Mechanisms of repigmentation induced by photobiomodulation therapy in vitiligo

Photobiomodulation (PBM) therapy is based on the exposure of biological tissues to low‐level laser light (coherent light) or light‐emitting diodes (LEDs; noncoherent light), leading to the modulation of cellular functions, such as proliferation and migration, which result in tissue regeneration. PBM therapy has important clinical applications in regenerative medicine. Vitiligo is an acquired depigmentary disorder resulting from disappearance of functional melanocytes in the involved skin. Vitiligo repigmentation depends on available melanocytes derived from (a) melanocyte stem cells located in the bulge area of hair follicles and (b) the epidermis at the lesional borders, which contains a pool of functional melanocytes. Since follicular melanoblasts (MBs) are derived from the melanocyte stem cells residing at the bulge area of hair follicle, the process of vitiligo repigmentation presents a research model for studying the regenerative effect of PBM therapy. Previous reports have shown favourable response for treatment of vitiligo with a low‐energy helium‐neon (He‐Ne) laser. This review focuses on the molecular events that took place during the repigmentation process of vitiligo triggered by He‐Ne laser (632.8 nm, red light). Monochromatic radiation in the visible and infrared A (IRA) range sustains matrix metalloproteinase (MMP), improves mitochondrial function, and increases adenosine triphosphate (ATP) synthesis and O₂ consumption, which lead to cellular regenerative pathways. Cytochrome c oxidase in the mitochondria was reported to be the photoacceptor upon which He‐Ne laser exerts its effects. Mitochondrial retrograde signalling is responsible for the cellular events by red light. This review shows that He‐Ne laser initiated mitochondrial retrograde signalling via a Ca²⁺‐dependent cascade. The impact on cytochrome c oxidase within the mitochondria, an event that results in activation of CREB (cyclic‐AMP response element binding protein)‐related cascade, is responsible for the He‐Ne laser promoting functional development at different stages of MBs and boosting functional melanocytes. He‐Ne laser irradiation induced (a) melanocyte stem cell differentiation; (b) immature outer root sheath MB migration; (c) differentiated outer root sheath MB melanogenesis and migration; and (d) perilesional melanocyte migration and proliferation. These photobiomodulation effects result in perifollocular and marginal repigmentation in vitiligo.     

Membrane‐bound stem cell factor is the major but not only driver of fibroblast‐induced murine skin mast cell differentiation

The maintenance and modulation of cutaneous mast cell (MC) numbers is held to be important for skin immune responses to allergens and pathogens. The increase in MC numbers in the skin is achieved by proliferation and the differentiation of precursor to mature MCs. Fibroblast‐derived SCF is thought to be the major skin MC growth factor and it potently induces MC proliferation. The mechanisms of fibroblast‐induced skin MC differentiation, including the role of SCF, however, remain insufficiently characterized and understood. Using cocultures of immature murine MCs and fibroblasts, we found that the adhesion of immature MCs to fibroblasts via VCAM‐1 and α₄β₇ integrin is very important for subsequent differentiation, which is driven by fibroblast membrane‐bound SCF and additional fibroblast‐derived membrane‐bound signals. Thus, our results show that fibroblast‐induced MC differentiation is induced by direct cell–cell contact and involves both Kit‐dependent and Kit‐independent pathways. Our findings add to the understanding of how immature mast cells mature in murine skin and encourage further analyses of the underlying mechanisms, which may result in novel targets for the modulation of skin mast cell driven diseases.     

Interleukin-3 stabilizes CD124/IL-4α surface expression in mast cells via Tyk2 and STAT6

Interleukin (IL)-4 signals can modulate mast cells, which express the IL-4Rα chain. The IL-4Rα can heterodimerise with the common γ-chain and utilizes JAK1 and JAK2 for signal transduction, while complexes of IL-4Rα with IL-13Rα1 subunit mediates signals via JAK2 and Tyk2. Here, we report that IL-3 is an essential factor for the continuous expression of the IL-4Rα chain on mast cells, which did not express the IL-13Rα1 chain. We demonstrate that the signals induced by IL-3 important for IL-4Rα expression are mediated by Tyk2 and STAT6 activation and the subsequent maintenance of HSP90 levels. In line with that, inhibition of either Tyk2, STAT6 or HSP90 impaired the IL-3-induced IL-4Rα upregulation. Consequently, the IL-3 maintained IL-4Rα surface expression via Tyk2 is essential for the costimulatory effect of IL-4 on the IL-33-induced production of IL-6 and IL-13.     

Steady-state versus chemotherapy-based hematopoietic cell mobilization after anti-CD38-based induction therapy in newly diagnosed multiple myeloma

Background

The incorporation of anti-CD38 monoclonal antibodies (mAb) in induction regimens of newly diagnosed transplant-eligible multiple myeloma (MM) patients has been established as a new standard. However, the optimal strategy of stem cell mobilization in this context is not yet clear.

Study Design and Methods

From May 2020 till September 2022, we retrospectively reviewed patients receiving anti-CD38 mAb-based induction therapy followed by stem cell mobilization either in a steady-state protocol (SSM) using 10 μg/kg granulocyte colony-stimulating factor (G-CSF) for 5 days or in a chemotherapy-based protocol (CM) using 1–4 g/m² cyclophosphamide and G-CSF.

Results

Overall, 85 patients (median age 61 years) were included in the analysis. In total, 90 mobilization attempts were performed, 42 with SSM and 48 with CM. There was no significant difference in the median concentration of CD34+ cells in peripheral blood (PB) prior to apheresis between SSM and CM (61/μL vs. 55.4/μL; p = .60). Cumulative CD34+ yields did not differ between the groups with median of 6.68 and 6.75 × 10⁶/kg body weight, respectively (p = .35). The target yield (≥4 × 10⁶ CD34+ cells/kg body weight) was reached in 88% (CM) and 86% (SSM), with a high proportion even after a single apheresis session (76% vs. 75%). Plerixafor was found to be more frequently used in SSM (52%) than in CM (23%; p < .01). A total of 83 patients underwent autologous transplantation and all were engrafted.

Conclusions

Stem cell collection in patients undergoing anti-CD38-based induction therapy is feasible with either CM or SSM, although SSM more frequently requires plerixafor.     

Modulation of central pain mechanisms using high-definition transcranial direct current stimulation: A double-blind,sham-controlled study

Background

The use of high-definition transcranial direct current stimulation (HD-tDCS) has shown analgesic effects in some chronic pain patients, but limited anti-nociceptive effects in healthy asymptomatic subjects.

Methods

This double-blinded sham-controlled study assessed the effects of HD-tDCS applied on three consecutive days on central pain mechanisms in healthy participants with (N = 40) and without (N = 40) prolonged experimental pain induced by intramuscular injection of nerve growth factor into the right hand on Day 1. Participants were randomly assigned to Sham-tDCS (N = 20 with pain, N = 20 without) or Active-tDCS (N = 20 with pain, N = 20 without) targeting simultaneously the primary motor cortex and dorsolateral prefrontal cortex for 20 min with 2 mA stimulation intensity. Central pain mechanisms were assessed by cuff algometry on the legs measuring pressure pain sensitivity, temporal summation of pain (TSP) and conditioned pain modulation (CPM), at baseline and after HD-tDCS on Day 2 and Day 3. Based on subject's assessment of received HD-tDCS (sham or active), they were effectively blinded.

Results

Compared with Sham-tDCS, Active-tDCS did not significantly reduce the average NGF-induced pain intensity. Tonic pain-induced temporal summation at Day 2 and Day 3 was significantly lower in the NGF-pain group under Active-tDCS compared to the pain group with Sham-tDCS (p ≤ 0.05). No significant differences were found in the cuff pressure pain detection/tolerance thresholds or CPM effect across the 3 days of HD-tDCS in any of the four groups.

Conclusion

HD-tDCS reduced the facilitation of TSP caused by tonic pain suggesting that efficacy of HD-tDCS might depend on the presence of sensitized central pain mechanisms.     

When should I eat: A circadian view on food intake and metabolic regulation

The circadian clock is a hierarchical timing system regulating most physiological and behavioral functions with a period of approximately 24 h in humans and other mammalian species. The circadian clock drives daily eating rhythms that, in turn, reinforce the circadian clock network itself to anticipate and orchestrate metabolic responses to food intake. Eating is tightly interconnected with the circadian clock and recent evidence shows that the timing of meals is crucial for the control of appetite and metabolic regulation. Obesity results from combined long-term dysregulation in food intake (homeostatic and hedonic circuits), energy expenditure, and energy storage. Increasing evidence supports that the loss of synchrony of daily rhythms significantly impairs metabolic homeostasis and is associated with obesity. This review presents an overview of mechanisms regulating food intake (homeostatic/hedonic) and focuses on the crucial role of the circadian clock on the metabolic response to eating, thus providing a fundamental research axis to maintain a healthy eating behavior.