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INTRODUCTION: Current treatment for Type 1 diabetes (T1D) is centered around insulin supplementation to manage the effects of pancreatic β cell loss. GDF15 is a potential preventative therapy against T1D progression that could work to curb increasing disease incidence. AREAS COVERED: This paper discusses the known actions of GDF15, a pleiotropic protein with metabolic, feeding, and immunomodulatory effects, connecting them to highlight the open opportunities for future research. The role of GDF15 in the prevention of insulitis and protection of pancreatic β cells against pro-inflammatory cytokine-mediated cellular stress are examined and the pharmacological promise of GDF15 and critical areas of future research are discussed. EXPERT OPINION: GDF15 shows promise as a potential intervention but requires further development. Preclinical studies have shown poor efficacy, but this result may be confounded by the measurement of gross GDF15 instead of the active form. Additionally, the effect of GDF15 in the induction of anorexia and nausea-like behavior and short-half-life present significant challenges to its deployment, but a systems pharmacology approach paired with chronotherapy may provide a possible solution to therapy for this currently unpreventable disease.

Extracellular vesicles (EVs) play important roles in cell-to-cell communication and are potential biomarkers as they carry markers of their derived tissues and disease signatures. However, obtaining pure EV preparations from biofluids is challenging due to contaminants with similar physicochemical properties. Here, we performed a meta-analysis of plasma EV proteomics data deposited in public repositories to refine the protein composition of EVs and investigate potential roles in type 1 diabetes development. With the concept that each purification method yields different proportions of distinct contaminants, we grouped proteins into clusters based on their abundance profiles. This allowed us to separate clusters with classical EV markers, such as CD9, CD40, C63 and CD81, from clusters of well-known contaminants, such as serum albumin, apolipoproteins and components of the complement and coagulation pathways. Two clusters containing a total of 1720 proteins combined were enriched with EV markers and depleted in common contaminants; therefore, they were considered to contain bona fide EV components. As possible origins of plasma EVs, these clusters had markers of tissues such as spleen, liver, brain, lungs, pancreas, and blood/immune cells. These clusters were also enriched in cell surface markers CD antigens, and proteins from cell-to-cell communication and signaling pathways, such as chemokine signaling and antigen presentation. We also show that the EV component and type 1 diabetes biomarker, platelet basic protein (PPBP/CXCL7) regulates apoptosis in both beta and macrophage cell lines. Overall, our meta-analysis refined the composition of plasma EVs, reinforcing a primary function as messengers for cell-to-cell communication and signaling. Furthermore, this analysis identifies optimal avenues to target EVs for development of disease biomarkers.

A 3-y-3-mo old male child presented with massive hypertrophy and bluish-purple discoloration of the left upper limb and adjacent chest wall of 3 mo duration. There was no h/o fever, weight loss, painful large joint swelling, or any bleeding manifestations. He had spindle like nonprogressive, painless swelling of all fingers of the left hand since infancy. The child was moribund with microangiopathic hemolytic anemia, thrombocytopenia, and consumptive coagulopathy without sepsis. He received multiple transfusions of fresh frozen plasma (FFP), platelets, and packed RBC. Paradoxical worsening of symptoms with platelet transfusions and radiological evidences led to the diagnosis of a very rare congenital multifocal vascular tumor, kaposiform hemangioendothelioma (KHE) with Kasabach-Merritt phenomenon (KMP). The index case of KHE was multifocal with cutaneous lesions, osteolytic bony lesions of all phalanx and metacarpals of the left hand, and intrathoracic extension. It was successfully managed with a combination of steroid, vincristine and sirolimus.

Solid tumors are commonly treated with cisplatin, which can cause off-target side effects in cancer patients. Chronotherapy is a potential strategy to reduce drug toxicity. To determine the effectiveness of timed-cisplatin treatment in mammals, we compared two conditions: clock disrupted jet-lag and control conditions. Under normal and disrupted clock conditions, triple-negative mammary carcinoma cells were injected subcutaneously into eight-week-old NOD. Cg-Prkdc(scid)/J female mice. Tumor volumes and body weights were measured in these mice before and after treatment with cisplatin. We observed an increase in tumor volumes in mice housed under disrupted clock compared to the normal clock conditions. After treatment with cisplatin, we observed a reduced tumor growth rate in mice treated at ZT10 compared to ZT22 and untreated cohorts under normal clock conditions. However, these changes were not seen with the jet-lag protocol. We also observed greater body weight loss in mice treated with ZT10 compared to ZT22 or untreated mice in the jet-lag protocol. Our observations suggest that the effectiveness of cisplatin in mammary carcinoma treatment is time-dependent in the presence of the circadian clock.

Solar ultraviolet B radiation (UVB) is one of the leading causes of various skin conditions, including photoaging, sunburn erythema and melanoma. As a protective response, the skin has inbuilt defense mechanisms, including DNA repair, cell cycle checkpoint, apoptosis, and melanin synthesis, of which DNA repair, cell cycle and apoptosis have been shown to be under control of the circadian clock. However, the mechanism by which the circadian clock regulates melanin synthesis is not well understood. Using human melanocytes and melanoma cells under circadian synchronized conditions, we report that the microphthalmia-associated transcription factor (MITF), a rate-limiting protein in melanin synthesis, is expressed rhythmically with 24-hour periodicity in the presence of BMAL1, a canonical clock protein. We further demonstrate that BMAL1 binds to the promoter region of MITF and transcriptionally regulates its expression, which positively influences melanin synthesis. Finally, we report that an increase in melanin levels due to BMAL1 overexpression protects human melanoma cells from UVB. In conclusion, our studies provide novel insights to the mechanistic role of the circadian clock in melanin synthesis and protection against UVB mediated DNA damage and genomic instability. SIGNIFICANCE: Melanin synthesis in melanocytes is an endogenous protective mechanism of the skin against solar ultraviolet B radiation (UVB). The present study shows that MITF, a rate-limiting protein in the melanin synthesis pathway, is transcriptionally regulated by BMAL1, a canonical clock protein, and positively influences melanin synthesis which potentially protects the skin cells against UVB. Therefore, the mechanism of MITF regulation by the circadian clock protein BMAL1 is one of the additional regulatory mechanisms may contribute to the defensive arsenal of the skin against solar UVB.

A 3-y-3-mo old male child presented with massive hypertrophy and bluish-purple discoloration of the left upper limb and adjacent chest wall of 3 mo duration. There was no h/o fever, weight loss, painful large joint swelling, or any bleeding manifestations. He had spindle like nonprogressive, painless swelling of all fingers of the left hand since infancy. The child was moribund with microangiopathic hemolytic anemia, thrombocytopenia, and consumptive coagulopathy without sepsis. He received multiple transfusions of fresh frozen plasma (FFP), platelets, and packed RBC. Paradoxical worsening of symptoms with platelet transfusions and radiological evidences led to the diagnosis of a very rare congenital multifocal vascular tumor, kaposiform hemangioendothelioma (KHE) with Kasabach-Merritt phenomenon (KMP). The index case of KHE was multifocal with cutaneous lesions, osteolytic bony lesions of all phalanx and metacarpals of the left hand, and intrathoracic extension. It was successfully managed with a combination of steroid, vincristine and sirolimus.

Doxorubicin (also called Adriamycin) is effective in treating a wide range of human cancers and currently considered as one of the most important drugs in cancer chemotherapeutics. The clinical use of doxorubicin is, however, associated with dosage-dependent cardiotoxicity and development of heart failure, which diminish the therapeutic index of this widely used anticancer drug. This article first surveys key research findings on doxorubicin redox biology that may impact its cardiotoxicity as well as anticancer activity. It then discusses emerging concepts, especially the topoisomerase IIb-p53-mitochondrion axis that may lead to the development of mechanistically based novel strategies to protect against cardiotoxicity and enhance the effectiveness of doxorubicin therapy.

Acute exposure of skin to UV-B causes DNA damage and sunburn erythema in both mice and humans. Previous studies documented time-of-day-related differences in sunburn responses after UV-B exposure in mice. Because humans are diurnal and mice are nocturnal, the circadian rhythm in human skin was hypothesized to be in opposite phase to the rhythm in mice. A study by Nikkola et al. demonstrates that humans are more prone to sunburn erythema after evening exposure to solar UV-B radiation as compared with morning exposure.

Animal models are essential for developing effective drugs for treating human cancer. Examination of the formation of lung surface foci of B16-F10 melanoma cells is a widely used animal model for studying cancer metastasis and drug intervention. This model, however, suffers from several drawbacks, including its non-quantitative nature and inability to yield information on cancer cell load inside the target organ. Here we report the development of a highly sensitive, bioluminescence-based method for quantifying melanoma cell load in mouse lungs following intravenous injection of luciferase-expressing B16-F10 melanoma cells. This method could readily detect as few as 1-10 cells in the samples and enable quantification of cancer cell load before the formation of surface foci in mouse lungs following metastasis of intravenously inoculated B16-F10 melanoma cells. This innovative bioluminometry-based method has important implications for studying anticancer drugs, including naturally occurring redox-active quinones that generate reactive oxygen species to kill cancer cells.