Oxalate regulates crystal-cell adhesion and macrophage metabolism via JPT2/PI3K/AKT signaling to promote the progression of kidney stones

Oxalate is an organic dicarboxylic acid that is a common component of plant foods.The kidneys are essential organs for oxalate excretion,but excessive oxalates may induce kidney stones.Jupiter microtubule associated homolog 2(JPT2)is a critical molecule in Ca^(2+)mobilization,and its intrinsic mechanism in oxalate exposure and kidney stones remains unclear.This study aimed to reveal the mechanism of JPT2 in oxalate exposure and kidney stones.Genetic approaches were used to control JPT2 expression in cells and mice,and the JPT2 mechanism of action was analyzed using transcriptomics and untargeted metabolomics.The results showed that oxalate exposure triggered the upregulation of JPT2,which is involved in nicotinic acid adenine dinucleotide phosphate(NAADP)-mediated Ca^(2+)mobilization.Transcriptomic analysis revealed that cell adhesion and macrophage inflammatory polarization were inhibited by JPT2 knockdown,and these were dominated by phosphatidylinositol 3-kinase(PI3K)/AKT signaling,respectively.Untargeted metabolomics indicated that JPT2 knockdown inhibited the production of succinic acid semialdehyde(SSA)in macrophages.Furthermore,JPT2 deficiency in mice inhibited kidney stones mineralization.In conclusion,this study demonstrates that oxalate exposure facilitates kidney stones by promoting crystal-cell adhesion,and modulating macrophage metabolism and inflammatory polarization via JPT2/PI3K/AKT signaling.

Bioactive compounds in Hericium erinaceus and their biological properties:a review

Hericium erinaceus is a nutritious edible and medicinal fungi,rich in a variety of functional active ingredients,with various physiological functions such as antioxidation,anticancer,and enhancing immunity.It is also effective in protecting the digestive system and preventing neurodegenerative diseases.In this review paper,we summarize the sources,structures and efficacies of the main active components in H.erinaceus fruiting body,mycelium,and culture media,and update the latest research progress on their biological activities and the related molecular mechanisms.Based on this information,we provide detailed challenges in current research,industrialization and information on the active ingredients of H.erinaceus.Perspectives for future studies and new applications of H.erinaceus are proposed.

Differences in the effects and action modes of gut commensals against dextran sulfate sodium-induced intestinal inflammation

Inflammatory bowel disease(IBD)is a complex relapsing inflammatory disease in the gut and is driven by complicated host-gut microbiome interactions.Gut commensals have shown different functions in IBD prevention and treatment.To gain a mechanistic understanding of how different commensals affect intestinal inflammation,we compared the protective effects of 6 probiotics(belonging to the genera Akkermansia,Bifidobacterium,Clostridium,and Enterococcus)on dextran sulfate sodium(DSS)-induced colitis in mice with or without gut microbiota.Anti-inflammatory properties(ratio of interleukin(IL)-10 and IL-12)of these strains were also evaluated in an in vitro mesenteric lymph nodes(MLN)co-culture system.Results showed that 4 probiotics(belonging to the species Bifidobacterium breve,Bifidobacterium bifidum,and Enterococcus faecalis)can alleviate colitis in normal mice.The probiotic strains differed in regulating the intestinal microbiota,cytokines(IL-10,IL-1βand interferon(IFN)-γ),and tight junction function(Zonulin-1 and Occludin).By constrast,Akkermansia muciniphila AH39 and Clostridium butyricum FHuNHHMY49T1 were not protective.Interestingly,B.breve JSNJJNM2 with high anti-inflammatory potential in the MLN model could relieve colitis symptoms in antibiotic cocktail(Abx)-treated mice.Meanwhile,E.faecalis FJSWX25M1induced low levels of cytokines in vitro and showed no beneficial effects.Therefore,we provided insight into the clinical application of probiotics in IBD treatment.

Umbilical Cord Blood-derived Mesenchymal Stem Cells Ameliorate Graft-Versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation through Multiple Immunoregulations

Summary： Although mesenchymal stem cells （MSCs） are increasingly used to treat graft-versus-host disease （GVHD）, their immune regulatory mechanism in the process is elusive. The present study aimed to investigate the curative effect of third-party umbilical cord blood-derived human MSCs （UCB-hMSCs） on GVHD patients after allogeneic hematopoietic stem cell transplantation （allo-HSCT） and their immune regulatory mechanism. Twenty-four refractory GVHD patients after allo-HSCT were treated with UCB-hMSCs. Immune cells including T lymphocyte subsets, NK ceils, Treg cells and dendritic cells （DCs） and cytokines including interleukin-17 （IL-17） and tumor necrosis factor-alpha （TNF-α） were monitored before and after MSCs transfusion. The results showed that the symptoms of GVHD were alleviated significantly without increased relapse of primary disease and transplant-related complications after MSCs transfusion. The number of CD3^＋, CD3＋CD4^＋ and CD3＋CD8^＋ cells decreased significantly, and that of NK cells remained unchanged, whereas the number of CD4^＋ and CD8^＋ Tregs increased and reached a peak at 4 weeks; the number of mature DCs, and the levels of TNF-α and IL-17 decreased and reached a trough at 2 weeks. It was concluded that MSCs ameliorate GVHD and spare GVL effect via immunoregulations.

Citrus fruits are rich in flavonoids for immunoregulation and potential targeting ACE2

The most recent outbreak of 2019 novel coronavirus,named as COVID-19,caused pneumonia epidemic in Wuhan with 2121 deaths cases as of February 20th 2020.Identification of effective antiviral agents to combat the novel coronavirus is urgently needed.Citrus fruit peel or wild citrus are rich in flavonoids,and clinically documented for roles in relief of cough and promotion of digestive health.Therefore,citrus fruits are assumed to possess antivirus activities or enhance the host immunity.A previous study found that hesperetin could act as a high potent inhibitor of SARS-CoV 3CLpro.We determined six flavonoid compounds’content in three citrus species by using LC-MS technique.The content of naringin and naringenin was at higher levels in pummelo.Hesperetin and hesperidin were highly accumulated in mandarin and sweet orange.The subsequent in vitro and in vivo experiments indicated that naringin could inhibit the expression of the proinflammatory cytokines(COX-2,iNOS,IL-1βand IL-6)induced by LPS in Raw macrophage cell line,and may restrain cytokine through inhibiting HMGB1 expression in a mouse model.The results revealed that naringin may have a potential application for preventing cytokine storm.We simulated molecular docking to predict the binding affinity of those flavonoids to bind Angiotensin-converting enzyme 2(ACE 2),which is a receptor of the coronavirus.Consideration of the potential anti-coronavirus and anti-inflammatory activity of flavonoids,the citrus fruit or its derived phytochemicals are promising in the use of prevention and treatment of SARS-CoV-2 infection.

Studies on Immunoregulation of Cytokine of Chickens after Inoculation with Marek's Disease Vaccines

The spleenic and thymus T lymphocyte proliferaitivc reactions (TLPR) were enhanced, the intcrlcukin 2(IL-2) inductive activity was raised, and the IL-2 receptor (IL-2R) inductive expression was increased significantly in chickens after inoculation with trivalcnt Marck’s disease vaccine in comparison with control chickens and those after vaccination with herpcsvirus of turkey (HVT) vaccine. In chickens after inoculation with HVT vaccine, in contrast with control chickens, the splcenic TLPR was strengthened and IL-2R inductive expression was hoisted significantly, the thymus TLPR, splccnic and thymus T lymphocyte IL-2 inductive activity, the thymus T lymphocyte IL-2R inductive expression were not significantly increased.

Immunoregulation of Lupus－like NZB／W F_1 Mice by Antimurine IL－1α，IL－6 Antibodies

Anti-murine IL-1α, IL-6 antibodies were intra-peritoneally injected to the lupus-like NZB/W F1 mice of 4 months with the dosage of 10μg per day for three days and then per month for three months. The mice were killed at the age of 11 months. The results showed that the treatment of the dosage could not absolutely prevent lupus nephritis; it could alleviate proteinuria, obviously reduce the levels of serum IL-lα and inhibit the secretion of IL-1α by celiac macrophage.As to the level of IL-6 and TNF-α no significant change was observed.

Immunoregulation Effect of Red Ginseng Aqueous Extract on Mice

[Objectives]The paper was to observe the effects of red ginseng aqueous extract on immune function of mice.[Methods]The aqueous extract of red ginseng was obtained by water extraction and concentration,and 10 mL of aqueous extract was equivalent to 2.86 g of raw materials.Total 240 mice were randomly divided into blank control group,low dose,medium dose and high dose groups of red ginseng aqueous extract,60 mice each group.Mice in low dose,medium dose and high dose groups were intragastrically administered with 0.24,0.48,1.43 g/kg red ginseng aqueous extract once a day respectively,and those in blank control group were intragastrically administered with equal volume of deionized water at the dose of 0.1 mL/10 g once a day for consecutive 30 d.The immunoregulation effects of red ginseng aqueous extract on mice were explored by organ/body weight ratio measurement,delayed type hypersensitivity(DTH)reaction,Con A-induced spleen T lymphocyte transformation test,antibody-producing cells test,half hemolytic value(HC 50)test,carbon particle clearance test,phagocytosis test of chicken red blood cells by macrophages and NK cell activity test.[Results]Compared with the blank control group,the degree of toe swelling in low dose group and medium dose group of red ginseng aqueous extract[(0.62±0.14)mm,(0.53±0.12)mm vs.(0.36±0.10)mm]significantly increased(P<0.05).The ability of T lymphocytes proliferation(0.173±0.054,0.189±0.063 vs.0.098±0.012)in low dose group and high dose group significantly increased(P<0.05).The number of haemolytic plaque(137.49×10^(3)±24.73×10^(3),148.43×10^(3)±27.53×10^(3) vs.112.96×10^(3)±26.28×10^(3))in medium dose group and high dose group significantly increased(P<0.05).The phagocytosis rate(35.67%±3.82%,49.26%±6.54%,57.92%±7.36%vs.24.34%±4.22%)and phagocytosis index(0.72±0.23,0.82±0.15,0.91±0.26 vs.0.35±0.11)of low dose,medium dose,high dose groups significantly increased(P<0.05).However,there was no statistical difference in spleen/body weight ratio,thymus/body weight ratio,half hemolytic value,carbon particle clearance and NK cell activity.[Conclusions]Red ginseng aqueous extract could enhance the immunity of mice.

Immunoregulation of KangAi injection combined with chemotherapy in advanced non-small cell lung cancer: a systematic review and meta-analysis

Objective: To evaluate the immunoregulation of KangAi (KA) injection combined with chemo-treatment (chemo) for Non-small cell lung cancer (NSCLC). Methods: We systematically searched the literature of PubMed, EMBASE, CENTRAL, MEDLINE, CNKI, Wanfang, and VIP databases for all Randomized controlled trials (published from the earliest possible year to January 2019, no language restrictions) comparing KA injection combined with chemo and chemo alone in patients with NSCLC. Our main endpoints were immune function, clinical efficiency, KPS score and adverse events. The Cochrane Risk of Bias tool was applied for quality assessment. Results: 11 studies involving 1060 participants were included. The immune function (MD=3.18, 95% CI: 0.98-4.00, P<0.00001), clinical response rate (RR=1.28, 95%CI: 1.17-1.40, P<0.00001), KPS score (RR=1.86, 95%CI: 1.35-2.57, P=0.0002), and adverse events (RR=0.57, 95%CI: 0.50-0.65, P<0.00001) in the group of KA injection plus Chemo were vastly different from those in Chemo alone. Conclusion: KA injection combined with Chemo in the treatment of NSCLC improved the immune function, clinical efficiency and safety compared to Chemo alone. However, because many of the methodologies included in randomized controlled trials are of poor quality, more rigorous design and large randomized controlled trials are needed to test this benefit.

Immunoregulation and anti-tumor effects of Polyporusus Bellatus： a review of recent research

Background： We summarized the Polyporusus Bellatus （PPS） efficacy of immunomodulation, liver protection and anti-tumor, then provide scientific basis for further research and clinical application. This dissertation first overview relevant literatures of PPS recent years and describe comprehensively the research progress of the immunoregulation, liver protection and anti-tumor effects and mechanism of PPS. The review shows that the PPS play anti-tumor effects through antioxidation, scavenging free radicals, inhibiting tumor cell proliferation, inducing apoptosis, affecting tumor gene expressions and enhancing immune functions. PPS can exert immunoregulatory, hepatoprotective and anti-tumor effects through multiple pathways and multiple targets, which provides a good application prospect in clinic.

Clinical application prospects and transformation value of dental follicle stem cells in oral and neurological diseases

Since dental pulp stem cells(DPSCs)were first reported,six types of dental SCs(DSCs)have been isolated and identified.DSCs originating from the craniofacial neural crest exhibit dental-like tissue differentiation potential and neuroectodermal features.As a member of DSCs,dental follicle SCs(DFSCs)are the only cell type obtained at the early developing stage of the tooth prior to eruption.Dental follicle tissue has the distinct advantage of large tissue volume compared with other dental tissues,which is a prerequisite for obtaining a sufficient number of cells to meet the needs of clinical applications.Furthermore,DFSCs exhibit a significantly higher cell proliferation rate,higher colony-formation capacity,and more primitive and better anti-inflammatory effects than other DSCs.In this respect,DFSCs have the potential to be of great clinical significance and translational value in oral and neurological diseases,with natural advantages based on their origin.Lastly,cryopreservation preserves the biological properties of DFSCs and enables them to be used as off-shelf products for clinical applications.This review summarizes and comments on the properties,application potential,and clinical transformation value of DFSCs,thereby inspiring novel perspectives in the future treatment of oral and neurological diseases.

Regulatory role of exosomes in colorectal cancer progression and potential as biomarkers

Colorectal cancer(CRC)remains an enormous challenge to human health worldwide.Unfortunately,the mechanism underlying CRC progression is not well understood.Mounting evidence has confirmed that exosomes play a vital role in CRC progression,which has attracted extensive attention among researchers.In addition to acting as messengers between CRC cells,exosomes also participate in the CRC immunomodulatory process and reshape immune function.As stable message carriers and liquid biopsy option under development,exosomes are promising biomarkers in the diagnosis or treatment of CRC.In this review we have described and analyzed the biogenesis and release of exosomes and current research on the role of exosomes in immune regulation and metastasis of CRC.Moreover,we have discussed candidate exosomal molecules as potential biomarkers to diagnose CRC,predict CRC progression,or determine CRC chemoresistance,and described the significance of exosomes in the immunotherapy of CRC.This review provides insight to further understand the role of exosomes in CRC progression and identify valuable biomarkers that facilitate the clinical management of CRC patients.

Research progress of artesunate in diabetes and its complications

Diabetes is a metabolic disease characterized by abnormally elevated blood glucose levels.Persistent hyperglycemia leads to diabetic nephropathy,diabetic retinopathy,diabetes with periodontal disease and other diabetic complications.These diseases have become the main causes of disability and death in diabetic patients.Artesunate is well known as an antimalarial drug for controlling malaria symptoms.Current studies have shown that artesunate improves diabetes and its complications by protecting islet cells,improving glucose and lipid metabolism,anti-inflammatory and immune regulation.Based on the research status in recent years,this paper focuses on the mechanism of artesunate in diabetes and its complications,to provide a theoretical basis for future diabetes research.

Progress and expectation of stem cell therapy for diabetic wound healing

Impaired wound healing presents great health risks to diabetics.Encouragingly,the current clinical successfully found out meaningful method to repair wound tissue,and stem cell therapy could be an effective method for diabetic wound healing with its ability to accelerate wound closure and avoid amputation.This minireview aims at introducing stem cell therapy for facilitating tissue repair in diabetic wounds,discussing the possible therapeutic mechanism and clinical application status and problems.

Colorectal cancer and immunity:what we know and perspectives

Strong evidence supports the concept of immunosurveillance and immunoediting in colorectal cancer. In particular, the density of T CD8+ and CD45+ lymphocyte infiltration was recently shown to have a better prognostic value than the classic tumor node metastasis classification factor. Other immune subsets, as macrophages, natural killer cells or unconventionnal lymphocytes, seem to play an important role. Induction of regulatory T cells (Tregs) or immunosuppressive molecules such as PD-1 or CTLA-4 and downregulation of antigen-presenting molecules are major escape mechanisms to antitumor immune response. The development of these mechanisms is a major obstacle to the establishment of an effective immune response, but also to the use of immunotherapy. Although immunotherapy is not yet routinely used in colorectal cancer, we now know that most treatments used (chemotherapy and biotherapy) have immunomodulatory effects, such as induction of immunogenic cell death by chemotherapy, inhibition of immunosuppression by antiangiogenic agents, and antibody-dependent cytotoxicity induced by cetuximab. Finally, many immunotherapy strategies are being developed and tested in phase I to III clinical trials. The most promising strategies are boosting the immune system with cytokines, inhibition of immunoregulatory checkpoints, vaccination with vectorized antigens, and adoptive cell therapy. Comprehension of antitumor immune response and combination of the different approaches of immunotherapy may allow the use of effective immunotherapy for treatment of colorectal cancer in the near future.

Contribution of TLR signaling to the pathogenesis of colitisassociated cancer in inflammatory bowel disease

In the intestine a balance between proinflammatory and repair signals of the immune system is essential for the maintenance of intestinal homeostasis. The innate immunity ensures a primary host response to microbial invasion, which induces an inflammatory process to localize the infection and prevent systemic dissemination of pathogens. The key elements of this process are the germline encoded pattern recognition receptors including Toll-like receptors (TLRs). If pathogens cannot be eliminated, they may elicit chronic inflammation, which may be partly mediated via TLRs. Additionally, chronic inflammation has long been suggested to trigger tissue tumorous transformation. Inflammation, the seventh hallmark of cancer, may affect all phases of tumor development, and evade the immune system. Inflammation acts as a cellular stressor and may trigger DNA damage or genetic instability. Furthermore, chronic inflammation can provoke genetic mutations and epigenetic mechanisms that promote malignant cell transformation. Colorectal cancers in inflammatory bowel disease patients are considered typical examples of inflammation-related cancers. Although data regarding the role of TLRs in the pathomechanism of cancer-associated colitis are rather conflicting, functionally these molecules can be classified as &#x0201d;largely antitumorigenic&#x0201d; and &#x0201d;largely pro-tumorigenic&#x0201d; with the caveat that the underlying signaling pathways are mainly context (i.e., organ-, tissue-, cell-) and ligand-dependent.

Regulatory T cells in viral hepatitis

The pathogenesis and outcome of viral infections are significantly influenced by the host immune response. The immune system is able to eliminate many viruses in the acute phase of infection. However, some viruses, like hepatitis C virus (HCV) and hepatitis B virus (HBV), can evade the host immune responses and establish a persistent infection. HCV and HBV persistence is caused by various mechanisms, like subversion of innate immune responses by viral factors, the emergence of T cell escape mutations, or T cell dysfunction and suppression. Recently, it has become evident that regulatory T cells may contribute to the pathogenesis and outcome of viral infections by suppressing antiviral immune responses. Indeed, the control of HCV and HBV specific immune responses mediated by regulatory T cells may be one mechanism that favors viral persistence, but it may also prevent the host from overwhelming T cell activity and liver damage. This review will focus on the role of regulatory T cells in viral hepatitis.

1,25-dihydroxyvitamin D_3 regulates LPS-induced cytokine production and reduces mortality in rats

AIM： To study the immunoregulatory effect of 1,25-dihydroxyvitamin-D3 Von dominant Thl response in rats. METHODS： Sixty adult Lewis rats were randomized into three groups. Rats in group 1 （n=25） were treated with 1,25-（OH）2D3 first and then challenged with LPS, rats in group 2 （n=25） were treated with vehicle first and then challenged with LPS. Ten animals in groups 1 and 2 were preserved for mortality observation. The remaining animals were injected （i.p） with endotoxin, 24 h after the last administration of 1,25-（OH）2D3 and vehicle. Rats in group 3 （n=10） were treated with 1,25-（OH）2D3 only. Serum IL-12, IFN-y, IL-2 and IL-4 levels were measured and target gene of 1,25-（OH）2D3 on Th cells was studied after 6 h. Gene abundance was verified by real-time quantitative PCR. RESULTS： No death occurred in rats pretreated with 1,25-（OH）2D3 after LPS injection. Death occurred 9 h after LPS injection in rats pretreated with the vehicle, and the number of deaths was 5 within 24 h, with a mortality rate of 50%. There was no change in the number of deaths within 96 h. Six hours after endotoxin stimulation, serum IL-12 and IFN-y levels decreased significantly in rats pretreated with 1,25-（OH）2D3 as compared with those in rats pretreated with the vehicle. The serum content of these two cytokines was very low in rats not challenged by endotoxin, and there was a significant difference as compared with the previous two groups. CONCLUSION： 1,25-（OH）2D3 attenuates injuryinduced by the lethal dose of 1PS, regulates Thl and Th2 cells at the transcription level, and dominantly responds to cytokine production in rats.

Mesenchymal stromal cells as potential immunomodulatory players in severe acute respiratory distress syndrome induced by SARSCoV- 2 infection

Severe acute respiratory syndrome coronavirus-2 and the related coronavirus disease-19(COVID-19)is a worldwide emerging situation,which was initially reported in December 2019 in Wuhan,China.Currently,more than 7258842 new cases,and more than 411879 deaths have been reported globally.This new highly transmitted coronavirus is responsible for the development of severe acute respiratory distress syndrome.Due to this disorder,a great number of patients are hospitalized in the intensive care unit followed by connection to extracorporeal membrane oxygenation for breath supporting and survival.Severe acute respiratory distress syndrome is mostly accompanied by the secretion of proinflammatory cytokines,including interleukin(IL)-2,IL-6,IL-7,granulocyte colony-stimulating factor(GSCF),interferon-inducible protein 10(IP10),monocyte chemotactic protein-1(MCP1),macrophage inflammatory protein 1A(MIP1A),and tumor necrosis factor alpha(TNF-α),an event which is known as“cytokine storm”.Further disease pathology involves a generalized modulation of immune responses,leading to fatal multiorgan failure.Currently,no specific treatment or vaccination against severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)has been developed.Mesenchymal stromal cells(MSCs),which are known for their immunosuppressive actions,could be applied as an alternative co-therapy in critically-ill COVID-19 patients.Specifically,MSCs can regulate the immune responses through the conversion of Th1 to Th2,activation of M2 macrophages,and modulation of dendritic cells maturation.These key immunoregulatory properties of MSCs may be exerted either by produced soluble factors or by cell-cell contact interactions.To date,several clinical trials have been registered to assess the safety,efficacy,and therapeutic potential of MSCs in COVID-19.Moreover,MSC treatment may be effective for the reversion of ground-glass opacity of damaged lungs and reduce the tissue fibrosis.Taking into account the multifunctional properties of MSCs,the proposed stem-cell-based therapy may be proven significantly effective in critically-ill COVID-19 patients.The current therapeutic strategy may improve the patient’s overall condition and in parallel may decrease the mortality rate of the current disease.

Effects of living and metabolically inactive mesenchymal stromal cells and their derivatives on monocytes and macrophages

Mesenchymal stromal cells (MSCs) are multipotent and self-renewing stem cellsthat have great potential as cell therapy for autoimmune and inflammatorydisorders, as well as for other clinical conditions, due to their immunoregulatoryand regenerative properties. MSCs modulate the inflammatory milieu by releasingsoluble factors and acting through cell-to-cell mechanisms. MSCs switch theclassical inflammatory status of monocytes and macrophages towards a nonclassicaland anti-inflammatory phenotype. This is characterized by an increasedsecretion of anti-inflammatory cytokines, a decreased release of pro-inflammatorycytokines, and changes in the expression of cell membrane molecules and inmetabolic pathways. The MSC modulation of monocyte and macrophage phenotypesseems to be critical for therapy effectiveness in several disease models, sincewhen these cells are depleted, no immunoregulatory effects are observed. Here,we review the effects of living MSCs (metabolically active cells) and metabolicallyinactive MSCs (dead cells that lost metabolic activity by induced inactivation) andtheir derivatives (extracellular vesicles, soluble factors, extracts, and microparticles)on the profile of macrophages and monocytes and the implications forimmunoregulatory and reparative processes. This review includes mechanisms ofaction exhibited in these different therapeutic appro-aches, which induce the antiinflammatoryproperties of monocytes and macrophages. Finally, we overviewseveral possibilities of therapeutic applications of these cells and their derivatives,with results regarding monocytes and macrophages in animal model studies andsome clinical trials.