Meta-ecosystem Frameworks Can Enhance Control of the Biotic Transport of Microplastics.

The lack of systematic approaches and analyses to identify, quantify, and manage the biotic transport of microplastics (MPs) along cross-ecosystem landscapes prevents the current goals of sustainable environmental development from being met. This Perspective proposes a meta-ecosystem framework, which considers organismal and resource flows among ecosystems to shed light on the research and management challenges related to both abiotic and biotic MP transport at landscape levels. We discuss MP transport pathways through species movements and trophic transfers among ecosystems and sub-ecosystems, and highlight these pathways in the mitigation of MP pollution. The integration of biotic pathways across landscapes prioritizes management actions for MP transport using diverse approaches such as wastewater treatment and plastic removal policies to mitigate contamination. In addition, our framework emphasizes the potential sink enhancement of MPs through habitat conservation and enhancement of riparian vegetation. By considering the mechanisms of meta-ecosystem dynamics through the processes of biotic dispersal, accumulation, and the ultimate fate of MPs, advances in the environmental impact assessment and management of MP production can proceed more effectively.

Synthesis and Inclusion Properties of a ß-Cyclodextrin Heptaphosphoramidate.

In this study, we report a novel per-6-substituted ß-cyclodextrin (4) featuring seven phosphoramidate moieties as an innovative host for inclusion. This structurally well-defined host has remarkable water solubility and was isolated in pure form. Analytical techniques such as NMR and ITC were used to probe the molecular interactions with different drug molecules. Our investigations revealed that host 4 can form 2:1 inclusion complexes with various drugs. Further studies showed that the inclusions of drugs by ß-CD host (4) are mostly enthalpy driven, highlighting the potential roles played by the phosphoramidate functionalities of the host. Comparatively, a per-O2, O3-acetylated analog (6) of compound 4 was also obtained, which also shows unusual water solubility but diminished inclusion capability.

Existing levels of biodiversity and river location may determine changes from small hydropower developments.

Global ecosystems are facing anthropogenic threats that affect their ecological functions and biodiversity. However, we still lack an understanding of how biodiversity can mediate the responses of ecosystems or communities to human disturbance across spatial gradients. Here, we examined how existing, spatial patterns of biodiversity influence the ecological effects of small hydropower plants (SHPs) on macroinvertebrates in river ecosystems. This study found that levels of biodiversity (e.g., number of species) can influence the degrees of its alterations by SHPs occurring along elevational gradients. The results of the study reveal that the construction of SHPs has various effects on biodiversity. For example, low-altitude areas with low biodiversity (species richness less than 12) showed a small increase in biodiversity compared to high-altitude areas (species richness more than 12) under SHP disturbances. The increases in the effective habitat area of the river segment could be a driver of the enhanced biodiversity in response to SHP effects. Changes in the numerically dominant species contributed to the overall level of community variation from disturbances. Location-specific strategies may mitigate the effects of SHPs and perhaps other disturbances.

Ultrasensitive upconverting nanoprobes for in situ imaging of drug-induced liver injury using miR-122 as the biomarker.

Drug-induced liver injury (DILI) is a frequent adverse drug reaction. The current clinical diagnostic methods are inadequate for accurate and early detection of DILI due to the lack of effective diagnostic biomarkers. Hepatocyte-specific miR-122 is released from injured hepatocytes promptly and its efflux is significantly correlated with the progression of DILI. Therefore, achieving precise in situ detection of miR-122 with high sensitivity is vital for early visualization of DILI. Herein, a new nanoprobe, consisting of miR-122 aptamer, upconversion nanoparticles (UCNPs) and Prussian blue nanoparticles (PBNPs) was introduced for the early and sensitive detection of DILI in situ. As the nanoprobes reached in the liver, miR-122 aptamer-based entropy-driven strand displacement (ESDR) signal amplification reaction was triggered and luminescence resonance energy transfer (LRET) between UCNPs and PBNPs was responded to achieve the high-fidelity detection of DILI. A negative correlation was observed between the intensity of upconversion luminescence (UCL) and the concentration of miR-122. UCL imaging conducted both in vivo and ex vivo indicated that a reduction in miR-122 concentration led to an increase in UCL intensity, revealing a precise state of DILI. The detection technique demonstrated a positive correlation between signal intensity and severity, offering a more straightforward and intuitive method of visualizing DILI.

Melittin analog p5RHH enhances recombinant adeno-associated virus transduction efficiency.

OBJECTIVE: Melittin and its derivative have been developed to support effective gene delivery systems. Their ability to facilitate endosomal release enhances the delivery of nanoparticle-based gene therapy. Nevertheless, its potential application in the context of viral vectors has not received much attention. Therefore, we would like to optimize the rAAV vector by Melittin analog to improve the transduction efficiency of rAAV in liver cancer cells and explore the mechanism of Melittin analog on rAAV. METHODS: Various melittin-derived peptides were inserted into loop VIII of the capsid protein in recombinant adeno-associated virus vectors. These vectors carrying either gfp or fluc genes were subjected to quantitative polymerase chain reaction assays and transduction assays in human embryonic kidney 293 (HEK293T) cells to investigate the efficiency of vector production and gene delivery. In addition, the ability of a specific p5RHH-rAAV vector to deliver genes was examined through in vitro transduction of different cultured cells and in vivo tail vein administration to C57BL/6 mice. Finally, the intricate details of the vector-mediated transduction mechanisms were explored by using pharmacological inhibitors of every stage of the rAAV2 intracellular life cycle. RESULTS: A total of 76 melittin-related peptides were identified from existing literature. Among them, CMA-3, p5RHH and aAR3 were found to significantly inhibit transduction of rAAV2 vector crude lysate. The p5RHH-rAAV2 vectors efficiently transduced not only rAAV-potent cell lines but also cell lines previously considered resistant to rAAV. Mechanistically, bafilomycin A1, a vacuolar endosome acidification inhibitor, completely inhibited the transgene expression mediated by the p5RHH-rAAV2 vectors. Most importantly, p5RHH-rAAV8 vectors also increased hepatic transduction in vivo in C57BL/6 mice. CONCLUSION: The incorporation of melittin analogs into the rAAV capsids results in a significant improvement in rAAV-mediated transgene expression. While further modifications remain an area of interest, our studies have substantially broadened the pharmacological prospects of melittin in the context of viral vector-mediated gene delivery. Please cite this article as: Meng J, He Y, Yang H, Zhou L, Wang S, Feng X, Al-shargi OY, Yu X, Zhu L, Ling, C. Melittin analog p5RHH enhances recombinant adeno-associated virus transduction efficiency. J Integr Med. 2024; 22(1): 72-82.

Epoxide-Mediated Trans-Thioglycosylation and Application to the Synthesis of Oligosaccharides Related to the Capsular Polysaccharides of C. jejuni HS:4.

The enzyme-resistant thioglycosides are highly valuable immunogens because of their enhanced metabolic stability. We report the first synthesis of a family of thiooligosaccharides related to the capsular polysaccharides (CPS) of Campylobacter jejuni HS:4 for potential use in conjugate vaccines. The native CPS structures of the pathogen consist of a challenging repeating disaccharide formed with ß(1→4)-linked 6-deoxy-ß-D-ido-heptopyranoside and N-acetyl-D-glucosamine; the rare 6-deoxy-ido-heptopyranosyl backbone and ß-anomeric configuration of the former monosaccharide makes the synthesis of this family of antigens very challenging. So far, no synthesis of the thioanalogs of the CPS antigens have been reported. The unprecedented synthesis presented in this work is built on an elegant approach by using ß-glycosylthiolate as a glycosyl donor to open the 2,3-epoxide functionality of pre-designed 6-deoxy-ß-D-talo-heptopyranosides. Our results illustrated that this key trans-thioglycosylation can be designed in a modular and regio and stereo-selective manner. Built on the success of this novel approach, we succeeded the synthesis of a family of thiooligosaccharides including a thiohexasaccharide which is considered to be the desired antigen length and complexity for immunizations. We also report the first direct conversion of base-stable but acid-labile 2-trimethylsilylethyl glycosides to glycosyl-1-thioacetates in a one-pot manner.

Gadolinium(III) complex formation with a ß-cyclodextrin ligand: an XAS study of a potential MRI contrast agent.

In the search for improved and safer gadolinium-based magnetic resonance imaging (MRI) contrast agents, macrocyclic cyclodextrins (CDs) attract great interest. Our group previously synthesized a cyclodextrin-based ligand with 1,2,3-triazolmethyl residues conjugated to ß-CD, called ß-CD(A), which efficiently chelates Gd(III) ions. To probe the local structure around the Gd(III) ion in the 1:1 Gd(III): ß-CD(A) complex in aqueous solution (pH 5.5), we used extended X-ray absorption fine structure (EXAFS) spectroscopy. Least-squares curve fitting of the Gd L3-edge EXAFS spectrum revealed 5 Gd-O (4 COO- and 1 H2O) and 4 Gd-N (from two imino and two 1,2,3-triazole groups) bonds around the Gd(III) ion with average distances 2.36 and 2.56 ± 0.02 Å, respectively. A similar EXAFS spectrum was obtained from an aqueous solution of the clinically used MRI contrast agent Na[Gd(DOTA)(H2O)], also 9-coordinated in its first shell. Careful analysis revealed that the mean Gd-N distance is shorter in the Gd(III): ß-CD(A) (1:1) complex, indicating stronger Gd-N bonding and stronger Gd(III) complex formation than with the DOTA4- ligand. This is consistent with the lower free Gd3+ concentration found previously for the Gd(III): ß-CD(A) (1:1) complex than for the [Gd(DOTA)(H2O)]- complex, and shows its potential as an MRI probe. EXAFS spectroscopy revealed a similar Gd(III) 9-coordination although slightly stronger for a modified ß-cyclodextrin: Gd(III) 1:1 complex, [Gd(LH4)]7-, in aqueous solution than for the clinically used MRI contrast agent Na[Gd(DOTA)(H2O)].

Precise tumor delineation in clinical tissues using a novel acidic tumor microenvironment activatable near-infrared fluorescent contrast agent.

Tumor selective near-infrared (NIR) fluorescent contrast agents has the potential to greatly enhance the efficiency and precision of tumor surgery by enabling real-time tumor margin identification for tumor resection guided by imaging. However, the development of these agents is still challenging. In this study, based on the acidic tumor microenvironment (TME), we designed and synthesized a novel pH-sensitive NIR fluorescent contrast agent OBD from ß-carboline. The fluorescence quantum yield of OBD exhibited a notable increase at pH 3.6, approximately 12-fold higher compared to its value at pH 7.4. After cellular uptake, OBD lighted up the cancer cells with high specificity and accumulated in the mitochondria. Spraying OBD emitted selective fluorescence in xenograft tumor tissues with tumor-to-normal tissue ratios (TNR) as high as 11.18, implying successful image-guided surgery. Furthermore, OBD was also shown to track metastasis in spray mode. After simple topical spray, OBD rapidly and precisely visualized the tumor margins of clinical colon and liver tissues with TNR over 4.2. Therefore, the small-molecule fluorescent contrast agent OBD has promising clinical applications in tumor identification during surgery.

The extracellular matrix as modifier of neuroinflammation and recovery in ischemic stroke and intracerebral hemorrhage.

Stroke is the second leading cause of death worldwide and has two major subtypes: ischemic stroke and hemorrhagic stroke. Neuroinflammation is a pathological hallmark of ischemic stroke and intracerebral hemorrhage (ICH), contributing to the extent of brain injury but also in its repair. Neuroinflammation is intricately linked to the extracellular matrix (ECM), which is profoundly altered after brain injury and in aging. In the early stages after ischemic stroke and ICH, immune cells are involved in the deposition and remodeling of the ECM thereby affecting processes such as blood-brain barrier and cellular integrity. ECM components regulate leukocyte infiltration into the central nervous system, activate a variety of immune cells, and induce the elevation of matrix metalloproteinases (MMPs) after stroke. In turn, excessive MMPs may degrade ECM into components that are pro-inflammatory and injurious. Conversely, in the later stages after stroke, several ECM molecules may contribute to tissue recovery. For example, thrombospondin-1 and biglycan may promote activity of regulatory T cells, inhibit the synthesis of proinflammatory cytokines, and aid regenerative processes. We highlight these roles of the ECM in ischemic stroke and ICH and discuss their potential cellular and molecular mechanisms. Finally, we discuss therapeutics that could be considered to normalize the ECM in stroke. Our goal is to spur research on the ECM in order to improve the prognosis of ischemic stroke and ICH.

Novel pH-activatable NIR fluorogenic spray mediated near-instant and precise tumor margins identification in human cancer tissues for surgical resection.

Rationale: Challenges such as developing a universal tumor-specific probe for tumor margin identification in diverse tumors with an easy-operative and fast-imaging pattern still exist. Hence, in the present study, a rapidly "off-on" near-infrared (NIR) fluorescent probe NBD with pH-activatable fluorescence and a large Stokes shift was constructed for spray mediated near-instant and precise clinical tumor margins identification. Methods: NBD was designed and synthesized by introducing both diphenyl amino group and benzo[e]indolium to ß-carboline at C-6 and C-3 positions respectively. The optical properties of NBD was characterized by absorption spectra, fluorescence spectra. Subsequently, we investigated its pH-dependent mechanism by 1H NMR and density functional theory (DFT) calculation. NBD was further under deeper investigation into its imaging performance in nude mice models (subcutaneous, orthotopic, metastatic tumor), and clinical tissues from patients with three clinically representative tumors (liver cancer, colon cancer, and lung cancer). Results: It was found that NBD had NIR fluorescence (742 nm), a large Stokes shift (160 nm), and two-photon absorbance (1040 nm). Fluorescence quantum yield (ФF) increased by 5.5-fold when pH decreased from 7.4 to 4.0, to show pH-dependent property. Furthermore, NBD could not only selectively light up all four cancer cell lines, but also delineate xenograft tumor and orthotopic microtumor to guide surgical tumor resection, and track metastatic tissues. Particularly, after simple topical spray (three minutes later), NBD could rapidly and precisely distinguish the boundary ranges of three kinds of clinical cancer specimens including liver, colon, and lung cancers, with high tumor-to-normal tissue signal ratios (6.48~9.80). Conclusions: Therefore, the proposed fluorescent probe NBD may serve as a versatile NIR fluorogenic spray for the near-instant visualization of tumor margins and assisting surgeons in surgerical resection of clinical cancers.

Regio- and stereo-controlled synthesis of 6-deoxy-ß-D-ido-heptopyranosides related to Campylobacter jejuni HS:4.

Campylobacter jejuni is a bacterial pathogen that causes hundreds of millions of cases of food-borne gastroenteritis worldwide annually. The infection caused by this bacterium is also associated with several forms of post-infectious autoimmune sequelae that can be very serious, including the life-threatening Guillain-Barré syndrome. The capsular polysaccharides (CPS) of C. jejuni HS:4 consist of a very unique repeating disaccharide unit that is characterized by a ß-1,4-linked 6-deoxy-ß-D-ido-heptopyranose and an N-acetyl-ß-D-glucosamine. Eliciting carbohydrate-specific antibodies against the CPS structures of C. jejuni HS:4 is an attractive strategy. The 6-deoxy-ido-configuration of the heptose combined with its ß-anomeric configuration makes the chemical synthesis of the disaccharide very challenging. Here, we report an efficient synthesis to obtain the key repeating disaccharide and its analog in reverse order plus a trisaccharide. Our synthesis features a highly efficient, one-step stereo- and regioselective conversion of ß-D-galacto-heptopyranosides to 6-deoxy-ß-D-ido-heptopyranosides via the intermediate 2,3-anhydro-ß-D-talo-heptopyranosides.

Acidic tumor microenvironment-activatable fluorescent diagnostic probe for the rapid identification and resection of human tumors via spraying.

A fluorescent diagnostic probe for real-time intraoperative image-guided tumor resection can significantly improve the efficiency and quality of oncological therapy, but their development is challenging. Herein, a novel fluorescent diagnostic probe called HLTC based on ß-carboline was designed and synthesized. HLTC was found to show a ∼10-fold enhancement of fluorescence quantum field with pH from 7.4 to 4.0, indicating its imaging potential in acid environment which is a typical hallmark of the tumor microenvironment (TME). Following fluorescence microscopy imaging showed HLTC could emit specific signals in cancer cells and sections, by both one-photon excitation and two-photon excitation. Importantly, HLTC enabled the precise and rapid delineation of both transplanted tumor and clinical tumor tissues within several minutes of simple topical spray. The tumor-to-background ratio (TBR) was up to 10.2 ± 1.0 at clinical liver cancer tissues and 9.9 ± 0.3 at clinical colon cancer tissues, allowing precise tumor margin identification and the effective guidance of surgical tumor resection. Furthermore, CCK8 assay, pharmacokinetic evaluation, blood analysis and H&E staining were performed, which verified high biocompatibility and biosafety of HLTC at working concentration. These results reveal the exciting potential of this small-molecule fluorescent diagnostic probe for real-time fluorescence-based navigation during surgical tumor resection.

Comprehensive evaluation of military training-induced fatigue among soldiers in China: A Delphi consensus study.

Objective: Military training-induced fatigue (MIF) often results into non-combat attrition. However, standard evaluation of MIF is unavailable. This study aimed to provide credible suggestions about MIF-evaluation. Methods: A 3-round Delphi study was performed. The authority of the experts was assessed by the authority coefficient (Aa). In round 1, categories of indicators were collected via anonymous survey of experts, then potential indicators were selected via literature search. In round 2, experts should evaluate the clinical implication, practical value, and importance of each potential indicators, or recommend new indicators based on feedback of round 1. Indicators with recommendation proportions ≥ 70% and new recommended indicators would be included in round 3 to be rated on a 5-point Likert scale. "Consensus in" was achieved when coefficient of concordance (Kendall's W) of a round was between 0.2 and 0.5 and the coefficient of variation (CV) of each aspect for an indicator was < 0.5. If round 3 could not achieve "consensus in," more rounds would be conducted iteratively based on round 3. Indicators included in the recommendation set were ultimately classified into grade I (highly recommended) or grade II (recommended) according to the mean score and CV of the aspects. Results: Twenty-three experts participated with credible authority coefficient (mean Aa = 0.733). "Consensus in" was achieved in round 3 (Kendall's W = 0.435, p < 0.001; all CV < 0.5). Round 1 recommended 10 categories with 73 indicators identified from 2,971 articles. After 3-round consultation, consensus was reached on 28 indicators focusing on the cardiovascular system (n = 4), oxygen transport system (n = 5), energy metabolism/metabolite level (n = 6), muscle/tissue damage level (n = 3), neurological function (n = 2), neuropsychological/psychological function (n = 3), endocrine function (n = 3), and exercise capacity (n = 2). Among these, 11 indicators were recommended as grade I: basic heart rate, heart-rate recovery time, heart rate variability, hemoglobin, blood lactic acid, urine protein, creatine kinase, reaction time, Borg Rating of Perceived Exertion Scale, testosterone/cortisol, and vertical jump height. Conclusion: This study developed a reliable foundation for the comprehensive evaluation of MIF among soldiers.

Retraction Notice to: Long Noncoding RNA OIP5-AS1 Promotes the Progression of Liver Hepatocellular Carcinoma via Regulating the hsa-miR-26a-3p/EPHA2 Axis.

[This retracts the article DOI: 10.1016/j.omtn.2020.05.032.].

Regiospecific O → N Acyl Migration as a Methodology to Access l-Altropyranosides with an N2,N4-Differentiation.

Pseudaminic acid and its biosynthetic altropyranoside precursors are bacterial components currently being investigated toward novel antibacterial strategies. One structural feature associated with these naturally occurring flagellar carbohydrates is the different N-acylation patterns on the two amido functionalities, posing a synthetic challenge. A new one-pot methodology is reported and a scope of diverse N2/N4-differentiated analogs are presented via a Staudinger reduction-mediated regiospecific O3 → N4 acyl migration, followed by an autonomous N2-acylation.

Opposite effect of basic combat training on mood state of recruits with different physical fitness: A study from perspective of fatigue.

Objective: Basic combat training (BCT) is a kind of necessary high-intensity training to help each military recruit convert into a qualified soldier. In China, both the physical fatigue and passive psychological state have been observed in new recruits during BCT. However, after same-intensity training, the degree of fatigue and passive mood vary among recruits. Therefore, this study aimed to explore the effect of BCT on mood state of recruits with different physical fitness levels from a perspective of fatigue. Materials and methods: Before and after BCT, the degree of fatigue and mood state of participants were evaluated via the Borg Rating of Perceived Exertion Scale and Profile of Mood States Questionnaire immediately after 20 push-ups as RPE and POMS scores [total mood disturbance (TMD), passive mood (Ttension, Tanger, Tfatigue, Tdepression, and Tconfusion) and positive mood (Tvigour and Testeem)]. The participants were divided into two groups according to the RPE score measured after BCT: (1) group 1: RPE score after BCT < 13 and (2) group 2: RPE score after BCT ≥ 13. Result: A total of 564 recruits were included (group 1: 456/564, 80.85%; group 2: 108/564, 19.15%). After BCT, in group 1, TMD (from 95.65 ± 17.89 to 87.52 ± 17.63) and passive mood Ttension (from 4.46 ± 3.18 to 3.79 ± 3.14), Tfatigue (from 4.94 ± 3.58 to 3.12 ± 3.04), Tdepression (from 2.86 ± 3.41 to 2.01 ± 2.75), Tconfusion (3.12 ± 2.72 to 2.42 ± 2.57) declined significantly (all within-group p < 0.001), but positive mood both increased significantly (Tvigour: from 13.21 ± 4.59 to 15.44 ± 5.42, Testeem: from 9.18 ± 3.36 to 11.04 ± 3.67; both within-group p < 0.001); while in group 2, only Tanger (from 4.27 ± 4.16 to 6.22 ± 5.94, within-group p = 0.001) and Testeem (from 8.36 ± 3.15 to 9.07 ± 3.67, within-group p = 0.031) increased significantly. Conclusion: BCT could alleviate passive mood and add to positive mood for recruits with better physical fitness, while had no ameliorative effects on or even deteriorate most of the passive mood for recruits with worse physical fitness.

Versican promotes T helper 17 cytotoxic inflammation and impedes oligodendrocyte precursor cell remyelination.

Remyelination failure in multiple sclerosis (MS) contributes to progression of disability. The deficient repair results from neuroinflammation and deposition of inhibitors including chondroitin sulfate proteoglycans (CSPGs). Which CSPG member is repair-inhibitory or alters local inflammation to exacerbate injury is unknown. Here, we correlate high versican-V1 expression in MS lesions with deficient premyelinating oligodendrocytes, and highlight its selective upregulation amongst CSPG members in experimental autoimmune encephalomyelitis (EAE) lesions modeling MS. In culture, purified versican-V1 inhibits oligodendrocyte precursor cells (OPCs) and promotes T helper 17 (Th17) polarization. Versican-V1-exposed Th17 cells are particularly toxic to OPCs. In NG2CreER:MAPTmGFP mice illuminating newly formed GFP+ oligodendrocytes/myelin, difluorosamine (peracetylated,4,4-difluoro-N-acetylglucosamine) treatment from peak EAE reduces lesional versican-V1 and Th17 frequency, while enhancing GFP+ profiles. We suggest that lesion-elevated versican-V1 directly impedes OPCs while it indirectly inhibits remyelination through elevating local Th17 cytotoxic neuroinflammation. We propose CSPG-lowering drugs as potential dual pronged repair and immunomodulatory therapeutics for MS.

Effects of different phosphorus-free water-retaining agents on the quality of frozen tilapia fillets.

Tilapia is an economically important fish worldwide, but its quality is affected by storage practices. To improve the quality of tilapia fillets during frozen storage, we examined the effect of pretreatment with various combinations of different concentrations of trehalose, potassium bicarbonate, and chitosan. Following pretreatment, we analyzed the tilapia fillets using quality indicators, including soaking weight gain, coating weight gain, water-holding capacity, thawing loss, pH, Ca2+-ATPase activity, and texture characteristics. Water distribution was analyzed using low-field nuclear magnetic resonance and the optimal combination of water-retaining agents was obtained using an L8(27) orthogonal experiment. The results showed that trehalose, potassium bicarbonate, and chitosan improved fillet quality at pretreatment concentrations of 5%-8%, 1.0%, and 0.5%, respectively. The optimal combination was 4% trehalose plus 1.2% potassium bicarbonate plus 0.2% chitosan. The Ca2+-ATPase activity and mastication property of the frozen fillets that were pretreated with the optimized formulation were 1.39 µmol Pi/mg protein·h and 8.55 mJ, respectively, which were 43.3% and 80.0% greater, respectively, than that of the control group. Using a suitable concentration and combination of water-retaining agents cannot only lock-in the internal water content of frozen tilapia fillets but also improve their quality during frozen storage. These results can inform practical storage practices of similar aquatic products.

A Distinct Hibiscus sabdariffa Extract Prevents Iron Neurotoxicity, a Driver of Multiple Sclerosis Pathology.

Iron deposition in the brain begins early in multiple sclerosis (MS) and continues unabated. Ferrous iron is toxic to neurons, yet the therapies used in MS do not counter iron neurotoxicity. Extracts of Hibiscus sabdariffa (HS) are used in many cultures for medicinal purposes. We collected a distinct HS extract and found that it abolished the killing of neurons by iron in culture; medications used in MS were ineffective when similarly tested. Neuroprotection by HS was not due to iron chelation or anthocyanin content. In free radical scavenging assays, HS was equipotent to alpha lipoic acid, an anti-oxidant being tested in MS. However, alpha lipoic acid was only modestly protective against iron-mediated killing. Moreover, a subfraction of HS without radical scavenging activity negated iron toxicity, whereas a commercial hibiscus preparation with anti-oxidant activity could not. The idea that HS might have altered properties within neurons to confer neuroprotection is supported by its amelioration of toxicity caused by other toxins: beta-amyloid, rotenone and staurosporine. Finally, in a mouse model of MS, HS reduced disability scores and ameliorated the loss of axons in the spinal cord. HS holds therapeutic potential to counter iron neurotoxicity, an unmet need that drives the progression of disability in MS.

Sphingosine-1-phosphate transporter spinster homolog 2 is essential for iron-regulated metastasis of hepatocellular carcinoma.

Iron dyshomeostasis is associated with hepatocellular carcinoma (HCC) development. However, the role of iron in HCC metastasis is unknown. This study aimed to elucidate the underlying mechanisms of iron's enhancement activity on HCC metastasis. In addition to the HCC cell lines and clinical samples in vitro, iron-deficient (ID) mouse models were generated using iron-free diet and transferrin receptor protein knockout, followed by administration of HCC tumors through either orthotopic or ectopic route. Clinical metastatic HCC samples showed significant ID status, accompanied by overexpression of sphingosine-1-phosphate transporter spinster homolog 2 (SPNS2). Mechanistically, ID increased SPNS2 expression, leading to HCC metastasis in both cell cultures and mouse models. ID not only altered the anti-tumor immunity, which was indicated by phenotypes of lymphatic subsets in the liver and lung of tumor-bearing mice, but also promoted HCC metastasis in a cancer cell autonomous manner through the SPNS2. Since germline knockout of globe SPNS2 showed significantly reduced HCC metastasis, we further developed hepatic-targeting recombinant adeno-associated virus vectors to knockdown SPNS2 expression and to inhibit iron-regulated HCC metastasis. Our observation indicates the role of iron in HCC pulmonary metastasis and suggests SPNS2 as a potential therapeutic target for the prevention of HCC pulmonary metastasis.