcers.

Potential prognostic factors for delayed healing of common, non-traumatic skin ulcers: A scoping review.

Healing of non‐traumatic skin ulcers is often suboptimal. Prognostic tools that identify people at high risk of delayed healing within the context of routine ulcer assessments may improve this, but robust evidence on which factors to include is lacking. Therefore, we scoped the literature to identify which potentially prognostic factors may warrant future systematic reviews and meta‐analyses. We conducted electronic searches in MEDLINE and Embase to identify studies in English published between 1997 and 2017 that tested the association between healing of the three most common non‐traumatic skin ulcers encountered by health care professionals (venous leg, diabetic foot, and pressure ulcers) and patient characteristics, ulcer characteristics, and results from clinical investigations. We included 42 studies that investigated factors which may be associated with the healing of venous leg ulcers (n = 17), diabetic foot ulcers (n = 15), and pressure ulcers (n = 10). Across ulcer types, ulcer characteristics were most commonly reported as potential prognostic factors for healing (n = 37), including the size of the ulcer area (n = 29) and ulcer duration at first assessment (n = 16). A total of 35 studies investigated the prognostic value of patient characteristics (n = 35), including age (n = 31), gender (n = 30), diabetes (n = 22), smoking status (n = 15), and history of deep vein thrombosis (DVT) (n = 13). Of these studies, 23 reported results from clinical investigations as potential prognostic factors, with the majority regarding vessel quality. Age, gender, diabetes, smoking status, history of DVT, ulcer area, and ulcer duration at time of first assessment warrant a systematic review and meta‐analysis to quantify their prognostic value for delayed ulcer healing.

Treatment: the role of contact X-ray brachytherapy (Papillon) in the management of early rectal cancer.

Treatment: the role of contact X-ray brachytherapy (Papillon) in the management of early rectal cancer.

Is Cirrhosis a Risk Factor for Acquired Double Pylorus?

Double pylorus (DP) refers to the presence of two separate openings from the stomach into the duodenum. It can be acquired or congenital. We present an interesting case of DP in a patient with cirrhosis which was incidentally found on esophagogastroduodenoscopy (EGD). A 54-year-old male with a past history of obesity and alcohol related cirrhosis presented to our outpatient liver clinic to establish care. The patient was diagnosed with cirrhosis few months ago. He reported a history of significant alcohol use for more than 20 years. Patient also had a history of tobacco use for 30 years but quit 2 years ago. His cirrhosis was decompensated as manifested by ascites. The patient was scheduled for EGD to screen for esophageal varices. EGD showed erosions and erythema in the antrum, and a deformity at the pylorus with a mucosal bridge across the pylorus [Figure 1] consistent with DP. Endoscope was passed through both openings, both of which lead to the duodenal bulb. There was no evidence of esophageal varices, gastric or duodenal ulcers. Biopsies were obtained from the stomach which were negative for Helicobacter pylori. The patient had a recent hospitalization for septic shock and acute kidney injury. Based on this, it was hypothesized to be an acquired DP secondary to possible stress ulceration from recent acute illness.3090 Figure 1. Esophagogastroduodenoscopy showing double pylorus.Majority of cases of double pylorus (DP) are acquired. Acquired cases of double pylorus are commonly secondary to a gastric ulcer that erodes and creates a fistula between the lesser curvature of the gastric antrum and the duodenal bulb. Patients with diseases resulting in chronic inflammation or an attenuated healing response are at a greater risk for the development of a DP. Our patient likely had stress ulceration during recent septic shock. The patient also had history of chronic alcohol use which has been reported to cause delayed ulcer healing and likely contributed to development of DP. Treatment of DP includes anti-acid secretion therapy with proton pump inhibitors and surgery is reserved for patients with refractory symptoms. Previously, double pylorus has rarely been reported in patients with cirrhosis. Our case along with other such reports raise the possibility that presence of underlying cirrhosis might lead to delayed ulcer healing, hence leading to DP. It is important for gastroenterologists to be aware of this condition and be cautious when using a side viewing endoscope.

Terminal Ileac Ulcers Mimicked Post-transplantation Lymphoproliferative Disorder in a Heart Recipient Treated With Everolimus: A Case Report

Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized and potentially fatal complication of cardiac transplantation that commonly involves the gastrointestinal tract. Herein, we report a case of life-threatening gastrointestinal bleeding from recurrent terminal ileac ulcers mimicking PTLD in a heart recipient treated with everolimus (EVL). A 40-year-old man underwent heart transplantation for dilated cardiomyopathy 3 years prior to the current admission and was treated with tacrolimus and EVL. He was admitted to a local hospital because of fever, abdominal pain, and diarrhea. His symptoms persisted and, 3 weeks later, hematochezia occurred; thus, he was transferred to our hospital. As computed tomography and 18F-fluorodeoxyglucose positron emission tomography showed bowel-wall thickening of the terminal ileum, gastrointestinal PTLD was initially suspected. However, although colonoscopy— performed after switching EVL to mycophenolate mofetil (MMF)—showed terminal ileac ulcers, the histologic examination revealed no findings corresponding to PTLD. As EVL may delay ulcer healing, MMF was maintained for 3 months. After repeated colonoscopy showed ulcer healing, MMF was switched back to EVL for cardiac allograft vasculopathy prevention. Three weeks later, he was emergently admitted to a local hospital for life-threatening gastrointestinal bleeding from a recurrent terminal ileal ulcer, which required hemostatic forceps hemostasis. As EVL is suspected to be associated with recurrent ileal ulcers, EVL was again switched back to MMF. The ileal ulcers resolved, without recurrence in 3 months of clinical follow-up. This case demonstrates that cases of life-threatening gastrointestinal bleeding from recurrent terminal ileac ulcers can mimic PTLD in a heart recipient treated with EVL.

Reduced NGF in Gastric Endothelial Cells Is One of the Main Causes of Impaired Angiogenesis in Aging Gastric Mucosa.

Background & AimsAging gastric mucosa has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully known. We examined whether impairment of angiogenesis in aging gastric mucosa is caused by deficiency of nerve growth factor (NGF) in gastric endothelial cells (ECs), and whether NGF therapy could reverse this impairment.MethodsIn gastric mucosal ECs (GECs) isolated from young and aging rats we examined the following: (1) in vitro angiogenesis, (2) NGF expression, and (3) the effect of NGF treatment on angiogenesis, GEC proliferation and migration, and dependence on serum response factor. In in vivo studies in young and aging rats, we examined NGF expression in gastric mucosa and the effect of NGF treatment on angiogenesis and gastric ulcer healing. To determine human relevance, we examined NGF expression in gastric mucosal biopsy specimens of aging (≥70 y) and young (≤40 y) individuals.ResultsIn cultured aging GECs, NGF expression and angiogenesis were reduced significantly by 3.0-fold and 4.1-fold vs young GECs. NGF therapy reversed impairment of angiogenesis in aging GECs, and serum response factor silencing completely abolished this response. In gastric mucosa of aging rats, NGF expression in GECs was reduced significantly vs young rats. In aging rats, local NGF treatment significantly increased angiogenesis and accelerated gastric ulcer healing. In aging human subjects, NGF expression in ECs of gastric mucosal vessels was 5.5-fold reduced vs young individuals.ConclusionsNGF deficiency in ECs is a key mechanism underlying impaired angiogenesis and delayed ulcer healing in aging gastric mucosa. Local NGF therapy can reverse these impairments.

Validation of a weight bearing ankle equinus value in older adults with diabetes

BackgroundAccurate measurement of ankle joint dorsiflexion is clinically important as a restriction has been linked to many foot and ankle pathologies, as well as increased ulcer risk and delayed ulcer healing in people with diabetes. Use of the reliable weight bearing (WB) Lunge test is limited as normal and restricted ranges for WB ankle joint dorsiflexion are not identified. Additionally the extent of WB dorsiflexion restriction that results in clinically adverse outcomes is unclear. Therefore the aim of this investigation is to validate a proposed weight bearing equinus value (dorsiflexion < 30°) in unimpaired cohorts, and secondly to investigate any clinical effects this degree of ankle dorsiflexion restriction has on forefoot plantar pressure variables in older adults with diabetes.MethodsAnkle dorsiflexion was measured using a Lunge test with the knee extended in young adults without diabetes (YA) and older adults with diabetes (DA). In-shoe and barefoot plantar pressure was recorded for the DA group. Spearman’s correlation was calculated to determine any association between the presence of ankle equinus and plantar pressure variables in the DA group. DA group differences in people with and without an equinus were examined.ResultsA weight bearing equinus of < 30°, assessed in a lunge using an inclinometer placed on the anterior tibia, falls within the restricted range in young unimpaired cohorts. In the DA group this degree of ankle restriction had a fair and significant association with elevated barefoot forefoot peak pressure (r = 0.274, p = 0.005) and pressure-time integrals (r = 0.321, p = .001). The DA equinus group had significantly higher barefoot peak pressure (mean kPa (SD): 787.1 (246.7) vs 652.0 (304.5), p = 0.025) and pressure-time integrals (mean kPa (SD): 97.8 (41.6) vs 80.4 (30.5), p = 0.017) than the DA non equinus group.ConclusionsWe support a preliminary weight bearing ankle equinus value of < 30°. This value represents a restricted range in young adults and is correlated with increased forefoot plantar pressure variables in older adults with diabetes. Mean population weight bearing ankle dorsiflexion data presented here for older adults with diabetes, will allow use of the more functional Lunge test with knee extended in research and clinical practice.

Risk Factors for Delayed Ulcer Healing after Endoscopic Submucosal Dissection of Gastric Neoplasms.

With improved technology, the size of artificial ulcers after endoscopic submucosal dissection (ESD) has increased. The aim of our study was to examine the risk factors for delayed gastric ulcer healing after ESD, including the possible benefit of potassium-competitive acid blocker (P-CAB) treatment. The primary outcome was the rate of healing of the artificial ulcers induced by ESD at 8 weeks post intervention. Design - retrospective case series. Setting - Aichi Medical University Hospital. Patients - patients who underwent ESD for gastric neoplasm, between April 2015 and March 2017. Intervention - ESD, with a follow-up endoscopic examination at 8 weeks post-ESD. Univariate and multivariate analyses were used to identify the independent risk factors for delayed healing. Of the 73 gastric neoplasms included in the analysis, delayed ulcer healing was identified in 21.9%. Dyslipidemia (p=0.04), ESD procedure time (p=0.003) and artificial ulcer size (p<0.001) were identified as risk factors for delayed healing, with location in the lower third of the stomach [Odds ratio (OR) 6.76; p=0.016] and artificial ulcer size (OR, 1.18; p=0.024) retained as independent risk factors. A cut-off ulcer size of 854 mm2 was predictive of delayed healing, with a sensitivity of 29.8% and specificity of 87.5%. For large ulcers, the rate of healing of 70% with vonoprazan was higher than the rate of 47.6% with proton pump inhibitors (PPIs), although this difference was not significant. For artificial ulcers after ESD with a resection diameter >35 mm, it might be desirable to use PPIs for >8 weeks or P-CAB.

Correlations between chronic venous leg ulcer and matrix metalloproteinases

Chronic venous leg ulcer (CVLU) is a common and refractory complication of chronic venous diseases, and is clinically characterized by chronic leg ulcers and pain. Matrix metalloproteinases (MMPs) are a kind of highly conservative and zinc-dependent endopeptidases, and can be divided into 6 types according to their substrates and structures. Among the 6 types, collagenases, gelatinases and stromelysins play a key role in the occurrence and development of CVLU. Moreover, the up-regulation of MMP-1,-2,-3,-8 and ratio of MMP-2 to tissue inhibitor of metalloproteinase-2 (TIMP-2) is associated with delayed ulcer healing, whereas the up-regulation of MMP-7,-10,-13 and TIMP-1,-2 facilitates ulcer healing. However, roles of MMP-9 and -12 in venous ulcers are still unclear and need further study. According to functional characteristics of some MMPs, intervention of their composition and functions may provide new therapeutic targets for the treatment of CVLU. Key words: Varicose ulcer; Lower extremity; Matrix metalloproteinases; Extracellular matrix; Wound healing

Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease.

TNF plays an integral role in inflammatory bowel disease (IBD), as evidenced by the dramatic therapeutic responses in Crohn's disease (CD) patients induced by chimeric anti-TNF mAbs. However, treatment of CD patients with etanercept, a decoy receptor that binds soluble TNF, fails to improve disease. To explore this discrepancy, we investigated the role of TNF signaling in Wnt/β-catenin-mediated intestinal stem cell and progenitor cell expansion in CD patients, human cells, and preclinical mouse models. We hypothesized that TNF exerts beneficial effects on intestinal epithelial cell (IEC) responses to injury. In CD patients, intestinal stem cell and progenitor cell Wnt/β-catenin signaling correlates with inflammation status. TNF-deficient (Tnf-/-) mice exhibited increased apoptosis, less IEC proliferation, and less Wnt signaling when stimulated with anti-CD3 mAb. Bone marrow (BM) chimera mice revealed that mucosal repair depended on TNF production by BM-derived cells and TNFR expression by radioresistant IECs. Wild-type→Tnfr1/2-/- BM chimera mice with chronic dextran sodium sulfate colitis exhibited delayed ulcer healing, more mucosal inflammation, and impaired Wnt/β-catenin signaling, consistent with the hypothesis that epithelial TNFR signaling participates in mucosal healing. The direct effect of TNF on stem cells was demonstrated by studies of TNF-induced Wnt/β-catenin target gene expression in murine enteroids and colonoid cultures and TNF-induced β-catenin activation in nontransformed human NCM460 cells (TOPFlash) and mice (TOP-GAL). Together, these data support the hypothesis that TNF plays a beneficial role in enhancing Wnt/β-catenin signaling during ulcer healing in IBD. These novel findings will inform clinicians and therapeutic chemists alike as they strive to develop novel therapies for IBD patients.

Effects of quinine on gastric ulcer healing in Wistar rats.

Background Quinine (QT) is an important anti-malarial drug; however, there is little information about its effects on the gut. Therefore, this study aimed to investigate the effects of a therapeutic dose of QT on the healing of gastric ulcer in rats. Methods Male Wistar rats weighing 150-200 g were divided into three groups: control rats without ulcer (group 1), ulcerated rats treated with 1 mL/kg (p.o.) normal saline (NS) (group 2), and ulcerated rats treated with 10 mg/kg (p.o.) QT (group 3). Ulcers were induced by serosal application of 80 % acetic acid to the stomach of rats anaesthetized with 50 mg/kg thiopentone sodium and treatment was given three times daily. Healing was assessed on days 3, 7 and 10 after ulcer induction by macroscopic measurement of: ulcer area, histology, lipid peroxidation, superoxide dismutase activity and gastric mucus secretion. Results At day 3, there was no significant difference (p>0.05) in ulcer areas between NS- and QT-treated rats. By day 10, however, the percentage area healed in NS treated (59.6±2.35 %) was significantly higher (p<0.05) than in QT rats (49.0±2.20 %) and clearing of inflammatory cells and re-epithelization was greater in NS-treated group. By days 7 and 10, lipid peroxidation was significantly higher in QT animals, when compared with NS-treated rats and controls (p<0.05). Superoxide dismutase activity and mucus secretion were significantly (p<0.05) higher in NS-treated than QT-treated rats. Conclusions QT delayed ulcer healing by prolonging the inflammatory phase of healing, increasing oxidative stress, reducing antioxidant activity and gastric mucus secretion.

Steroid Treatment Impairs Intestinal Stem Cell (ISC) Activation and Contributes to Delayed Ulcer Healing in Inflammatory Bowel Disease (IBD)

In cases of moderate to severe inflammatory bowel disease (IBD), exogenous glucocorticoid steroids (GC) are the preferred treatment due to their safety and efficacy in alleviating symptoms. Despite the clinical benefits, endoscopic data show that GCs delay ulcer healing through mechanisms that are poorly understood. Intestinal stem cells (ISC) require Wnt/β‐catenin signaling for maintenance of the crypt proliferative compartment, and Wnt responsiveness is an important component of a functional mucosal healing response. The objective of our study was to determine whether GCs impair ISC activation in ulcer re‐epithelialization. Specifically, we hypothesized that that steroids impair canonical Wnt/β‐catenin signaling required for ISC activation needed for mucosal repair.MethodsWe examined the effects of dexamethasone, a GC steroid, on cell signaling pathways involved in Wnt/β‐catenin, PI3 Kinase, and NFkB signaling. We utilized NCM460 (NCM) cells, a normal human colonic intestinal epithelial cell (IEC) line, mouse epithelial cells isolated after DSS‐mediated colitis induction, and epithelial isolations from patient biopsies obtained from University of Kentucky and VA Lexington Hospitals. IEC from untreated and steroid‐treated (7 days) UC patients with equivalent levels of colitis were compared.ResultsIn steroid‐treated NCMs, we saw a significant decrease in transcript levels of Wnt target gene Axin2, a marker of Wnt‐responsive multipotent IECs that participate directly in ulcer healing, and the β‐catenin transcriptional co‐activator CREB Binding Protein (CBP). After transfecting NCM460s with lentivirus containing a TCF/LEF luciferase construct (a marker of Wnt transcriptional activation), we saw that steroid treatment diminished TNF‐mediated increase in TCF/LEF signaling back to control levels. In both murine and IECs isolated from patient biopsies, GC inhibited colitis‐induced Axin2, p‐LRP6 (marker of Wnt signaling) and nuclear β‐catenin protein levels. Together, these data indicate strongly that GCs impair Wnt signaling.DiscussionOur results indicate that GCs impair Wnt/β‐catenin signaling during ulcer healing in in vitro and in vivo models of colitis. While steroids play a significant role in regulating the basal immune response to IBD, our data suggest steroids inhibit epithelial signaling required for ulcer healing. Given the recent data implicating NFkB in Wnt signaling activation, our studies suggest a potential explanation for GC‐induced impairment of stem cell activation needed for mucosal repair in IBD.Support or Funding Information1I01CX001353‐01A1 VA Merit 5TL1TR000115‐05 TL1 Pre‐doctoral CTSA Funding