Lithium impacts the function of hematopoietic stem cells via disturbing the endoplasmic reticulum stress and Hsp90 signaling.

Lithium (Li) has been widely used in clinical therapy and new Li-ion battery industry. To date, the impact of Li on the development of immune cells is largely unknown. The aim of this study was to investigate the impact of Li on hematopoiesis. C57BL/6 (B6) mice were treated with 50 ppm LiCl, 200 ppm LiCl, or the control via drinking water for 3 months, and thereafter the hematopoiesis was evaluated. Treatment with Li increased the number of mature lymphoid cells while suppressing the number of mature myeloid cells in mice. In addition, a direct action of Li on hematopoietic stem cells (HSC) suppressed endoplasmic reticulum (ER) stress to reduce the proliferation of HSC in the bone marrow (BM), thus leading to fewer HSC in mice. On the other hand, the suppression of ER stress by Li exposure increased the expression of Hsp90, which promoted the potential of lymphopoiesis but did not impact that for myelopoiesis in HSC in the BM of mice. Moreover, in vitro treatment with Li also likely disturbed the ER stress-Hsp90 signaling, suppressed the proliferation, and increased the potential for lymphopoiesis in human HSC. Our study reveals a previously unrecognized toxicity of Li on HSC and may advance our understanding for the immunotoxicology of Li.

Mercury chloride activates the IFNγ-IRF1 signaling in myeloid progenitors and promotes monopoiesis in mice.

Inorganic mercury (Hg2+) is a highly toxic heavy metal in the environment. To date, the impacts of Hg2+ on the development of monocytes, or monopoiesis, have not been fully addressed. The aim of the present study was to investigate the impact of Hg2+ on monopoiesis. In this study, we treated B10.S mice and DBA/2 mice with 10 µM or 50 µM HgCl2 via drinking water for 4 wk, and we then evaluated the development of monocytes. Treatment with 50 µM HgCl2, but not 10 µM HgCl2, increased the number of monocytes in the blood, spleen and bone marrow (BM) of B10.S mice. Accordingly, treatment with 50 µM HgCl2, but not 10 µM HgCl2, increased the number of common myeloid progenitors (CMP) and granulocyte-macrophage progenitors (GMP) in the BM. Functional analyses indicated that treatment with 50 µM HgCl2 promoted the differentiation of CMP and GMP to monocytes in the BM of B10.S mice. Mechanistically, treatment with 50 µM HgCl2 induced the production of IFNγ, which activated the Jak1/3-STAT1/3-IRF1 signaling in CMP and GMP and enhanced their differentiation potential for monocytes in the BM, thus likely leading to increased number of mature monocytes in B10.S mice. Moreover, the increased monopoiesis by Hg2+ was associated with the increased inflammatory status in B10.S mice. In contrast, treatment with 50 µM HgCl2 did not impact the monopoiesis in DBA/2 mice. Our study reveals the impact of Hg on the development of monocytes.

Lead exposure suppresses the Wnt3a/ß-catenin signaling to increase the quiescence of hematopoietic stem cells via reducing the expression of CD70 on bone marrow-resident macrophages.

Lead (Pb) is a heavy metal highly toxic to human health in the environment. The aim of this study was to investigate the mechanism of Pb impact on the quiescence of hematopoietic stem cells (HSC). WT C57BL/6 (B6) mice treated with 1250 ppm Pb via drinking water for 8 weeks had increased the quiescence of HSC in the bone marrow (BM), which was caused by the suppressed activation of the Wnt3a/ß-catenin signaling. Mechanically, a synergistic action of Pb and IFNγ on BM-resident macrophages (BM-Mφ) reduced their surface expression of CD70, which thereby dampened the Wnt3a/ß-catenin signaling to suppress the proliferation of HSC in mice. In addition, a joint action of Pb and IFNγ also suppressed the expression of CD70 on human Mφ to impair the Wnt3a/ß-catenin signaling and reduce the proliferation of human HSC purified from umbilical cord blood of healthy donors. Moreover, correlation analyses showed that the blood Pb concentration was or tended to be positively associated with the quiescence of HSC, and was or tended to be negatively associated with the activation of the Wnt3a/ß-catenin signaling in HSC in human subjects occupationally exposed to Pb. Collectively, these data indicate that an occupationally relevant level of Pb exposure suppresses the Wnt3a/ß-catenin signaling to increase the quiescence of HSC via reducing the expression of CD70 on BM-Mφ in both mice and humans.

Biodegradable MOFilters for Effective Air Filtration and Sterilization by Coupling MOF Functionalization and Mechanical Polarization of Fibrous Poly(lactic acid).

High-performance air filtration materials are important for addressing the airborne pollutants. Herein, we propose an unprecedented access to biodegradable poly(lactic acid) (PLA)-based MOFilters with excellent filtering performance and antibacterial activity. The fabrication involved a stepwise in situ growth of zeolitic imidazolate framework-8 (ZIF-8) crystals at the surface of microfibrous PLA membranes, followed by mechanical polarization under high pressure and low temperature (5 MPa, 40 °C) to trigger the ordered alignment of dipoles in PLA chains and ZIF-8. The unique structural features allowed these PLA-based MOFilters to achieve an exceptional combination of excellent tensile properties, high dielectric constant (up to 2.4 F/m), and enhanced surface potential as high as 4 kV. Arising from the remarkable surface activity and electrostatic adsorption effect, a significant increase (from over 12% to nearly 20%) in PM0.3 filtration efficiency was observed for the PLA-based MOFilters compared to that of pure PLA counterparts, with weak relation to the airflow velocities (10-85 L/min). Moreover, the air resistance was controlled at a considerably low level for all the MOFilters, that is, below 183 Pa even at 85 L/min. It is worth noting that distinct antibacterial properties were achieved for the MOFilters, as illustrated by the inhibitive rates of 87 and 100% against Escherichia coli and Staphylococcus aureus, respectively. The proposed concept of PLA-based MOFilters offers unprecedented multifunction integration, which may fuel the development of biodegradable versatile filters with high capturing and antibacterial performances yet desirable manufacturing feasibility.

Bioelectrets in Electrospun Bimodal Poly(lactic acid) Fibers: Realization of Multiple Mechanisms for Efficient and Long-Term Filtration of Fine PMs.

Despite the great potential in fabrication of biodegradable and eco-friendly air filters by electrospinning poly(lactic acid) (PLA) membranes, the filtering performance is frequently dwarfed by inadequate physical sieving or electrostatic adsorption mechanisms to capture airborne particulate matters (PMs). Here, using the parallel spinning approach, the unique micro/nanoscale architecture was established by conjugation of neighboring PLA nanofibers, creating bimodal fibers in electrospun PLA membranes for the enhanced slip effect to significantly reduce the air resistance. Moreover, the bone-like nanocrystalline hydroxyapatite bioelectret (HABE) was exploited to enhance the dielectric and polarization properties of electrospun PLA, accompanied by the controlled generation of junctions induced by the microaggregation of HABE (10-30 wt %). The incorporated HABE was supposed to orderly align in the applied E-field and largely promote the charging capability and surface potential, gradually increasing to 7.2 kV from the lowest level of 2.5 kV for pure PLA. This was mainly attributed to HABE-induced orientation of PLA backbone chains and C═O dipoles, as well as the interfacial charges trapped at the interphases of HABE-PLA and crystalline region-amorphous PLA. Given the multiple capturing mechanisms, the micro/nanostructured PLA/HABE membranes were characterized by excellent and sustainable filtering performance, e.g., the filtration efficiency of PM0.3 was promoted from 59.38% for pure PLA to 94.38% after addition of 30 wt % HABE at a moderate airflow capacity of 32 L/min and from 30.78 to 83.75% at the highest level of 85 L/min. It is of interest that the pressure drop was significantly decreased, mainly arising from the slip effect between the ultrafine nanofibers and conjugated microfibers. The proposed combination of the nanostructured electret and the multistructuring strategy offers the function integration of efficient filtration and low resistance that are highly useful to pursue fully biodegradable filters.

Cadmium impairs the development of natural killer cells and bidirectionally modifies their capacity for cytotoxicity.

Cadmium (Cd) is a highly toxic heavy metal in the environment. The aim of this study was to investigate the impact of Cd on natural killer (NK) cells. C57BL/6 mice were treated with 10 ppm Cd via drinking water for 3 months, and the development of NK cells in the bone marrow (BM) and the cytotoxicity of mature NK (mNK) cells in the peripheral immune organs were evaluated thereafter; the impact of Cd on the cytotoxicity of mNK cells from human peripheral blood mononuclear cells (PBMC) was also investigated. Whereas Cd treatment impaired the differentiation of NK progenitors in the BM, Cd treatment activated the JAK3/STAT5 signaling to drive the proliferation of mNK cells and thereby lead to a compensation increase of mNK cells in the peripheral immune organs of mice. Additionally, Cd treatment bidirectionally regulated the cytotoxicity of mouse mNK cells to differential tumor cells, dependent on the levels of Fas expression in the tumor cells; mechanically, Cd treatment activated the JAK3/STAT5 signaling to promote the expression of FasL in mNK cells to increase their cytotoxicity, while Cd treatment reduced the expression of granzyme B in mNK cells to impair their cytotoxicity in the peripheral immune organs of mice. Likewise, in vitro assays indicated that Cd treatment also activated the JAK3/STAT5 signaling to increase the expression of FasL, whereas Cd treatment reduced the expression of granzyme B in human mNK cells. Thus Cd treatment impaired the development of NK cells in the BM and bidirectionally regulated the cytotoxicity of mNK cells in the peripheral immune organs, which may extend our current understanding for the immunotoxicity of Cd.

Biomineralization of bone-like hydroxyapatite to upgrade the mechanical and osteoblastic performances of poly(lactic acid) scaffolds.

Biomimetic mineralization of high-strength apatite structure essentially relies on mimicking the inorganic building blocks of naturally occurring bones. However, conventional routes still have substantial function gaps in providing precision control over the geometrical dimensions and crystalline morphology of biomineralized apatite. Herein, we conceived the concept of microwave-assisted biomineralization (MAB) to customize 1D hydroxyapatite nanowhiskers (HANWs) at graphene templates, rendering the formation of graphene-hydroxyapatite (Gr-HA) nanohybrids. The HANWs essentially resembled bone apatite in elemental composition (Ca/P = 1.74), diameter (~20 nm), crystallinity (63 %), and rodlike geometry (aspect ratio of ~6). The Gr-HA nanohybrids were uniformly incorporated into poly(lactic acid) (PLA) microfibers (~1 µm) by electrospinning, engendering fibrous membranes with a set of Gr-HA loadings (10, 20 and 30 wt%). Intimate interactions were generated between Gr-HA and PLA matrix, contributing to significant promotion of the mechanical properties for PLA composite membranes. For example, the yield strength and elastic modulus of the PLA composite membranes loaded with 30 wt% Gr-HA achieved 5.4 and 66.4 MPa, increasing nearly 182 % and over 94 % compared to those of pure PLA, respectively. Moreover, the bone-like HANWs endowed PLA membranes with excellent cytocompatibility and good bioactivity, as demonstrated by over 38 % increase in cell viability and rapid apatite formation in mineral solution. The impressive combination of mechanical properties and biological characteristics make the PLA/Gr-HA scaffolds promising for guided tissue/bone regeneration therapy.

Lead suppresses interferon γ to induce splenomegaly via modification on splenic endothelial cells and lymphoid tissue organizer cells in mice.

Splenomegaly is a symptom characterized by the presence of an enlarged spleen. The impact of environmental factors on splenomegaly is largely unknown. In this study, C57BL/6 mice were treated with 125 ppm or 1250 ppm lead (Pb) via drinking water for 8 wk, and the process of splenomegaly was evaluated. Treatment with 1250 ppm Pb, but not 125 ppm Pb, caused splenomegaly, which was associated with increased capacity for erythrocyte clearance. Intriguingly, Pb-caused splenomegaly was independent of lymphoid tissue inducer (LTi) cells, which produce lymphotoxins α and ß (LTα/ß) to activate endothelial cells and LT organizer (LTo) cells and drive the development of spleen physiologically. A direct action of Pb on endothelial cells and LTo cells did not impact their proliferation. On the other hand, during steady state, a tonic level of interferon (IFN)γ acted on endothelial cells and LTo cells to suppress splenomegaly, as IFNγ receptor (IFNγR)-deficient mice had enlarged spleens relative to wild-type mice; during Pb exposure, splenic IFNγ production was suppressed, thus leading to a loss of the inhibitory effect of IFNγ on splenomegaly. Mechanically, Pb acted on splenic CD4+ T cells to suppress IFNγ production, which impaired the Janus kinase (Jak)1/ signal transducer and activator of transcription (STAT)1 signaling in endothelial cells and LTo cells; the weakened Jak1/STAT1 signaling resulted in the enhanced nuclear factor-κB (NF-κB) signaling in endothelial cells and LTo cells, which drove their proliferation and caused splenomegaly. The present study reveals a previously unrecognized mechanism for the immunotoxicity of Pb, which may extend our current understanding for Pb toxicology.

High-heat and UV-barrier poly(lactic acid) by microwave-assisted functionalization of waste natural fibers.

The application of poly(lactic acid) (PLA) in the packaging area is frequently dwarfed by the inadequate gas/water barrier properties, low heat resistance and high UV transmittance. Herein, an environmentally friendly and high-efficiency microwave-assisted functionalization (MAF) approach was proposed to aqueous grafting waste bamboo fibers with the bridging agent. It permitted significant promotion of interfacial interactions between the MAF bamboo fibers (MAFBs) and neighboring PLA chains, contributing to uniform dispersion and intimate interphase. Featuring the morphological features, the MAFB-reinforced (5, 10 and 20 wt%) PLA biocomposites achieved an unexpected combination of high mechanical properties, exceptional resistance to heat deflection and UV irradiation, and excellent water barrier performance. Upon addition of only 5 wt% MAFBs, the tensile strength and toughness of PLA composite films were increased to 46.5 MPa and 0.6 MJ/m3, increasing over 52 % and nearly 107 % compared to those of the counterpart loaded pristine bamboo fibers (PBFs), respectively. This was favorably accompanied by the remarkably reduced water vapor permeability, falling down to the lowest value of 3.5 × 10-11 g∙m/Pa∙s∙m2 for PLA/MAFB (80/20) with a decrease of nearly 79 % compared to the counterpart. It is of interest to note the MAFB-enabled nearly 100 % UV-blocking ratio for PLA loaded 10 and 20 wt% fibers, as well as excellent resistance to heat deflection even at high temperatures like 120 °C. This effort paves the way to multifunctional natural fibers with high affinity to PLA for elegant implementation of high-heat and UV-resistant packaging materials in an ecofriendly manner.

Pea pod-mimicking hydroxyapatite nanowhisker-reinforced poly(lactic acid) composites with bone-like strength.

The anisotropic hierarchical structures of naturally derived materials have offered useful design principles for the fabrication of high-strength and functional materials. Herein, we unraveled a structure-by-bionics approach to construction of pea pod-mimicking architecture for poly(lactic acid) (PLA) composites impregnated with hydroxyapatite nanowhiskers (HANWs). The HANWs (length of 80-120 nm, diameter of ~30 nm) were customized using microwave-assisted aqueous biomineralization at minute level, which were incorporated into PLA microfibers by electrospinning with filler loadings of 10-30 wt%. The membranes comprising HANW-modified PLA microfibers were stacked and structured into composite films, strategically involving high-pressure compression at a relatively low temperature to impart the confined structuring mechanisms. It thus allowed partial melting and thinning of PLA microfibers into nanofibers, onto which the discrete HANWs were tightly adhered and embedded, showing distinguished architectural configurations identical with pea pod. More importantly, the mechanical properties and bioactivity were remarkably promoted, as demonstrated by the increments of over 54 % and nearly 72 % for the yield strength and elastic modulus (71.6 and 2547 MPa) of the structured composite loaded 30 wt% HANWs compared to those of pure PLA (46.4 and 1484 MPa), as accompanied by significant improvements in the bioactivity to nucleate and create apatite entities in mineral solution. The unusual combination of excellent biological characteristics and bone-like mechanical elasticity and extensibility make the structured PLA composites promising for guided bone/tissue regeneration therapy.