Mitofusin 1 silencing decreases the senescent associated secretory phenotype, promotes immune cell recruitment and delays melanoma tumor growth after chemotherapy.

Cellular senescence is a therapy endpoint in melanoma, and the senescence-associated secretory phenotype (SASP) can affect tumor growth and microenvironment, influencing treatment outcomes. Metabolic interventions can modulate the SASP, and mitochondrial energy metabolism supports resistance to therapy in melanoma. In a previous report we showed that senescence, induced by the DNA methylating agent temozolomide, increased the level of fusion proteins mitofusin 1 and 2 in melanoma, and silencing Mfn1 or Mfn2 expression reduced interleukin-6 secretion by senescent cells. Here we expanded these observations evaluating the secretome of senescent melanoma cells using shotgun proteomics, and explored the impact of silencing Mfn1 on the SASP. A significant increase in proteins reported to reduce the immune response towards the tumor was found in the media of senescent cells. The secretion of several of these immunomodulatory proteins was affected by Mfn1 silencing, among them was galectin-9. In agreement, tumors lacking mitofusin 1 responded better to treatment with the methylating agent dacarbazine, tumor size was reduced and a higher immune cell infiltration was detected in the tumor. Our results highlight mitochondrial dynamic proteins as potential pharmacological targets to modulate the SASP in the context of melanoma treatment.

The impact of photodynamic therapy on skin homeostasis in patients with actinic keratosis: A prospective observational study.

BACKGROUND: Photodynamic therapy (PDT) is an effective treatment for actinic keratosis (AKs), but there is little information on how PDT affects skin barrier function. The objectives of this study are: To compare skin barrier function between skin with AKs and healthy skin and to evaluate the impact of PDT on skin homeostasis in patients with AKs. METHODS: A prospective observational study was conducted in patients with AKs to evaluate epidermal barrier function and skin homeostasis before and 1 ek after receiving PDT. RESULTS: A total of 21 subjects were included in the study, male/female ratio was 17:4, mean age was 75.86 years. The number of AKS observed before starting treatment was reduced with respect to those diagnosed 1 month after starting PDT (14.83 vs. 1.91, p < 0.0001). Application of PDT for treating AKs modifies epidermal barrier function. Immediately after the first session temperature, transepidermal water loss (TEWL), stratum corneum hydration (SCH) and total antioxidant capacity (TAC) increased while pH decreased on lesional skin. After 1-month follow-up, the only remained change was the increased in SCH. Higher increases in temperature were observed when using occlusive PDT compared to mixed modality. 5-ALA and M-ALA seem to have a similar impact on skin barrier. CONCLUSIONS: PDT can improve skin barrier function in patients with AKs. Skin homeostasis parameters can be used to assess efficacy and optimize dosing.

Pilonidal Sinus Disease is Associated with Severe Hidradenitis Suppurativa in a Spanish Cohort.

Hidradenitis suppurativa is a chronic inflammatory disorder of the hair follicle with a high level of morbidity. Pilonidal sinus disease is a comorbid disorder and may be the reason for first contact with the healthcare system of patients with hidradenitis suppurativa. The aim of this study was to evaluate the frequency of association of pilonidal sinus disease and hidradenitis suppurativa and to explore whether pilonidal sinus disease defines a different clinical profile for patients with hidradenitis suppurativa. A cross-sectional study in which data regarding past history of pilonidal sinus disease, clinical and sociodemographic information were recorded during the first visit to the Hidradenitis Suppurativa Clinic of 2 tertiary hospitals. A total of 839 patients were included in the study. Of these, 51.7% (434/839) were male and mean age was 37.3 ± 13.6 years. Pilonidal sinus disease was present in 32.6% (269/839) of the patients and was associated with an early debut of hidradenitis suppurativa, a higher Hurley stage, inflammatory phenotype and a greater number of fistulas and perianal involvement. Elapsed time between pilonidal sinus disease and diagnosis of hidradenitis suppurativa was associated with higher disease severity. Pilonidal sinus disease is a frequent comorbidity and risk marker for hidradenitis suppurativa disease severity. Pilonidal sinus disease could be a sentinel event to identify patients who would benefit from close treatment and follow-up.

Potential Predictors of Cardiovascular Risk Improvement in Patients with Hidradenitis Suppurativa Treated with Adalimumab: A Pivotal Study of Factors Associated with Carotid Intima-Media Thickness Reduction.

INTRODUCTION: Hidradenitis suppurativa (HS) has been linked to higher cardiovascular risk (CVR) due to its inflammatory burden. There is little evidence on how biologic treatment could modify the cardiovascular risk of patients with HS. The aims of the present study were to explore the modification of CVR in patients under adalimumab treatment and to explore the potential factors associated with CVR improvement. METHODS: A prospective longitudinal study was performed. A cohort of patients with HS treated with adalimumab was followed up. Carotid intima-media thickness (IMT) and other clinical and biochemical CVR factors were collected at baseline and 32 weeks after starting the treatment. RESULTS: Twenty-seven patients with severe HS were included. Overall, there were no differences in IMT between baseline (633 µm) and 32 weeks follow-up (634 µm). However, 40.7% (11/27) of the patients presented an improvement in IMT. This group (IMT responders) had a higher prevalence of dyslipidemia, diabetes mellitus, higher HbA1c levels, consumed more tobacco, and had higher BMI at baseline. Moreover, these patients had lower IHS4 scores at baseline and tended to have a greater IMT basal value, indicating a higher burden of subclinical atherosclerosis. CONCLUSIONS: Adalimumab treatment might benefit a subset of patients with HS in terms of cardiovascular risk reduction. In light of the results of the present study patients with classical cardiovascular risk factors, and those with higher burden of subclinical atherosclerosis and with less inflammatory load, may be more likely to improve their IMT during adalimumab treatment.

Type D Personality as a Marker of Poorer Quality of Life and Mood Status Disturbances in Patients with Skin Diseases: A Systematic Review.

Type D personality is characterized by social inhibition and negative affectivity. Poorer outcomes and worse quality of life have been linked to type D personality in patients with a variety of non-dermatological diseases. Despite increasing evidence of the importance of type D personality in skin diseases, there are no reviews on this subject. The aim of this review is to summarize the current evidence regarding type D personality and skin diseases. A systematic search was performed using Medline and Web of Science databases from inception to 11 October 2022. Studies addressing the presence of type D personality, its associated factors, its impact on the outcomes of the disease or the quality of life of the patients were included in the systematic review. A total of 20 studies, including 3,124 participants, met the eligibility criteria and were included in the review. Acne, hidradenitis suppurativa, psoriasis, melanoma, atopic dermatitis, chronic spontaneous urticaria and pruritic disorders were the main diseases assessed. Type D personality was more frequent among patients with skin diseases than among controls. Type D personality was found to be associated with poorer quality of life and higher rates of psychological comorbidities in patients with skin diseases. In conclusion, type D personality appears to be a marker of patients with increased risk of poorer quality of life and higher rates of psychological comorbidities. Screening for type D personality in specialized dermatology units might be beneficial to identify patients who are more psychologically vulnerable to the consequences of chronic skin diseases.

Patterns of Surgical Recurrence in Patients with Hidradenitis Suppurativa.

BACKGROUND: Surgery is an essential part of hidradenitis suppurativa (HS) treatment. Understanding and reducing surgical recurrence are crucial to obtaining the best results in patients' treatment. OBJECTIVE: The aim of the study was to characterize surgical recurrences in a cohort of patients with HS treated with wide excision and second-intention healing. METHODS: A prospective nested case-control study was conducted. A cohort of patients with HS treated with wide excision and second-intention healing was monitored for 68 weeks. The surgical procedure was classified as case (recurrence) or control (no recurrence). The type of recurrence was classified according to the elementary lesion in tunnel or abscess and inflammatory nodule (AN) recurrence. Sociodemographic and clinical data likely related to recurrence and the type of recurrence were evaluated. RESULTS: Sixty-three patients were included, receiving a total of 82 surgical procedures. The mean age of the patients was 36.18 years, and the surgical site presented a Hurley stage II severity in 79.26% (65/82) of the interventions. Tunnel recurrence was observed in 8.5% (7/82) and AN recurrence in 15.85% (13/82) of the interventions. Obesity was associated with a higher risk of recurrence, for both tunnel and AN recurrence. Hurley III at the surgical site, a history of pilonidal sinus, and higher International Hidradenitis Suppurativa Severity Score System (IHS4) after surgery and at week 68 increased the risk of tunnel recurrence. CONCLUSION: We propose classifying surgical recurrence based on the elemental type of lesion. Tunnel recurrence could originate in the depth of the surgical scar and could be associated with both surgical site factors and inflammatory load. AN recurrence could originate in the borders of the surgical scar and may particularly benefit from preoperative ultrasound.

Exploring the role of systemic immune-inflammation index and neutrophil-lymphocyte ratio in cardiovascular risk stratification for patients with hidradenitis suppurativa: A cross-sectional study.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the hair follicle that has previously been associated with a higher cardiovascular risk (CVR). Although different methods have been described for CVR stratification in HS, there is little evidence about the role of hemogram indexes in CVR in HS. Given its potential convenience, the aim of this study was to assess the role of the hemogram indexes systemic immune-inflammation index (SII) and neutrophil-lymphocyte ratio (NLR) in CVR stratification for patients with HS. A cross-sectional study was performed to assess the role of SII and NLR in CVR stratification in patients with moderate to severe HS who were candidates for biologic therapy. SII, NLR, carotid intima-media thickness, and other clinical and biochemical CVR factors were assessed before the start of the treatment. Fifty patients were included. The male:female ratio was 3:2, and the mean International Hidradenitis Suppurativa Severity Score System score was 21.6. After multivariate analysis, SII correlated with higher values of systolic blood pressure, metabolic syndrome, and higher risk of insulin resistance (p < 0.05). NLR was associated with insulin resistance (p < 0.05). These associations were independent of age, sex, body mass index, severity of the disease, and tobacco consumption. The implementation of SII and NLR in daily practice may be of benefit for identifying patients with HS at higher risk of high blood pressure, insulin resistance, or metabolic syndrome. Since these indexes are simple to calculate, they could be used as a screening tool in HS-specific units.

Type D Personality Is Associated with Poorer Quality of Life in Patients with Chronic Spontaneous Urticaria: A Cross-sectional Study.

Type D personality (TDp) is a stable personality type that has been associated with poor quality of life in the general population and in patients with a variety of diseases, such as cancer, cardiac diseases, and dermatological diseases (e.g. psoriasis). To date, the potential association between chronic spontaneous urticaria and TDp has not been studied. The aim of this study is to analyse the impact of TDp on patients with chronic spontaneous urticaria, regarding mood disturbances, quality of life, sexuality, and sleep disturbances. A cross-sectional study including 75 patients with chronic spontaneous urticaria was performed. Data on socio- demographic variables and disease activity, quality of life, sleep, sexual dysfunction, anxiety, depression and TDp were collected using validated questionnaires. TDp was present in 28% (21/75) of the patients. Although TDp was not related to worse disease control, the presence of anxiety and depression was higher in patients with TDp. Regarding quality of life, TDp was associated with poorer quality of life and higher frequency of sleep disturbances. Prevalence of TDp in patients with chronic spontaneous urticaria is similar to that in the general population. It is associated with mood status disturbances and worse quality of life regardless of disease severity, especially in the emotional and psychological domains. This group of patients could benefit from additional psychological support as a complement to their medical treatment.

Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening.

Trypanothione synthetase (TryS) catalyses the synthesis of N1,N8-bis(glutathionyl)spermidine (trypanothione), which is the main low molecular mass thiol supporting several redox functions in trypanosomatids. TryS attracts attention as molecular target for drug development against pathogens causing severe and fatal diseases in mammals. A drug discovery campaign aimed to identify and characterise new inhibitors of TryS with promising biological activity was conducted. A large compound library (n = 51,624), most of them bearing drug-like properties, was primarily screened against TryS from Trypanosoma brucei (TbTryS). With a true-hit rate of 0.056%, several of the TbTryS hits (IC50 from 1.2 to 36 µM) also targeted the homologue enzyme from Leishmania infantum and Trypanosoma cruzi (IC50 values from 2.6 to 40 µM). Calmidazolium chloride and Ebselen stand out for their multi-species anti-TryS activity at low µM concentrations (IC50 from 2.6 to 13.8 µM). The moieties carboxy piperidine amide and amide methyl thiazole phenyl were identified as novel TbTryS inhibitor scaffolds. Several of the TryS hits presented one-digit µM EC50 against T. cruzi and L. donovani amastigotes but proved cytotoxic against the human osteosarcoma and macrophage host cells (selectivity index ≤ 3). In contrast, seven hits showed a significantly higher selectivity against T. b. brucei (selectivity index from 11 to 182). Non-invasive redox assays confirmed that Ebselen, a multi-TryS inhibitor, induces an intracellular oxidative milieu in bloodstream T. b. brucei. Kinetic and mass spectrometry analysis revealed that Ebselen is a slow-binding inhibitor that modifies irreversible a highly conserved cysteine residue from the TryS's synthetase domain. The most potent TbTryS inhibitor (a singleton containing an adamantine moiety) exerted a non-covalent, non-competitive (with any of the substrates) inhibition of the enzyme. These data feed the drug discovery pipeline for trypanosomatids with novel and valuable information on chemical entities with drug potential.

Potential Benefits of the Mediterranean Diet and Physical Activity in Patients with Hidradenitis Suppurativa: A Cross-Sectional Study in a Spanish Population.

There is scarce scientific information regarding the potential benefits of healthy lifestyles in patients with hidradenitis suppurativa (HS). The objective of this study is to explore the potential association between the adherence to a Mediterranean diet (MD), physical activity and HS severity. A cross-sectional study that included patients with HS was conducted. Disease severity was evaluated by the International Hidradenitis Suppurativa Severity Score System (IHS4) and self-reported disease activity using a Numeric Rating Scale (NRS, 0−10). The adherence to a MD was assessed by the PREvención con DIeta MEDiterránea (PREDIMED) questionnaire and the level of physical activity by the International Physical Activity questionnaire. A total of 221 patients with HS were included in our study. The adherence to a MD was average for a Spanish population. A higher adherence to a MD was associated with lower disease activity, lower self-reported Hurley and lower IHS4. The use of extra virgin olive oil as the main culinary lipid was the dietary habit that implied a lower degree of disease activity (p < 0.05). Regarding physical activity, both the self-reported severity and IHS4 presented an inverse association with the intensity of physical activity. The adherence to a MD and the intensity of physical activity were positively associated. The Mediterranean dietary pattern may have an impact on HS. Greater adherence to a MD is related to lower HS severity and more physical activity also correlates to lower disease severity. The MD could be an appropriate dietary pattern for patients with HS due to its anti-inflammatory properties, and combining this with increased levels of physical activity could have additional benefits.

Combined versus conventional photodynamic therapy with 5-aminolaevulinic acid nanoemulsion (BF-200 ALA) for actinic keratosis: A randomized, single-blind, prospective study.

BACKGROUND: Photodynamic therapy (PDT) has become one of the most effective therapies for the treatment of actinic keratosis, allowing the removal of more than one lesion in a single session. However, the pain sustained by the patient during treatment and local skin reactions can limit its use. OBJECTIVES: To determine the efficacy and safety of combined PDT (daylight PDT followed by conventional PDT) vs conventional PDT 12 weeks after treatment. METHODS: The study was performed as a randomized, single-center, non-inferiority clinical trial with two parallel groups. A total of 51 patients with grade I and II AKs on the scalp or face were randomized. Twenty-five patients received one session of combined PDT (combPDT), and 26 patients received one session of conventional PDT (cPDT). The primary endpoint was the reduction of AKs, 12 weeks after treatment. The secondary endpoint was the reduction in pain and local skin reaction. RESULTS: The reduction rate of grade I and II AKs was similar in combPDT and cPDT, showing no statistically significant differences between both groups, 76.67% vs 86.63% [P = .094] and 80.48% vs 83.08% [P = .679], respectively. However, pain was significantly lower in the combPDT group (2.56 vs 5, P < .01), as were local skin reactions. CONCLUSIONS: CombPDT has proven to be as effective as cPDT for the treatment of grade I and II AKs located on the scalp and face. Furthermore, combPDT has been shown to be considerably more tolerable than cPDT, causing only mild local skin reactions.

Cumulative Inflammation and HbA1c Levels Correlate with Increased Intima-Media Thickness in Patients with Severe Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that has been associated with a greater risk of metabolic and cardiovascular comorbidities. The aim of this study is to assess cardiovascular risk by means of intima-media thickness (IMT), metabolic syndrome, and other potential biomarkers in patients with severe hidradenitis suppurativa who are candidates for biologic therapy and to explore potentially associated factors. A cross-sectional study was performed. Body mass index (BMI), carotid intima-media thickness (IMT), and blood tests, including glycemic and lipid profile, insulin, vitamin D, and inflammation markers were performed. Fifty patients were included in the study; the male/female ratio was 3:2. The mean age was 38 years, and the mean disease duration was 21.8 years. The mean carotid IMT was 651.39 µm. A positive association of IMT with disease duration, tobacco consumption, and HbA1c levels was observed. HbA1c correlated with the age of onset, hypertension, metabolic syndrome, and glucose levels. Vitamin D levels inversely correlated with the number of areas affected. In conclusion, patients with severe HS present a higher cardiovascular risk, but it is not distributed equally within the patients: Tobacco consumption, inadequate glycemic control, and disease duration could be useful clinical and biochemical markers to identify patients at higher risk.

Four years stability of type D personality in patients with moderate to severe psoriasis and its implications for psychological impairment

Abstract Background: Psoriasis is a systemic auto-inflammatory disease that is related to an increased risk of organic and psychological comorbidities. Type D is a stable personality trait in healthy subjects but there is no data regarding its stability in patients with moderate-severe psoriasis. Objectives: To assess the stability of type D personality in patients with moderate to severe psoriasis as well as assessing the influence of type D personality on anxiety and depression. Methods: Prospective cohort study. Forty psoriasis patients with type D personality and sixtysix patients with psoriasis without type D personality were included in the study. Participants completed the DS14 test and HADS at baseline and four years later. Results: At baseline, the prevalence of type D personality was 37.7% and at week 208 it was 27.3%. The stability of type D personality was higher in patients with an incomplete education level and in those who were separated/divorced or windowed. During follow-up, 15% of patients developed type D personality. Male sex, having topical treatment, the presence of previous depression, anxiety, and high levels of negative affectivity at baseline increase the risk of developing type D personality. Study limitations: Sample size, psoriasis severity restricted to moderate and severe and all patients being under treatment for psoriasis. Conclusion The presence of type D personality varies over time in psoriasis patients. Therefore, type D personality is possibly more a state than a trait phenomenon, modified by environmental factors. Type D personality is associated with a higher risk of anxiety.

Decreased proteasomal cleavage at nitrotyrosine sites in proteins and peptides.

Removal of moderately oxidized proteins is mainly carried out by the proteasome, while highly modified proteins are no longer degradable. However, in the case of proteins modified by nitration of tyrosine residues to 3-nitrotyrosine (NO2Y), the role of the proteasome remains to be established. For this purpose, degradation assays and mass spectrometry analyses were performed using isolated proteasome and purified fractions of native cytochrome c (Cyt c) and tyrosine nitrated proteoforms (NO2Y74-Cyt c and NO2Y97-Cyt c). While Cyt c treated under mild conditions with hydrogen peroxide was preferentially degraded by the proteasome, NO2Y74- and NO2Y97-Cyt c species did not show an increased degradation rate with respect to native Cyt c. Peptide mapping analysis confirmed a decreased chymotrypsin-like cleavage at C-terminal of NO2Y sites within the protein, with respect to unmodified Y residues. Additionally, studies with the proteasome substrate suc-LLVY-AMC (Y-AMC) and its NO2Y-containing analog, suc-LLVNO2Y-AMC (NO2Y-AMC) were performed, both using isolated 20S-proteasome and astrocytoma cell lysates as the proteasomal source. Comparisons of both substrates showed a significantly decreased proteasome activity towards NO2Y-AMC. Moreover, NO2Y-AMC, but not Y-AMC degradation rates, were largely diminished by increasing the reaction pH, suggesting an inhibitory influence of the additional negative charge contained in NO2Y-AMC secondary to nitration. The mechanism of slowing of proteasome activity in NO2Y-contaning peptides was further substantiated in studies using the phenylalanine and nitro-phenylalanine peptide analog substrates. Finally, degradation rates of Y-AMC and NO2Y-AMC with proteinase K were the same, demonstrating the selective inability of the proteasome to readily cleave at nitrotyrosine sites. Altogether, data indicate that the proteasome has a decreased capability to cleave at C-terminal of NO2Y residues in proteins with respect to the unmodified residues, making this a possible factor that decreases the turnover of oxidized proteins, if they are not unfolded, and facilitating the accumulation of nitrated proteins.

Synthesis, LC-MS/MS analysis, and biological evaluation of two vaccine candidates against ticks based on the antigenic P0 peptide from R. sanguineus linked to the p64K carrier protein from Neisseria meningitidis.

A peptide from the P0 acidic ribosomal protein (pP0) of ticks conjugated to keyhole limpet hemocyanin from Megathura crenulata has shown to be effective against different tick species when used in host vaccination. Turning this peptide into a commercial anti-tick vaccine will depend on finding the appropriate, technically and economically feasible way to present it to the host immune system. Two conjugates (p64K-Cys1pP0 and p64K-ßAla1pP0) were synthesized using the p64K carrier protein from Neisseria meningitidis produced in Escherichia coli, the same cross-linking reagent, and two analogues of pP0. The SDS-PAGE analysis of p64K-Cys1pP0 showed a heterogeneous conjugate compared to p64K-ßAla1pP0 that was detected as a protein band at 91kDa. The pP0/p64K ratio determined by MALDI-MS for p64K-Cys1pP0 ranged from 1 to 8, being 3-5 the predominant ratio, while in the case of p64K-ßAla1pP0 this ratio was 5-7. Cys1pP0 was partially linked to 35 out of 39 Lys residues and the N-terminal end, while ßAla1pP0 was mostly linked to the six free cysteine residues, to the N-terminal end, and, in a lesser extent, to Lys residues. The assignment of the conjugation sites and side reactions were based on the identification of type 2 peptides. Rabbit immunizations showed the best anti-pP0 titers and the highest efficacy against Rhipicephalus sanguineus ticks when the p64K-Cys1pP0 was used as vaccine antigen. The presence of high molecular mass aggregates observed in the SDS-PAGE analysis of p64K-Cys1pP0 could be responsible for a better immune response against pP0 and consequently for its better efficacy as an anti-tick vaccine. Graphical abstract.

Treatment challenges in clinically amyopathic dermatomyositis: A case series and review of new therapeutic options for skin involvement.

The term clinically amyopathic dermatomyositis (CADM) is used to represent a subgroup of patients with the typical cutaneous features of dermatomyositis (DM) in the absence of muscle involvement. Similar to classic DM, CADM can be associated with other connective tissue disorders and systemic manifestations such as interstitial lung disease and malignancy. Owing to the frequent discordance between muscle response and skin disease, the therapeutic approach to CADM represents a challenge. The current literature suggests that CADM treatment should follow a specific protocol, influenced by visceral involvement and the expression of certain myositis-specific antibodies, and different from the recommendation in the presence of myositis. Here, we present five new cases of CADM. We describe the available therapeutic options for skin manifestations in this type of DM, and we propose a step-by-step therapeutic scheme, using the cutaneous dermatomyositis disease area and severity index to assess response. Our literature review establishes mycophenolate mofetil and intravenous immunoglobulin as the most frequently successful therapies in refractory skin disease.