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Melittin is a major active ingredient of the bee venom produced by honeybees (Apis mellifera) that exerts various biological effects, such as anti-inflammatory, anti-tumor, anti-microbial, and antioxidant. The role of melittin in modulating melanin production by melanocytes is not known. Therefore, the present study aimed to study the effect of melittin on melanin production by human melanocytes along with its antioxidant status. Cultured human melanocytes were treated with melittin in a dose- and time-dependent manner, followed by the study of the cell viability, cell proliferation, and total melanin content. The effects of melittin in combination with narrow-band ultraviolet B (NB-UVB) on the total melanin content, melanocyte dendricity, oxidative stress, and the expression of genes associated with melanogenesis were investigated. An increased melanin content was observed with a low dose of melittin (LDM) (alone or in combination with NB-UVB), and there was a corresponding increase in the tyrosinase activity, melanocyte dendricity, and melanogenesis-associated genes. The present study concluded that LDM alone or LDM (+NB-UVB) can induce melanin synthesis by increasing the tyrosinase activity in melanocytes by limiting the oxidative stress, and this may be therapeutically exploited as an adjuvant therapy for vitiligo. [ABSTRACT FROM AUTHOR]

Cardiomyopathy (particularly dilated cardiomyopathy (DCM)) significantly contributes to development and progression of heart failure (HF), and inflammatory factors further deteriorate the symptoms. Morphological and functional defects of the heart in doxorubicin (DOX)-induced cardiomyopathy (cardiotoxicity) are similar to those of DCM. We used anagonist of PGC-1α (PPAR (peroxisome proliferator-activated receptor-gamma)-γ coactivator-1α) that is considered as the 'master regulator' of mitochondrial biogenesis with an aim to rescue the DOX-induced deleterious effects on the heart. Forty male C57BL/6J mice (8 weeks old) were divided in four groups, Control, DOX, ZLN005, and ZLN005 + DOX (n = 10 each group). The DOX-induced (10 mg/kg, single dose) cardiomyopathy mimics a DCM-like phenotype with marked morphologic alteration in cardiac tissue and functional derangements. Significant increased staining was observed for Masson Trichrome/Picrosirius red and α-Smooth Muscle Actinin (α-SMA) that indicated enhanced fibrosis in the DOX group compared to the control that was attenuated by (peroxisome proliferator-activated receptor-gamma (PPAR-γ) coactivator) (PGC)-1α (alpha) agonist (four doses of 2.5 mg/kg/dose; cumulative dose = 10 mg/kg). Similarly, elevated expression of necroptosis markers along with enhanced oxidative stress in the DOX group were alleviated by PGC-1α agonist. These data collectively suggested the potent therapeutic efficacy of PGC-1α agonist in mitigating the deleterious effects of DOX-induced cardiomyopathy, and it may be targeted in developing the future therapeutics for the management of DCM/HF. [ABSTRACT FROM AUTHOR]

This document is a letter in response to previous publications regarding the prevention of paradoxical flare of disease activity following rituximab (RTX) treatment. The authors discuss the role of secondary skin infections as a factor in post-rituximab paradoxical pemphigus flare in patients with pemphigus. The letter does not involve any patients and does not use artificial intelligence in its preparation. The authors are affiliated with the Department of Dermatology, Venereology and Leprosy at GCS Medical College Hospital and Research Centre in Ahmedabad, India. [Extracted from the article]

ABSTRACT: Tyrosinase and tyrosinase-related protein-2 (Tyrp2) play a pivotal role in melanin production within melanocytes. Both share a high degree of structural and sequence similarity, with a Root-Mean-Square Deviation (RMSD) of 0.75 Å and 62% sequence similarity, including 43% sequence identity. Despite these similarities, differences in the allosteric sites, particularly the residues that constitute these sites, contribute to distinct regulatory mechanisms. This study elucidates the contrasting allosteric modulation of tyrosinase and Tyrp2 by two flavonoids: (a) luteolin and (b) apigenin, respectively. Luteolin demonstrated its allosteric inhibitory property against tyrosinase by disturbing the spatial arrangement of histidine residues critical for copper coordination, essential for enzymatic activity. Conversely, apigenin serves as an allosteric activator for Tyrp2, enhancing structural stability and maintaining the active site conformation. Despite the structural resemblance between luteolin and apigenin, differentiated by a single hydroxyl group, their impact on melanin synthesis diverges — luteolin inhibits, whereas apigenin stimulates the process. Both showed high binding affinity at the allosteric site of tyrosinase and Tyrp2. Luteolin significantly alters the spatial arrangement of key histidine residues (HIS180, HIS202 and HIS211), forming coordination bonds in tyrosinase, affecting copper coordination and coordination with the peroxide (O22−) ion. However, apigenin did not remain bound to tyrosinase for an extended period, ruling out its role as an allosteric modulator. In contrast, apigenin stayed at the allosteric site of the Tyrp2 protein and showed a positive allosteric regulator role. The findings offer a mechanistic view of melanin synthesis regulation, demonstrating the potential of subtle structural variations in modulators to selectively influence enzyme activity in related biosynthetic pathways. This underscores the intricate control within melanogenic systems and the possibility of targeting these pathways for therapeutic and cosmetic applications. [ABSTRACT FROM AUTHOR]