Cells

Several small guanosine triphosphatases (GTPases) from the Ras protein superfamily regulate glucose-stimulated insulin secretion in the pancreatic islet β-cell. The Rho family GTPases Cdc42 and Rac1 are primarily involved in relaying key signals in several cellular functions, including vesicle trafficking, plasma membrane homeostasis, and cytoskeletal dynamics. They orchestrate specific changes at each spatiotemporal region within the β-cell by coordinating with signal transducers, guanine nucleotide exchange factors (GEFs), GTPase-activating factors (GAPs), and their effectors. The Arf family of small GTPases is involved in vesicular trafficking (exocytosis and endocytosis) and actin cytoskeletal dynamics. Rab-GTPases regulate pre-exocytotic and late endocytic membrane trafficking events in β-cells. Several additional functions for small GTPases include regulating transcription factor activity and mitochondrial dynamics. Importantly, defects in several of these GTPases have been found associated with type 2 diabetes (T2D) etiology. The purpose of this review is to systematically denote the identities and molecular mechanistic steps in the glucose-stimulated insulin secretion pathway that leads to the normal release of insulin. We will also note newly identified defects in these GTPases and their corresponding regulatory factors (e.g., GDP dissociation inhibitors (GDIs), GEFs, and GAPs) in the pancreatic β-cells, which contribute to the dysregulation of metabolism and the development of T2D.

The 70-kDa heat shock proteins (HSP70s) are abundantly present in cancer, providing malignant cells selective advantage by suppressing multiple apoptotic pathways, regulating necrosis, bypassing cellular senescence program, interfering with tumor immunity, promoting angiogenesis and supporting metastasis. This direct involvement of HSP70 in most of the cancer hallmarks explains the phenomenon of cancer “addiction” to HSP70, tightly linking tumor survival and growth to the HSP70 expression. HSP70 operates in different states through its catalytic cycle, suggesting that it can multi-function in malignant cells in any of these states. Clinically, tumor cells intensively release HSP70 in extracellular microenvironment, resulting in diverse outcomes for patient survival. Given its clinical significance, small molecule inhibitors were developed to target different sites of the HSP70 machinery. Furthermore, several HSP70-based immunotherapy approaches were assessed in clinical trials. This review will explore different roles of HSP70 on cancer progression and emphasize the importance of understanding the flexibility of HSP70 nature for future development of anti-cancer therapies.

Rice (Oryza sativa L.) is one of the most important food crops, feeding half of the world’s population. However, rice production is affected by cadmium (Cd) toxicity. Due to an increase in Cd-contaminated soil and rice grains, and the serious harm to human health from Cd, research on Cd uptake, transport and resistance in rice has been widely conducted, and many important advances have been made. Rice plants absorb Cd mainly from soil through roots, which is mediated by Cd absorption-related transporters, including OsNramp5, OsNramp1, OsCd1, OsZIP3, OsHIR1,OsIRT1 and OsIRT2. Cd uptake is affected by soil’s environmental factors, such as the concentrations of Cd and some other ions in soil, soil properties, and other factors can affect the bioavailability of Cd in soil. Then, Cd is transported within rice plants mediated by OsZIP6, OsZIP7, OsLCD, OsHMA2, CAL1, OsCCX2, OsLCT1 and OsMTP1, from roots to shoots and from shoots to grains. To resist Cd toxicity, rice has evolved many resistance strategies, including the deposition of Cd in cell walls, vacuolar Cd sequestration, Cd chelation, antioxidation and Cd efflux. In addition, some unresolved scientific questions surrounding Cd uptake, transport and resistance in rice are proposed for further study.

Ovarian cancer (OC) is the most lethal female gynecological malignancy, mostly due to diagnosis in late stages when treatment options are limited. Hedgehog-GLI (HH-GLI) signaling is a major developmental pathway involved in organogenesis and stem cell maintenance, and is activated in OC. One of its targets is survivin (BIRC5), an inhibitor of apoptosis protein (IAP) that plays a role in multiple processes, including proliferation and cell survival. We wanted to investigate the role of different GLI proteins in the regulation of survivin isoform expression (WT, 2α, 2B, 3B, and Δex3) in the SKOV-3 OC cell line. We demonstrated that survivin isoforms are downregulated in GLI1 and GLI2 knock-out cell lines, but not in the GLI3 knock-out. Treatment of GLI1 knock-out cells with GANT-61 shows an additional inhibitory effect on several isoforms. Additionally, we examined the expression of survivin isoforms in OC samples and the potential role of BIRC5 polymorphisms in isoform expression. Clinical samples showed the same pattern of survivin isoform expression as in the cell line, and several BIRC5 polymorphisms showed the correlation with isoform expression. Our results showed that survivin isoforms are regulated both by different GLI proteins and BIRC5 polymorphisms in OC.

Angiogenesis, a new vessel formation from the pre-existing ones, is essential for embryonic development, wound repair and treatment of ischemic heart and limb diseases. However, dysregulated angiogenesis contributes to various pathologies such as diabetic retinopathy, atherosclerosis and cancer. Reactive oxygen species (ROS) derived from NADPH oxidase (NOX) as well as mitochondria play an important role in promoting the angiogenic switch from quiescent endothelial cells (ECs). However, how highly diffusible ROS produced from different sources and location can communicate with each other to regulate angiogenesis remains unclear. To detect a localized ROS signal in distinct subcellular compartments in real time in situ, compartment-specific genetically encoded redox-sensitive fluorescence biosensors have been developed. Recently, the intercellular communication, “cross-talk”, between ROS derived from NOX and mitochondria, termed “ROS-induced ROS release”, has been proposed as a mechanism for ROS amplification at distinct subcellular compartments, which are essential for activation of redox signaling. This “ROS-induced ROS release” may represent a feed-forward mechanism of localized ROS production to maintain sustained signaling, which can be targeted under pathological conditions with oxidative stress or enhanced to promote therapeutic angiogenesis. In this review, we summarize the recent knowledge regarding the role of the cross-talk between NOX and mitochondria organizing the sustained ROS signaling involved in VEGF signaling, neovascularization and tissue repair.

Nghiên cứu về vi-rút gây hội chứng hô hấp cấp tính nặng coronavirus 2 (SARS-CoV2) hiện đang bị hạn chế trong các phòng thí nghiệm BSL-3. Các tiểu phần giống vi-rút (VLPs) của SARS-CoV2 cung cấp một hệ thống BSL-1, không có khả năng sao chép, có thể được sử dụng để đánh giá quá trình lắp ráp và xâm nhập của vi-rút vào tế bào trong các điều kiện nuôi cấy tế bào dễ kiểm soát. Tại đây, chúng tôi mô tả một hệ thống VLP của SARS-CoV2 sử dụng sự bổ sung các mảnh nanoluciferase (Nluc) để theo dõi quá trình lắp ráp và xâm nhập. Chúng tôi đã sử dụng hệ thống này theo hai cách. Đầu tiên, chúng tôi đã điều tra các yêu cầu để lắp ráp VLP. VLPs được sản xuất thông qua việc tổng hợp đồng thời ba protein màng của vi-rút, spike (S), envelope (E), và matrix (M), cùng với nucleocapsid chứa trong tế bào chất (N). Chúng tôi phát hiện rằng việc sản xuất và tiết VLP phụ thuộc rất nhiều vào các protein N. Các protein N từ các betacoronavirus liên quan có thể thay thế biến thiên cho N homologous của SARS-CoV2, và các protein N betacoronavirus hỗn hợp có hiệu quả trong việc hỗ trợ sản xuất VLP nếu chúng chứa các miền carboxy-terminal của N coronavirus 2 (CTD). Điều này xác định các CTD là các yếu tố quan trọng trong việc lắp ráp các tiểu phần vi-rút. Thứ hai, chúng tôi đã sử dụng hệ thống này bằng cách điều tra sự xâm nhập của vi-rút vào tế bào. VLPs được sản xuất với các mảnh peptide Nluc được gắn vào các protein E, M, hoặc N và sau đó mỗi loại được cấy vào tế bào mục tiêu biểu hiện các mảnh Nluc bổ sung. Việc bổ sung tạo thành Nluc chức năng được sử dụng để đánh giá sự xâm nhập của vi-rút vào tế bào. Chúng tôi phát hiện rằng mỗi VLP đều hiệu quả trong việc theo dõi sự xâm nhập của vi-rút vào tế bào, với mức độ khác nhau, phụ thuộc vào các yếu tố cảm thụ của tế bào chủ. Tổng thể, chúng tôi đã phát triển và sử dụng một hệ thống VLP có tính ứng dụng cao trong việc xác định các đặc điểm lắp ráp và xâm nhập của SARS-CoV2.

Skin undergoes continuous renewal throughout an individual’s lifetime relying on stem cell functionality. However, a decline of the skin regenerative potential occurs with age. The accumulation of senescent cells over time probably reduces tissue regeneration and contributes to skin aging. Keratinocytes and dermal fibroblasts undergo senescence in response to several intrinsic or extrinsic stresses, including telomere shortening, overproduction of reactive oxygen species, diet, and sunlight exposure. Epigenetic mechanisms directly regulate skin homeostasis and regeneration, but they also mark cell senescence and the natural and pathological aging processes. Progeroid syndromes represent a group of clinical and genetically heterogeneous pathologies characterized by the accelerated aging of various tissues and organs, including skin. Skin cells from progeroid patients display molecular hallmarks that mimic those associated with naturally occurring aging. Thus, investigations on progeroid syndromes strongly contribute to disclose the causal mechanisms that underlie the aging process. In the present review, we discuss the role of epigenetic pathways in skin cell regulation during physiologic and premature aging.

The mammalian or mechanistic target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) pathways regulate cell growth, differentiation, migration, and survival, as well as angiogenesis and metabolism. Dysregulation of these pathways is frequently associated with genetic/epigenetic alterations and predicts poor treatment outcomes in a variety of human cancers including cutaneous malignancies like melanoma and non-melanoma skin cancers. Recently, the enhanced understanding of the molecular and genetic basis of skin dysfunction in patients with skin cancers has provided a strong basis for the development of novel therapeutic strategies for these obdurate groups of skin cancers. This review summarizes recent advances in the roles of PI3K/Akt/mTOR and their targets in the development and progression of a broad spectrum of cutaneous cancers and discusses the current progress in preclinical and clinical studies for the development of PI3K/Akt/mTOR targeted therapies with nutraceuticals and synthetic small molecule inhibitors.

The AAA-ATPases Pex1 and Pex6 are required for the formation and maintenance of peroxisomes, membrane-bound organelles that harbor enzymes for specialized metabolism. Together, Pex1 and Pex6 form a heterohexameric AAA-ATPase capable of unfolding substrate proteins via processive threading through a central pore. Here, we review the proposed roles for Pex1/Pex6 in peroxisome biogenesis and degradation, discussing how the unfolding of potential substrates contributes to peroxisome homeostasis. We also consider how advances in cryo-EM, computational structure prediction, and mechanisms of related ATPases are improving our understanding of how Pex1/Pex6 converts ATP hydrolysis into mechanical force. Since mutations in PEX1 and PEX6 cause the majority of known cases of peroxisome biogenesis disorders such as Zellweger syndrome, insights into Pex1/Pex6 structure and function are important for understanding peroxisomes in human health and disease.

Growth hormone-releasing hormone (GHRH) is secreted primarily from the hypothalamus, but other tissues, including the lungs, produce it locally. GHRH stimulates the release and secretion of growth hormone (GH) by the pituitary and regulates the production of GH and hepatic insulin-like growth factor-1 (IGF-1). Pituitary-type GHRH-receptors (GHRH-R) are expressed in human lungs, indicating that GHRH or GH could participate in lung development, growth, and repair. GHRH-R antagonists (i.e., synthetic peptides), which we have tested in various models, exert growth-inhibitory effects in lung cancer cells in vitro and in vivo in addition to having anti-inflammatory, anti-oxidative, and pro-apoptotic effects. One antagonist of the GHRH-R used in recent studies reviewed here, MIA-602, lessens both inflammation and fibrosis in a mouse model of bleomycin lung injury. GHRH and its peptide agonists regulate the proliferation of fibroblasts through the modulation of extracellular signal-regulated kinase (ERK) and Akt pathways. In addition to downregulating GH and IGF-1, GHRH-R antagonist MIA-602 inhibits signaling pathways relevant to inflammation, including p21-activated kinase 1-signal transducer and activator of transcription 3/nuclear factor-kappa B (PAK1-STAT3/NF-κB and ERK). MIA-602 induces fibroblast apoptosis in a dose-dependent manner, which is an effect that is likely important in antifibrotic actions. Taken together, the novel data reviewed here show that GHRH is an important peptide that participates in lung homeostasis, inflammation, wound healing, and cancer; and GHRH-R antagonists may have therapeutic potential in lung diseases.