Development of small molecule drugs targeting immune checkpoints.

Immune checkpoint inhibitors (ICIs) are used to relieve and refuel anti-tumor immunity by blocking the interaction, transcription, and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints. Thousands of small molecule drugs or biological materials, especially antibody-based ICIs, are actively being studied and antibodies are currently widely used. Limitations, such as anti-tumor efficacy, poor membrane permeability, and unneglected tolerance issues of antibody-based ICIs, remain evident but are thought to be overcome by small molecule drugs. Recent structural studies have broadened the scope of candidate immune checkpoint molecules, as well as innovative chemical inhibitors. By way of comparison, small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features. Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions, including immune regulation, anti-angiogenesis, and cell cycle regulation. In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins, which will lay the foundation for further exploration.

Topological Electronic Transition Contributing to Improved Thermoelectric Performance in p-Type Mg3Sb2- xBix Solid Solutions.

Topological electronic transition is the very promising strategy for achieving high band degeneracy (NV) and for optimizing thermoelectric performance. Herein, this work verifies in p-type Mg3Sb2- xBix that topological electronic transition could be the key mechanism responsible for elevating the NV of valence band edge from 1 to 6, leading to much improved thermoelectric performance. Through comprehensive spectroscopy characterizations and theoretical calculations of electronic structures, the topological electronic transition from trivial semiconductor is unambiguously demonstrated to topological semimetal of Mg3Sb2- xBix with increasing the Bi content, due to the strong spin-orbit coupling of Bi and the band inversion. The distinct evolution of Fermi surface configuration and the multivalley valence band edge with NV of 6 are discovered in the Bi-rich compositions, while a peculiar two-step band inversion is revealed for the first time in the end compound Mg3Bi2. As a result, the optimal p-type Mg3Sb0.5Bi1.5 simultaneously obtains a positive bandgap and high NV of 6, and thus acquires the largest thermoelectric power factor of 3.54 and 6.93 µW cm-1 K-2 at 300 and 575 K, respectively, outperforming the values in other compositions. This work provides important guidance on improving thermoelectric performance of p-type Mg3Sb2- xBix utilizing the topological electronic transition.

Macrophage migration inhibitory factor mediates skin aging via CD74: Insights from single-cell and bulk RNA sequencing data.

Cell-cell communication is crucial for regulating signaling and cellular function. However, the precise cellular and molecular changes remain poorly understood in skin aging. Based on single-cell and bulk RNA data, we explored the role of cell-cell ligand-receptor interaction in skin aging. We found that the macrophage migration inhibitory factor (MIF)/CD74 ligand-receptor complex was significantly upregulatedin aged skin, showing the predominant paracrine effect of keratinocytes on fibroblasts. Enrichment analysis and in vitro experiment revealed a close association of the activation of the MIF/CD74 with inflammatory pathways and immune response. Mechanistically, MIF/CD74 could significantly inhibit PPARγ protein, which thus significantly increased the degree of fibroblast senescence, and significantly up-regulated the expression of senescence-associated secretory phenotype (SASP) factors and FOS gene. Therefore, our study reveals that MIF/CD74 inhibits the activation of the PPAR signaling pathway, subsequently inducing the production of SASP factors and the upregulation of FOS expression, ultimately accelerating fibroblast senescence.

LncRNA UCA1 promotes keratinocyte-driven inflammation via suppressing METTL14 and activating the HIF-1α/NF-κB axis in psoriasis.

Keratinocytes are closely associated with innate immunity and inflammatory responses, and are dysregulated during the development of psoriasis, but the underlying mechanisms are not yet fully understood. This work aims to reveal the effects of long non-coding RNA (lncRNA) UCA1 in psoriatic keratinocytes. UCA1 was identified as a psoriasis-related lncRNA that highly expressed in psoriatic lesions. The transcriptome and proteome data of keratinocyte cell line HaCaT showed that UCA1 could positively regulate inflammatory functions, such as response to cytokine. Furthermore, UCA1 silencing decreased inflammatory cytokine secretion and innate immunity gene expression in HaCaT, its culture supernatant also decreased the migration and tube formation ability of vascular endothelial cells (HUVECs). Mechanistically, UCA1 activated the NF-κB signaling pathway, which is regulated by HIF-1α and STAT3. We also observed a direct interaction between UCA1 and N6-methyladenosine (m6A) methyltransferase METTL14. Knocking down METTL14 counteracted the effects of UCA1 silencing, indicating that it can suppress inflammation. In addition, the levels of m6A-modified HIF-1α were decreased in psoriatic lesions, indicating that HIF-1α is a potential target of METTL14. Taken together, this work indicates that UCA1 positively regulates keratinocyte-driven inflammation and psoriasis development by binding to METTL14, and activating HIF-1α and NF-κB signaling pathway. Our findings provide new insights into the molecular mechanisms of keratinocyte-driven inflammation in psoriasis.

Cancer stem cells: a target for overcoming therapeutic resistance and relapse.

Cancer stem cells (CSCs) are a small subset of cells in cancers that are thought to initiate tumorous transformation and promote metastasis, recurrence, and resistance to treatment. Growing evidence has revealed the existence of CSCs in various types of cancers and suggested that CSCs differentiate into diverse lineage cells that contribute to tumor progression. We may be able to overcome the limitations of cancer treatment with a comprehensive understanding of the biological features and mechanisms underlying therapeutic resistance in CSCs. This review provides an overview of the properties, biomarkers, and mechanisms of resistance shown by CSCs. Recent findings on metabolic features, especially fatty acid metabolism and ferroptosis in CSCs, are highlighted, along with promising targeting strategies. Targeting CSCs is a potential treatment plan to conquer cancer and prevent resistance and relapse in cancer treatment.

Temperature-Driven Twin Structure Formation and Electronic Structure of Epitaxially Grown Mg3Sb2 Films on Mismatched Substrates.

Mg3Sb2-based compounds are one type of important room-temperature thermoelectric materials and the appropriate candidate of type-II nodal line semimetals. In Mg3Sb2-based films, compelling research topics such as dimensionality reduction and topological states rely on the controllable preparation of films with high crystallinity, which remains a big challenge. In this work, high quality Mg3Sb2 films are successfully grown on mismatched substrates of sapphire (000l), while the temperature-driven twin structure evolution and characteristics of the electronic structure are revealed in the as-grown Mg3Sb2 films by in situ and ex situ measurements. The transition of layer-to-island growth of Mg3Sb2 films is kinetically controlled by increasing the substrate temperature (Tsub), which is accompanied with the rational manipulation of twin structure and epitaxial strains. Twin-free structure could be acquired in the Mg3Sb2 film grown at a low Tsub of 573 K, while the formation of twin structure is significantly promoted by elevating the Tsub and annealing, in close relation to the processes of strain relaxation and enhanced mass transfer. Measurements of scanning tunneling spectroscopy (STS) and angle-resolved photoemission spectroscopy (ARPES) elucidate the intrinsic p-type conduction of Mg3Sb2 films and a bulk band gap of ~0.89 eV, and a prominent Fermi level downshift of ~0.2 eV could be achieved by controlling the film growth parameters. As elucidated in this work, the effective manipulation of the epitaxial strains, twin structure and Fermi level is instructive and beneficial for the further exploration and optimization of thermoelectric and topological properties of Mg3Sb2-based films.

[The physiological and psychological mechanisms of infra-slow oscillation].

Infra-slow oscillation (ISO) is a kind of brain rhythm between 0.01 and 0.5 Hz. ISO is widely distributed in multiple brain regions. As an important psychophysiological activity, the ISO interacts with high-frequency neural rhythm via cross-frequency coupling, but has different activity patterns from high-frequency neural activity. Physiologically, the ISO may be generated by the dynamic activity of thalamus, glia, and ions. Psychologically, the frequency, amplitude, and phase of ISO could all regulate cognitive activities, but in different ways. Investigations on the ISO expands the neural rhythm research to lower frequency range, further promoting the construction of rhythmic theory of brain function.

Global Signal Topography of the Human Brain: A Novel Framework of Functional Connectivity for Psychological and Pathological Investigations.

The global signal (GS), which was once regarded as a nuisance of functional magnetic resonance imaging, has been proven to convey valuable neural information. This raised the following question: what is a GS represented in local brain regions? In order to answer this question, the GS topography was developed to measure the correlation between global and local signals. It was observed that the GS topography has an intrinsic structure characterized by higher GS correlation in sensory cortices and lower GS correlation in higher-order cortices. The GS topography could be modulated by individual factors, attention-demanding tasks, and conscious states. Furthermore, abnormal GS topography has been uncovered in patients with schizophrenia, major depressive disorder, bipolar disorder, and epilepsy. These findings provide a novel insight into understanding how the GS and local brain signals coactivate to organize information in the human brain under various brain states. Future directions were further discussed, including the local-global confusion embedded in the GS correlation, the integration of spatial information conveyed by the GS, and temporal information recruited by the connection analysis. Overall, a unified psychopathological framework is needed for understanding the GS topography.

UVB-Induced ciRS-7 Activates Melanogenesis by Paracrine Effects.

Antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as or ciRS-7) is an important member of the circular RNA family and is involved in the regulation of numerous biological functions. Keratinocytes and fibroblasts (FBs) affect melanogenesis through paracrine effects. However, whether ciRS-7 is involved in melanogenesis by regulating paracrine effects remains unclear. This study demonstrates for the first time that ciRS-7 is highly expressed in keratinocytes, FBs, and melanocytes (MCs). Ultraviolet B (UVB) irradiation promotes ciRS-7 expression in keratinocytes and FBs. Following inhibition of ciRS-7 expression in keratinocytes and FBs, the culture supernatant from these cells inhibited melanogenesis of MCs. Further analyses revealed that the expression and secretion of fibroblast growth factor 2 (FGF2) and phosphorylation of STAT3 and AKT in keratinocytes and FBs were significantly downregulated following inhibition of ciRS-7 expression, whereas the level of miR-7 was increased. Overexpression of miR-7 in keratinocytes and FBs significantly inhibited the expression of FGF2. In conclusion, our findings demonstrate that UVB-induced ciRS-7 triggers melanogenesis in MCs through regulation of the miR-7/STAT3 and AKT/FGF2 paracrine axis in both keratinocytes and FBs. ciRS-7 may serve as a regulator in the development of pigmented skin diseases.

Identification of the ceRNA networks in α-MSH-induced melanogenesis of melanocytes.

α-MSH is known for melanogenesis stimulation, and ceRNA is a new method involved in physiological regulation. However, whether ceRNA participates in α-MSH-induced melanogenesis remains unknown. We used ceRNA array to detect the expression profiles of lncRNAs, circRNAs, and mRNAs in melanocytes after α-MSH treatment. Moreover, the melanogenesis-related ceRNA regulatory networks were screened and validated. The expression profile analysis showed that 20 lncRNAs and 49 circRNAs changed five-fold after α-MSH treatment, while 933 mRNAs changed two-fold. Based on differentially expressed genes, GO and KEGG analysis were conducted and revealed that 14 genes were enriched in melanogenesis. Then, multiple lncRNA or circRNA-miRNA-mRNA ceRNA networks and lncRNA/circRNA-miRNA-mRNA quaternary ceRNA networks were identified. Thereinto, ENST00000606533, circ_0091223, and TYR expression were upregulated in α-MSH-treated melanocytes, while their complementary miR-1291 was decreased. Dual-luciferase reporter assay further verified that ENST00000606533 and circ_0091223 could bind to miR-1291. ENST00000606533 and circ_0091223 siRNAs decreased circ_0091223, ENST00000606533, and TYR expression, but increased miR-1291 expression. Conversely, miR-1291 mimics inhibited ENST00000606533, circ_0091223, and TYR expression. Moreover, miR-1291 inhibitor could reverse the inhibitory effect of the two siRNAs on TYR expression. Hence, the "ENST00000606533/circ_0091223-miR-1291-TYR" ceRNA network is involved in α-MSH-induced melanogenesis, and ceRNA networks may be potential therapeutic targets for skin pigmentation disorders.

Spatial variability of low frequency brain signal differentiates brain states.

Temporal variability of the neural signal has been demonstrated to be closely related to healthy brain function. Meanwhile, the evolving brain functions are supported by dynamic relationships among brain regions. We hypothesized that the spatial variability of brain signal might provide important information about brain function. Here we used the spatial sample entropy (SSE) to investigate the spatial variability of neuroimaging signal during a steady-state presented face detection task. Lower SSE was found during task state than during resting state, associating with more repetitive functional interactions between brain regions. The standard deviation (SD) of SSE during the task was negatively related to the SD of reaction time, suggesting that the spatial pattern of neural activity is reorganized according to particular cognitive function and supporting the previous theory that greater variability is associated with better task performance. These results were replicated with reordered data, implying the reliability of SSE in measuring the spatial organization of neural activity. Overall, the present study extends the research scope of brain signal variability from the temporal dimension to the spatial dimension, improving our understanding of the spatiotemporal characteristics of brain activities and the theory of brain signal variability.

Field-effect transistor bioassay for ultrasensitive detection of folate receptor 1 by ligand-protein interaction.

A miniaturized and integrated bioassay was developed based on molybdenum disulfide (MoS2) field-effect transistor (FET) functionalized with bovine serum albumin-folic acid (BSA-FA) for monitoring FOLR1. We performed the electrical test of FOLR1 within the range 100 fg/mL to 10 ng/mL, and the limit of detection was 0.057 pg/mL. The ultrahigh sensitivity of the bioassay was realized by ligand-protein interaction between FA and FOLR1, with a ligand-protein binding ratio of 3:1. The formation of FA-FOLR1 was confirmed with ELISA. The binding affinity dissociation constant KD was 12 ± 6 pg/mL. This device can work well for FOLR1 detection in human serum, which presents its promising application in point-of-care diagnosis. This study supports the future applications of such ligand-protein-based bioassays in the clinical practices. Graphical abstract MoS2-based FET device for detecting folate receptor 1 (FOLR1) was fabricated. The molecular folic acid as a probe can specifically bound to FOLR1 with a high affinity.

Frequency-dependent circuits anchored in the dorsal and ventral left anterior insula.

The hub role of the right anterior insula (AI) has been emphasized in cognitive neurosciences and been demonstrated to be frequency-dependently organized. However, the functional organization of left AI (LAI) has not been systematically investigated. Here we used 100 unrelated datasets from the Human Connectome Project to study the frequency-dependent organization of LAI along slow 6 to slow 1 bands. The broadband functional connectivity of LAI was similar to previous findings. In slow 6-slow 3 bands, both dorsal and ventral seeds in LAI were correlated to the salience network (SN) and language network (LN) and anti-correlated to the default mode network (DMN). However, these seeds were only correlated to the LAI in slow 2-slow 1 bands. These findings indicate that broadband and narrow band functional connections reflect different functional organizations of the LAI. Furthermore, the dorsal seed had a stronger connection with the LN and anti-correlation with DMN while the ventral seed had a stronger connection within the SN in slow 6-slow 3 bands. In slow 2-slow 1 bands, both seeds had stronger connections with themselves. These observations indicate distinctive functional organizations for the two parts of LAI. Significant frequency effect and frequency by seed interaction were also found, suggesting different frequency characteristics of these two seeds. The functional integration and functional segregation of LDAI and LVAI were further supported by their cognitive associations. The frequency- and seed-dependent functional organizations of LAI may enlighten future clinical and cognitive investigations.

Cistanche deserticola polysaccharide induces melanogenesis in melanocytes and reduces oxidative stress via activating NRF2/HO-1 pathway.

As a main part of pigmentation disorders, skin depigmentation diseases such as vitiligo and achromic naevus are very common and get more attention now. The pathogenesis of depigmentation includes melanocyte dysfunction and loss, which are possibly caused by heredity, autoimmunity and oxidative stress. Among them, oxidative stress plays a key role; however, few clinical treatments can deal with oxidative stress. As reported, Cistanche deserticola polysaccharide (CDP) is an effective antioxidant; based on that, we evaluated its role in melanocyte and further revealed the mechanisms. In this study, we found that CDP could promote melanogenesis in human epidermal melanocytes (HEMs) and mouse melanoma B16F10 cells, it also induced pigmentation in zebrafish. Furthermore, CDP could activate mitogen-activated protein kinase (MAPK) signal pathway, then up-regulated the expression of microphthalmia-associated transcription factor (MITF) and downstream genes TYR, TRP1, TRP2 and RAB27A. Otherwise, we found that CDP could attenuate H2 O2 -induced cytotoxicity and apoptosis in melanocytes. Further evidence revealed that CDP could enhance NRF2/HO-1 antioxidant pathway and scavenge intracellular ROS. In summary, CDP can promote melanogenesis and prevent melanocytes from oxidative stress injury, suggesting that CDP helps maintain the normal status of melanocytes. Thus, CDP may be a novel drug for the treatment of depigmentation diseases.

Roles of inflammation factors in melanogenesis (Review).

The occurrence of hyperpigmentation or hypopigmentation after inflammation is a common condition in dermatology and cosmetology. Since the exact mechanism of its occurrence is not yet known, prevention and treatment are troublesome. Previous studies have confirmed that α­melanocyte­stimulating hormone, stem cell factor and other factors can promote melanogenesis­related gene expression through the activation of signaling pathways. Recent studies have revealed that a variety of inflammatory mediators can also participate in the regulation of melanogenesis in melanocytes. In this review, we summarized that interleukin­18, interleukin­33, granulocyte­macrophage colony stimulating factor, interferon­Î³, prostaglandin E2 have the effect of promoting melanogenesis, while interleukin­1, interleukin­4, interleukin­6, interleukin­17 and tumor necrosis factor can inhibit melanogenesis. Further studies have found that these inflammatory factors may activate or inhibit melanogenesis­related signaling pathways (such as protein kinase A and mitogen activated protein kinase) by binding to corresponding receptors, thereby promoting or inhibiting the expression of melanogenesis­related genes and regulating skin pigmentation processes. This suggests that the development of drugs or treatment methods from the perspective of regulating inflammation can provide new ideas and new targets for the treatment of pigmented dermatosis. This review outlines the current understanding of the inflammation factors' roles in melanogenesis.

The Long Noncoding RNA UCA1 Negatively Regulates Melanogenesis in Melanocytes.

The long noncoding RNA UCA1 was first discovered in bladder cancer and is known to regulate the proliferation and migration of melanoma. However, its role in melanogenesis is unclear. In this study, we aimed to explore the role and mechanism of UCA1 in melanogenesis. Our findings showed that the expression of UCA1 was negatively correlated with melanin content in melanocytes and pigmented nevus. Overexpression of UCA1 in melanocytes decreased melanin content and the expression of melanogenesis-related genes, whereas knockdown of UCA1 in melanocytes had the opposite effect. High-throughput sequencing revealed that microphthalmia-associated transcription factor (MITF), an important transcription factor affecting melanogenesis, was also negatively correlated with the expression of UCA1. Furthermore, the transcription factor CRE-binding protein (CREB), which promotes MITF expression, was negatively regulated by UCA1. The cAMP/protein kinase A (PKA), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) signaling pathways, which are upstream of the CREB/MITF/melanogenesis axis, were activated or inhibited in response to silencing or enhancing UCA1 expression, respectively. In addition, enhanced UCA1 expression downregulates the expression of melanogenesis-related genes induced by UVB in melanocytes. In conclusion, UCA1 may negatively regulate the CREB/MITF/melanogenesis axis through inhibiting the cAMP/PKA, ERK, and JNK signaling pathways in melanocytes. UCA1 may be a potential therapeutic target for the treatment of pigmented skin diseases.

Ganoderma lucidum polysaccharide reduces melanogenesis by inhibiting the paracrine effects of keratinocytes and fibroblasts via IL-6/STAT3/FGF2 pathway.

Our previous study found that Ganoderma lucidum polysaccharide (GLP), bioactive ingredients from Ganoderma lucidum, protected fibroblasts from photoaging. However, whether GLP can affect melanogenesis in melanocytes through regulating paracrine mediators that secreted by keratinocytes and fibroblasts is unclear. We aimed to investigate the efficacy and mechanisms of action of GLP in melanogenesis by regulating paracrine effects of keratinocytes and fibroblasts. The effect of GLP on cell viability affected by GLP was measured by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. After an immortal keratinocyte line (HaCaT) and primary fibroblasts (FB) were treated with GLP, the supernatants of HaCaT and FB cells were collected and cocultured with an immortalized melanocyte line (PIG1). The expression levels of melanogenesis-associated genes in PIG1 cells were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. Furthermore, FRS-2, ERK, JNK, and p38 phosphorylation levels were measured. Then, major melanogenic paracrine mediators in HaCaT and FB cells treated with GLP were evaluated by qRT-PCR and enzyme-linked immunosorbent assay (ELISA). In addition, the expression of IL-6 and STAT3 was examined in HaCaT and FB cells. GLP was not cytotoxic to HaCaT and FB cells. The supernatants of GLP-treated HaCaT and FB cells downregulated the expression levels of MITF, TYR, TYRP1, TYRP2, RAB27A, and FSCN1 genes and inhibited the phosphorylation of FRS-2, ERK, JNK, and p38 in PIG1 cells. GLP also decreased FGF2 secretion in HaCaT and FB cells. Moreover, GLP reduced IL-6 expression and STAT3 phosphorylation in HaCaT and FB cells. GLP reduced melanogenesis in melanocytes by inhibiting the paracrine effects of keratinocytes and fibroblasts via IL-6/STAT3/FGF2 pathway.

Ganoderma lucidum polysaccharide inhibits UVB-induced melanogenesis by antagonizing cAMP/PKA and ROS/MAPK signaling pathways.

Ultraviolet (UV)-induced pigmentation is very common in clinical practice, but the current treatments are rarely effective, accompanied by some side effects. Ganoderma lucidum polysaccharide (GLP) is a natural antioxidant with no toxic side effects, which can antagonize UVB-induced fibroblast photo aging. The study aims to explore the role of GLP in inhibiting UVB-induced melanogenesis and its possible mechanism. The expression of melanogenesis genes such as microphthalmia-associated transcription factor (MITF), tyrosine (TYR), tyrosinase related protein 1 (TYRP1), tyrosinase related protein 2 (TYRP2), ras-related protein Rab-27A (Rab27A), and Myosin shows an upward trend after exposure of B16F10 and PIG1 cells to UVB irradiation, but GLP can downregulate the expression of genes related to UVB-induced melanogenesis. GLP can inhibit UVB-activated protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) signaling pathways. Besides, GLP protects mitochondria from UVB damage and inhibits reactive oxygen species (ROS) production. Also, UVB-induced cyclic adenosine monophosphate (cAMP) can be inhibited. It has been found in the experiments of UVB-induced skin pigmentation in zebrafish that GLP is capable of inhibiting UVB-induced skin pigmentation. Meanwhile, it can greatly relieve erythema reaction in guinea pig skin caused by high-dosage UVB irradiation. In conclusion, this study shows that GLP can inhibit UVB-induced melanogenesis by antagonizing cAMP/PKA and ROS/MAPK signaling pathways and is a potential natural safe whitening sunscreen additive.