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Cell-free compounds of mesenchymal stem cells (MSCs) could be a safer and cheaper substitution for MSC transplantation and have gained substantial research interest for antiaging skin treatments. However, whether those bioactive components should be obtained from the cytoplasm or supernatant is yet to be determined. In this study, we examined the ingredients of the MSC cytoplasm extract (MSC-ex) and MSC supernatant (MSC-s) and evaluated their effect in a photoaging model. Although MSC-ex has a richer protein composition than MSC-s, the latter has a proteome associated with wound healing and blood vessel development. Over 85% of the proteins in MSC-s were also found in MSC-ex, including extracellular matrix protein and various growth factors. The results of real-time PCR and western blot also demonstrate that both MSC-s and MSC-ex can upregulate collagen, transforming growth factor β (TGF-β), and vascular endothelial growth factor (VEGF) and downregulate IL-1β and matrix metalloproteinase-1 (MMP-1), which were considered critical for antiphotoaging. This supports our observations in the Hematoxylin and Eosin (HE) and Masson staining assay that they have a comparable effect as MSCs in terms of enhancing dermal thickness, and stimulating collagen regeneration. Although MSC-s and MSC-ex showed a weaker immunosuppression effect than MSCs, moisture measurement showed that they repair damage more rapidly than MSCs. Furthermore, the histological results showed that MSC-s maintains a super effect on immunosuppression, epidermal repair, and angiogenesis. That may be associated with the higher content of laminin, TGF-β, and VEGF in MSC-s, as well as its super cytokine transcriptional regulation ability. Thus, both MSC-s and MSC-ex can safely and effectively promote the repair of skin light injury, similar to MSCs. Our findings can broaden the range of active factors available in cell-free treatment, determine the difference between MSC-s and MSC-ex, and provide a reference for the development of similar products in regenerative medicine.

Birefringence is a fundamental optical property that can induce phase retardation of polarized light. Tuning the birefringence of liquid crystals is a core technology for light manipulation in current applications in the visible and infrared spectral regions. Due to the strong absorption or instability of conventional liquid crystals in deep-ultraviolet light, tunable birefringence remains elusive in this region, notwithstanding its significance in diverse applications. Here we show a stable and birefringence-tunable deep-ultraviolet modulator based on two-dimensional hexagonal boron nitride. It has an extremely large optical anisotropy factor of 6.5 × 10

Proteins of the RNF183 (RING finger 183) family proteins have been reported to be of great importance in tumor the initiation and progression. However, the biological role and regulatory mechanism of RNF183 in non small cell lung cancer (NSCLC) development and progression are poorly defined. Hence, lung adenocarcinoma (LUAD) cell proliferation, cell apoptosis and cell cycle were measured using Cell Counting Kit-8 and flow cytometry analysis, respectively. The correlation between RNF183 and SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase) was measured using coimmunoprecipitation and ubiquitination analysis in vitro. Tumor growth of NSCLC cells in vivo was measured using the nude mouse xenograft model. In this study, we verify that elevated RNF183 expression in tumor tissues of LUAD, origin from the TCGA, GEPIA, TIMER, and UALCAN database. RNF183 regulates apoptosis and cell cycle in vitro and tumor growth in vivo by activating the STAT3 pathway through ubiquitination of SHP2, a negative feedback regulator of the STAT3 pathway. Taken together, our results demonstrate that RNF183 regulates proliferation, apoptosis, and cell cycle in LUAD cells via modulation of SHP2/STAT3 signaling, suggesting the potential for targeting the RNF183-SHP2/STAT3 pathway for use in LUAD treatment.

Journal of the American Chemical Society 145(1), 152 - 159 (2023). doi:10.1021/jacs.2c09007, Crystalline coordination polymers with high electrical conductivities and charge carrier mobilities might open new opportunities for electronic devices. However, current solvent-based synthesis methods hinder compatibility with microfabrication standards. Here, we describe a solvent-free chemical vapor deposition method to prepare high-quality films of the two-dimensional conjugated coordination polymer Cu-BHT (BHT = benzenehexanothiolate). This approach involves the conversion of a metal oxide precursor into Cu-BHT nanofilms with a controllable thickness (20–85 nm) and low roughness (, Published by ACS Publications, Washington, DC

Collective behavior widely exists in nature, ranging from the macroscopic cloud of swallows to the microscopic cloud of colloidal particles. The behavior of an individual inside the collective is distinctive from its behavior alone, as it follows its neighbors. The introduction of such collective behavior in two-dimensional (2D) materials may offer new degrees of freedom to achieve desired but unattained properties. Here, we report a highly sensitive magneto-optic effect and transmissive magneto-coloration via introduction of collective behavior into magnetic 2D material dispersions. The increase of ionic strength in the dispersion enhances the collective behavior of colloidal particles, giving rise to a magneto-optic Cotton-Mouton coefficient up to 2700 T-2 m-1 which is the highest value obtained so far, being 3 orders of magnitude larger than other known transparent media. We also reveal linear dependence of magneto-coloration on the concentration and hydration ratios of ions. Such linear dependence and the extremely large Cotton-Mouton coefficient cooperatively allow fabrication of giant magneto-birefringent devices for color-centered visual sensing.

The calcineurin inhibitor-FK506-is a first-line immunosuppressant that regulates T cell secretion of IL-2 and other cytokines. However, the mechanism of its protective effect on target cells and its role on tumour recurrence and interaction with anti-tumour immune checkpoint inhibitors, such as PD-L1 blocking, are still unclear. Here, in a murine heart transplantation model, we observed the upregulation of programmed death-ligand 1 (PD-L1) expression by FK506 in both dendritic cells (DCs) and allografts. Blocking PD-L1 during FK506 treatment increased IFN-γ and TNF-α expression, enhanced CD4

Cold storage for organ preservation in kidney transplantation is a core predisposing factor for delayed graft function and the long-term outcome of transplanted kidneys. Hydroxysafflor yellow A (HSYA) is the most effective water-soluble active monomer in Safflower with a strong property of inhibiting hypoxia and reoxygenation (H/R). However, the evidence concerning the effect of HSYA on H/R in kidney transplantation is limited. To investigate whether HSYA has a protective effect on cold H/R injury，we investigated the possible protective mechanism. Here, we incubated HK-2 cells to establish a cold H/R model and observed HSYA activation in an in vitro model of cold-storage rewarming which included the cell survival rate, cell morphology and ultrastructure, protein expression of Bcl-2, Bax, CytC, Apaf-1, and caspase-3, and status of mitochondrial permeability transformation pores (MPTPs). Our data showed that HSYA pretreatment increased the survival rate of the cells, alleviated mitochondrial damage, decreased the expression of apoptosis-related proteins and inhibited the openness of mitochondrial permeability transformation pores. Our findings suggested that HSYA may be a major predisposing mediator of mitochondrial apoptosis and renal tubular injury in cold storage-associated transplantation and may be an effective therapeutic target for improving graft function and graft survival.

Proteins of the RNF183 (RING finger 183) family proteins have been reported to be of great importance in tumor the initiation and progression. However, the biological role and regulatory mechanism of RNF183 in non small cell lung cancer (NSCLC) development and progression are poorly defined. Hence, lung adenocarcinoma (LUAD) cell proliferation, cell apoptosis and cell cycle were measured using Cell Counting Kit-8 and flow cytometry analysis, respectively. The correlation between RNF183 and SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase) was measured using coimmunoprecipitation and ubiquitination analysis in vitro. Tumor growth of NSCLC cells in vivo was measured using the nude mouse xenograft model. In this study, we verify that elevated RNF183 expression in tumor tissues of LUAD, origin from the TCGA, GEPIA, TIMER, and UALCAN database. RNF183 regulates apoptosis and cell cycle in vitro and tumor growth in vivo by activating the STAT3 pathway through ubiquitination of SHP2, a negative feedback regulator of the STAT3 pathway. Taken together, our results demonstrate that RNF183 regulates proliferation, apoptosis, and cell cycle in LUAD cells via modulation of SHP2/STAT3 signaling, suggesting the potential for targeting the RNF183-SHP2/STAT3 pathway for use in LUAD treatment.

Background: Multiple sclerosis (MS), an inflammatory disease of the central nervous system (CNS), leads to demyelination, neuronal injury, and loss of white matter, yet still can't be cured. Exosomes are double-layered membrane vesicles of 30–200 nm in size, which can easily penetrate the blood–brain barrier (BBB). Exosomes derived from umbilical cord mesenchymal stem cells exosomes (UMSC-exos) has been shown to treat experimental autoimmune encephalomyelitis (EAE) through the action of anti-inflammatory and immunomodulatory, but its clinical translation has been hampered by their inefficacious accumulation in CNS. Therefore, we developed a TAxI-peptide-chimeric UMSC-exos termed TAxI-exos for CNS-specific accumulation and curative effect in EAE.Methods: We used an EAE model in vivo, and actived T cells and BV-2 cells models in vitro. After two immunizations to establish the EAE model, UMSC-exos, TAxI-exos or DiR labeled exosomes were administered to EAE mice EAE mice for one dose (150μg) before the peak at day 15. On day 30, the mice were sacrificed to collect spinal cords, spleens, and blood for analysis of demyelination, inflammation, microglia, the proportions of T-cell subsets, and the expression of inflammatory cytokines. In vitro, for immune mechanism analyses, PBMCs and splenocytes isolated from healthy C57BL/6 mice, were activated and incubated with 0.15mg/mL UMSC-exos or TAxI-exos. Activated BV-2 cells were used to explore the targeting-ability and polarization-regulating ability of UMSC-exos and TAxI-exos.Results: As expected, TAxI-exos had significant curative effects in EAE mice compared with UMSC-exos via an enhanced targeting-ability. The treatment alleviated inflammation, facilitated microglial cell polarization from M1 to M2, reduced the proportions of T-cell subsets, increased the expression levels of IL-4, IL-10, TGF-β, and IDO-1, and decreased the levels of IL-2, IL-6, IL-17A, IFN-γ, and TNF-α. Conclusions: TAxI-exos have a great CNS-targeting ability and suppress pathological processes in EAE mice, which have a great potential therapeutic utility for MS and other CNS diseases.

Magnetically influenced light-matter interaction provides a contactless, noninvasive and power-free way for material characterization and light modulation. Shape anisotropy of active materials mainly determines the sensitivity of magneto-optic response, thereby making magnetic two-dimensional (2D) materials suitable in achieving the giant magneto-birefringence effect as discovered recently. Consequently, relationship between magneto-birefringence response and shape anisotropy of 2D materials is critical but has remained elusive, restricting its widespread applications. Here, we report the highly sensitive and largely tunable magneto-coloration via manipulating the shape-anisotropy of magnetic 2D materials. We reveal a quadratic increasing relationship between the magneto-optic Cotton-Mouton coefficient and the lateral size of 2D materials and achieve a more than one order of magnitude tunable response. This feature enables the engineerable transmissive magneto-coloration of 2D materials by tailoring their shape anisotropy. Our work deepens the understanding of the tunability of magneto-optic response by size effect of active materials, offering various opportunities for their applications in vast areas where color is concerned.

Lymphohematopoietic stem cells (L-HSCs) generated from self-somatic cell-derived induced pluripotent stem cells (iPSCs) are a potential source of cells for the treatment of hematological disorders. However, the generation of truly functional L-HSCs from iPSCs has yet to be achieved. Thus, whether iPSCs have the inherent potential to generate a normal differentiated phenotype and functional population of multiple lineages of terminally differentiated lymphocytes needs to be assessed. Here, we used tetraploid embryo complementation to provide a normal environment for the differentiation of hematopoietic cells from iPSCs and embryonic stem cells (ESCs). We then evaluated the characteristics, populations, and functions of lymphocytes derived from iPSCs, ESCs, and naive isogenic C57BL/6 mice. The results showed that iPSC-derived lymphocytes (iPSLs) expressed normal levels of major histocompatibility complex-I (MHC-I) and exhibited a fully pluripotent capacity to differentiate into CD4(+) T, CD8(+) T, regulatory T, B, and natural killer cells. Following in vitro stimulation with either concanavalin A or an alloantigen, iPSLs exhibited the same capacities for proliferation and cytokine secretion as ESC-derived or isogenic lymphocytes. Furthermore, iPSC-derived bone marrow cells could differentiate into multiple lymphocyte lineages that reconstituted the lymphocyte population in syngeneic lethally irradiated recipient animals. Our results demonstrated that iPSCs have the inherent potential to differentiate into multiple lineages of functional lymphocytes without bias, and further support the practical application of iPSC-based treatments to hematological disorders.

It is well known that adoptive transfer of donor-derived tolerogenic dendritic cells (DC) helps to reduce acute allograft rejection. However, this method cannot effectively prevent grafts from infiltration of inflammatory cells and fibrosis, and thus has minimal effect on chronic allograft rejection. In this study, we used mitomycin C (MMC) to generate tolerogenic DC and demonstrated that donor (Balb/c)-derived MMC-DC could induce hyporesponsiveness of recipient (C57BL/6) T cells in vitro, potentially by inducing T-cell apoptosis, decreasing IL-2 and IL-12 secretion, and increasing regulatory T-cell numbers and IL-10 secretion. Furthermore, anti-CD154 monoclonal antibody (mAb) treatment combined with donor-derived MMC-DC prolonged the survival of the allografts in vivo. The mechanisms were similar to those in vitro. Impressively, both acute and chronic rejection were prevented when donor and F1 generation (Balb/c × C57BL/6) derived MMC-DC were injected together with anti-CD154 mAb into recipients before heart allotransplantation. In summary, we showed that donor and F1-derived tolerogenic DC have a synergistic effect on induction and maintenance of T-cell regulation and the secretion of immunosuppressive cytokines. Moreover, adoptive transfer of these two types of DC could inhibit both acute and chronic transplant rejection in mice.

Memory T cells are known to play a key role in prevention of allograft tolerance in alloantigen-primed mice. Here, we used an adoptively transferred memory T cell model and an alloantigen-primed model to evaluate the abilities of different combinations of monoclonal antibodies (mAb) to block key signaling pathways involved in activation of effector and memory T cells. In the adoptively transferred model, the use of anti-CD134L mAb effectively prevented activation of CD4(+) memory T cells and significantly prolonged islet survival, similar to the action of anti-CD122 mAb to CD8(+) memory T cells. In the alloantigen-primed model, use of anti-CD134L and anti-CD122 mAbs in addition to co-stimulatory blockade with anti-CD154 and anti-LFA-1 prolonged secondary allograft survival and significantly reduced the proportion of memory T cells; meanwhile, this combination therapy increased the proportion of regulatory T cells (Tregs) in the spleen, inhibited lymphocyte infiltration in the graft, and suppressed alloresponse of recipient splenic T cells. However, we also detected high levels of alloantibodies in the serum which caused high levels of damage to the allogeneic spleen cells. Our results suggest that combination of four mAbs can significantly suppress the function of memory T cells and prolong allograft survival in alloantigen primed animals.

Donor-reactive CD4(+)memory T cells threaten the survival of transplanted organs. In this study, we used anti-CD44 monoclonal antibody (mAb) to inhibit adoptively transferred B6-reactive CD4(+)memory T cells (BALB/c origin) and to induce tolerance of B6 hearts in nude mice. The median survival time (MST) of the grafts was 6 days in the isotype group, and more than 100 days in the group treated with 8 doses of anti-CD44 at four-day intervals. Histological analysis revealed that the mean rejection level was Grade 3 in the isotype group, and Grade 0 or 1 in the multi-dose anti-CD44 treatment group. Compared with the isotype group, the multiply treated anti-CD44 group had significantly decreased IL-2 and IFN-γ expressions, while IL-10 and TGF-β were increased in the serum and the graft. Foxp3 in the graft was also increased. These data demonstrate that alloreactive CD4(+) memory T cells mediate the destruction of allografts, and the adhesion molecule CD44 plays an important role in this course. Anti-CD44 mAb may promote the reduction of CD4(+)memory T cells and the production of regulatory T cells (Tregs). Furthermore, Tregs are maintained at a certain level while suppressing cellular immunity and inducing the grafts long-term survival in transplant recipients.

Memory T cells are known to play a key role in prevention of allograft tolerance in alloantigen-primed mice. Here, we used an adoptively transferred memory T cell model and an alloantigen-primed model to evaluate the abilities of different combinations of monoclonal antibodies (mAb) to block key signaling pathways involved in activation of effector and memory T cells. In the adoptively transferred model, the use of anti-CD134L mAb effectively prevented activation of CD4(+) memory T cells and significantly prolonged islet survival, similar to the action of anti-CD122 mAb to CD8(+) memory T cells. In the alloantigen-primed model, use of anti-CD134L and anti-CD122 mAbs in addition to co-stimulatory blockade with anti-CD154 and anti-LFA-1 prolonged secondary allograft survival and significantly reduced the proportion of memory T cells; meanwhile, this combination therapy increased the proportion of regulatory T cells (Tregs) in the spleen, inhibited lymphocyte infiltration in the graft, and suppressed alloresponse of recipient splenic T cells. However, we also detected high levels of alloantibodies in the serum which caused high levels of damage to the allogeneic spleen cells. Our results suggest that combination of four mAbs can significantly suppress the function of memory T cells and prolong allograft survival in alloantigen primed animals.

Various memory cell populations existing before organ transplantation are believed to be important barriers to extending the graft survival time. Here, we report that arsenic trioxide (As(2)O(3)), a common component of some Chinese traditional preparations, could obviously reduce the proliferation of splenic T cells in alloantigen-primed mice in vitro. Furthermore, we evaluated As(2)O(3) treatment alone or in combination with blocking monoclonal antibodies (mAb) against co-stimulatory molecules (LFA-1 and CD154) in the prevention of heart transplant rejection in alloantigen-primed mice. Alloantigen-primed mice were randomly divided into 4 groups of 6 animals each. The control group was given normal saline; the As(2)O(3) group received As(2)O(3) (5 mg/kg/d) (i.p.) on days 0-10 post-transplantation; the Ab group received 100 μg anti-LFA-1 mAb+250 μg anti-CD154 mAb (i.p.) on the day of transplantation and 3 more times every alternate day and the As(2)O(3)+Ab group received a combined As(2)O(3) and Ab treatment protocol. The survival of the allografts was almost doubled among the As(2)O(3) group and Ab group compared with the control group (5, 5.6 vs 3.3 days). A marked prolongation (16 days) of graft survival was achieved by the combination protocol compared with the control group (3.3 days; P0.05). None of the treatment group showed side effects. Five days after transplantation, cardiac allografts, splenic T cells and serum were harvested for analysis. Compared with the control group, most of the treatment groups showed: (i) alleviation of allograft rejection in different levels; (ii) IFN-γ expression was reduced and TGF-β expression increased in both peripheral blood and within the grafts; (iii) the proportions of CD4(+) or CD8(+) memory T cells in the spleen of the recipients were significantly reduced while the expression of regulatory T cells (Tregs) was enhanced; (iv) the alloresponses of memory T cells were inhibited, and levels of alloantibodies in recipients' sera were also decreased. Among all these changes, the As(2)O(3)+Ab group showed the most significant changes. Our study highlights an obvious synergistic action of As(2)O(3) when combined with co-stimulatory molecules blockade in prolonging the survival of cardiac allografts in alloantigen-primed mice.

Memory T cells present a unique challenge in transplantation. Although memory T cells express robust immune responses to invading pathogens, they may be resistant to the effects of immunosuppressive therapies used to prolong graft survival. In previous studies, we found that compound K, the synthesized analogue of highly unsaturated fatty acids from Isatis tinctoria L., reduced acute cardiac allograft rejection in mice (Wang et al., 2009 [1]). Here, we further investigated the effect of compound K on cardiac allograft rejection in alloantigen-primed mice. We found that compound K significantly inhibited CD4(+) and CD8(+) memory T cells proliferation in a mixed lymphocyte reaction (MLR). In vivo, compound K combined with anti-CD154 and anti-LFA-1 monoclonal antibodies (mAbs) significantly extended the survival time of heart grafts in alloantigen-primed mice with no obvious toxic side effects. Furthermore, our data suggests that compound K works by reducing the expression of both IL-2 and IFN-gamma within the graft rather than enhancing expression of regulatory T cells (Tregs). Compound K can also inhibit the alloresponses of memory T cells, while increasing the proportion of CD4(+) memory T cells in the spleen of the recipients and significantly reducing the level of alloantibodies in the serum. Our study highlights the unique immune effects of compound K that may be further explored for clinical use in extending the survival of transplant grafts.