SlSPX1-SlPHR complexes mediate the suppression of arbuscular mycorrhizal symbiosis by phosphate repletion in tomato.

Forming mutualistic symbioses with arbuscular mycorrhizae (AMs) improves the acquisition of mineral nutrients for most terrestrial plants. However, the formation of AM symbiosis usually occurs under phosphate (Pi)-deficient conditions. Here, we identify SlSPX1 (SYG1 (suppressor of yeast GPA1)/Pho81(phosphate 81)/XPR1 (xenotropic and polytropic retrovirus receptor 1) as the major repressor of the AM symbiosis in tomato (Solanum lycopersicum) under phosphate-replete conditions. Loss of SlSPX1 function promotes direct Pi uptake and enhances AM colonization under phosphate-replete conditions. We determine that SlSPX1 integrates Pi signaling and AM symbiosis by directly interacting with a set of arbuscule-induced SlPHR proteins (SlPHR1, SlPHR4, SlPHR10, SlPHR11, and SlPHR12). The association with SlSPX1 represses the ability of SlPHR proteins to activate AM marker genes required for the arbuscular mycorrhizal symbiosis. SlPHR proteins exhibit functional redundancy, and no defective AM symbiosis was detected in the single mutant of SlPHR proteins. However, silencing SlPHR4 in the Slphr1 mutant background led to reduced AM colonization. Therefore, our results support the conclusion that SlSPX1-SlPHRs form a Pi-sensing module to coordinate the AM symbiosis under different Pi-availability conditions.

Auxin-mediated regulation of arbuscular mycorrhizal symbiosis: A role of SlGH3.4 in tomato.

Most land plants can establish symbiosis with arbuscular mycorrhizal (AM) fungi to increase fitness to environmental challenges. The development of AM symbiosis is controlled by intricate procedures involving all phytohormones. However, the mechanisms underlying the auxin-mediated regulation of AM symbiosis remains largely unknown. Here, we report that AM colonisation promotes auxin response and indole-3-acetic acid (IAA) accumulation, but downregulates IAA biosynthesis genes in tomato (Solanum lycopersicum). External IAA application modulates the AM symbiosis by promoting arbuscule formation at low concentrations but repressing it at high concentrations. An AM-induced GH3 gene, SlGH3.4, encoding a putative IAA-amido synthetase, negatively regulates mycorrhization via maintaining cellular auxin homoeostasis. Loss of SlGH3.4 function increased free IAA content and arbuscule incidence, while constitutively overexpressing SlGH3.4 in either tomato or rice resulted in decreased IAA content, total colonisation level and arbuscule abundance in mycorrhizal roots. Several auxin-inducible expansin genes involved in AM formation or resistance to pathogen infection were upregulated in slgh3.4 mycorrhizal roots but downregulated in the SlGH3.4-overexpressing plants. Taken together, our results highlight a positive correlation between the endogenous IAA content and mycorrhization level, particularly arbuscule incidence, and suggest that the SlGH3.4-mediated auxin homoeostasis and regulation of expansin genes is involved in finely tuning the AM development.

Novel Mycorrhiza-Specific P Transporter PvPht1;6 Contributes to As Accumulation at the Symbiotic Interface of As-Hyperaccumulator Pteris vittata.

Arsenic (As) is toxic and ubiquitous in the environment, posing a growing threat to human health. As-hyperaccumulator Pteris vittata has been used for phytoremediation of As-contaminated soil. Symbiosis with arbuscular mycorrhizal fungi (AMF) enhances As accumulation by P. vittata, which is different from As inhibition in typical plants. In this study, P. vittata seedlings inoculated with or without AMF were cultivated in As-contaminated soils for 2 months. AMF-root symbiosis enhanced plant growth, with 64.5% greater As contents in the fronds. After exposure to AsV for 2 h, the arsenate (AsV) and arsenite (AsIII) contents in AMF-roots increased by 1.8- and 3.6-fold, suggesting more efficient As uptake by P. vittata with AMF-roots. Plants take up and transport AsV via phosphate transporters (Phts). Here, for the first time, we identified a novel mycorrhiza-specific Pht transporter, PvPht1;6, from P. vittata. The transcripts of PvPht1;6 were strongly induced in AMF-roots, which were localized to the plasma membrane of arbuscule-containing cells. By complementing a yeast mutant lacking 5-Phts, we confirmed PvPht1;6's transport activity for both P and AsV. In contrast to typical AMF-inducible phosphate transporter LePT4 from tomato, PvPht1;6 showed greater AsV transport capacity. The results suggest that PvPht1;6 is probably critical for AsV transport at the periarbuscular membrane of P. vittata root cells, revealing the underlying mechanism of efficient As accumulation in P. vittata with AMF-roots.

Circulating sortilin levels are associated with inflammation in patients with moyamoya disease.

BACKGROUND: Systemic inflammation has been implicated in the pathogenesis of moyamoya disease (MMD). Sortilin is a critical regulator of proinflammatory cytokine secretion in several cell types. The present study investigated the association between circulating sortilin and proinflammatory cytokine levels and the occurrence of MMD. METHODS: Forty-two MMD cases and 76 age- and sex-matched controls were enrolled in this study between January 2018 and June 2019 at the Affiliated Hospital of Jining Medical University. The demographic and clinical characteristics were evaluated, and the circulating serum and cerebrospinal fluid (CSF) levels of sortilin, sortilin-related receptor with A-type repeats (SorLA), and proinflammatory cytokines including C-reactive protein (CRP), interleukin (IL)-6, interferon (IFN)-γ were measured by enzyme-linked immunosorbent assay. Linear regression and correlation analyses were used to estimate the associations between sortilin, SorLA, and proinflammatory cytokine levels. RESULTS: MMD patients had higher serum levels of sortilin (P = 0.012), CRP (P = 0.013), IL-6 (P = 0.004), and IFN-γ (P = 0.033) than healthy controls. In MMD patients, serum sortilin was positively correlated with serum proinflammatory cytokines (CRP: r = 0.459, P = 0.0022; IL-6: r = 0.445, P = 0.0032; and IFN-γ: r = 0.448, P = 0.0029) and CSF sortilin (r = 0.440, P = 0.0035); the latter was positively correlated with CSF levels of CRP (r = 0.542, P = 0.0002), IL-6 (r = 0.440, P = 0.0036), and IFN-γ (r = 0.443, P = 0.0033). CONCLUSIONS: Elevated sortilin level is associated MMD onset and may be a clinically useful biomarker along with proinflammatory cytokine levels.

Role of t-PA and PAI-1 variants in temporal lobe epilepsy in Chinese Han population.

BACKGROUND: Epilepsy is one of the most common chronic disabling neurologic diseases. The purpose of our study was to investigate whether there is an association between t-PA (tissue plasminogen activator, rs2020918 and rs4646972), PAI-1 (plasminogen activator inhibitor 1, rs1799768) polymorphisms and susceptibility to temporal lobe epilepsy (TLE) in Chinese Han population. METHOD: One hundred and twenty-one cases of patients who were diagnosed as TLE and 146 normal controls were enrolled and the genotypes of t-PA and PAI-1 were detected by polymerase chain reaction-ligase detection reaction (PCR-LDR) method after the genomic DNA being extracted from peripheral blood. RESULT: There were significant differences for the genotypic frequencies at the two polymorphic sites in t-PA gene between TLE patients and controls (P = 0.019; P = 0.001). Furthermore, the frequency of rs2020918 (C > T) with T (CT + TT) and rs4646972 (311 bp insertion/-) with 311 bp deletion (311 bp/- + -/-) was significantly higher among TLE patients relative to controls respectively (P = 0.006; P = 0.001). However, no significant difference in genotypic and allelic frequency was found at the polymorphic site in PAI-1 gene between TLE patients and controls (P = 0.735). CONCLUSION: We reported for the first time to our knowledge the significant role of the two SNPs in t-PA gene (rs2020918 and rs4646972) in developing susceptibility to TLE in Chinese Han population.

Phytohormones Regulate the Development of Arbuscular Mycorrhizal Symbiosis.

Most terrestrial plants are able to form a root symbiosis with arbuscular mycorrhizal (AM) fungi for enhancing the assimilation of mineral nutrients. AM fungi are obligate symbionts that depend on host plants as their sole carbon source. Development of an AM association requires a continuous signal exchange between the two symbionts, which triggers coordinated differentiation of both partners, to enable their interaction within the root cells. The control of the AM symbiosis involves a finely-tuned process, and an increasing number of studies have pointed to a pivotal role of several phytohormones, such as strigolactones (SLs), gibberellic acids (GAs), and auxin, in the modulation of AM symbiosis, through the early recognition of events up to the final arbuscular formation. SLs are involved in the presymbiotic growth of the fungus, while auxin is required for both the early steps of fungal growth and the differentiation of arbuscules. GAs modulate arbuscule formation in a dose-dependent manner, via DELLA proteins, a group of GRAS transcription factors that negatively control the GA signaling. Here, we summarize the recent findings on the roles of these plant hormones in AM symbiosis, and also explore the current understanding of how the DELLA proteins act as central regulators to coordinate plant hormone signaling, to regulate the AM symbiosis.

Three cis-Regulatory Motifs, AuxRE, MYCRS1 and MYCRS2, are Required for Modulating the Auxin- and Mycorrhiza-Responsive Expression of a Tomato GH3 Gene.

Auxin is well known to be a key regulator that acts in almost all physiological processes during plant growth, and in interactions between plants and microbes. However, to date, the regulatory mechanisms underlying auxin-mediated plant-arbuscular mycorrhizal (AM) fungi symbiosis have not been well deciphered. Previously we identified a GH3 gene, SlGH3.4, strongly responsive to both auxin induction and mycorrhizal symbiosis. Here, we reported a refined dissection of the SlGH3.4 promoter activity using the ß-glucuronidase (GUS) reporter. The SlGH3.4 promoter could drive GUS expression strongly in mycorrhizal roots of soybean and rice plants, and in IAA-treated soybean roots, but not in IAA-treated rice roots. A promoter deletion assay revealed three cis-acting motifs, i.e. the auxin-responsive element, AuxRE, and two newly identified motifs named MYCRS1 and MYCRS2, involved in the activation of auxin- and AM-mediated expression of SlGH3.4. Deletion of the AuxRE from the SlGH3.4 promoter caused almost complete abolition of GUS staining in response to external IAA induction. Seven repeats of AuxRE fused to the Cauliflower mosaic virus (CaMV) 35S minimal promoter could direct GUS expression in both IAA-treated and AM fungal-colonized roots of tobacco plants. Four repeats of MYCRS1 or MYCRS2 fused to the CaMV35S minimal promoter was sufficient to drive GUS expression in arbuscule-containing cells, but not in IAA-treated tobacco roots. In summary, our results offer new insights into the molecular mechanisms underlying the potential cross-talk between the auxin and the AM regulatory pathways in modulating the expression of AM-responsive GH3 genes in diverse mycorrhizal plants.

Salvianolic acid B protects against lipopolysaccharide-induced behavioral deficits and neuroinflammatory response: involvement of autophagy and NLRP3 inflammasome.

BACKGROUND: The NLRP3 inflammasome activation and neuroinflammation are known to be involved in the pathology of depression, whereas autophagy has multiple effects on immunity, which is partly mediated by the regulation of inflammasome and clearance of proinflammatory cytokines. Given the emerging evidence that autophagy dysfunction plays an essential role in depression, it is very likely that autophagy may interact with the inflammatory process in the development and treatment of depression. Salvianolic acid B (SalB), a naturally occurring compound extracted from Salvia miltiorrhiza, contains anti-inflammatory and antidepression properties and has recently been proven to modulate autophagy. In this study, we sought to investigate whether autophagy is involved in the inflammation-induced depression and the antidepressant effects of SalB. METHODS: The effects of prolonged lipopolysaccharide (LPS) treatment and SalB administration on behavioral changes, neuroinflammation, autophagic markers and NLRP3 activation in rat hippocampus were determined by using behavioral tests, real-time PCR analysis, western blot, and immunostaining. RESULTS: Our data showed that periphery immune challenge by LPS for 2 weeks successfully induced the rats to a depression-like state, accompanied with enhanced expression of pro-inflammatory cytokines and NLRP3 inflammasome activation. Interestingly, autophagic markers, including Beclin-1, and the ratio of LC3II to LC3I were suppressed following prolonged LPS exposure. Meanwhile, co-treatment with SalB showed robust antidepressant effects and ameliorated the LPS-induced neuroinflammation. Additionally, SalB restored the compromised autophagy and overactivated NLRP3 inflammasome in LPS-treated rats. CONCLUSIONS: Collectively, these data suggest that autophagy may interact with NLRP3 activation to contribute to the development of depression, whereas SalB can promote autophagy and induce the clearance of NLRP3, thereby resulting in neuroprotective and antidepressant actions.

Arabidopsis E3 ubiquitin ligase PLANT U-BOX13 (PUB13) regulates chitin receptor LYSIN MOTIF RECEPTOR KINASE5 (LYK5) protein abundance.

Long-chain chitooligosaccharides are fungal microbe-associated molecular patterns (MAMPs) that are recognized by LYSIN MOTIF RECEPTOR KINASE5 (LYK5), inducing the formation of a complex with CHITIN ELICITOR RECEPTOR KINASE1 (CERK1). Formation of this complex leads to activation of the CERK1 intracellular kinase domain and induction of plant innate immunity in Arabidopsis. We found that addition of chitooctaose induced LYK5 protein accumulation as a result of de novo gene expression and the inhibition of LYK5 protein degradation. Screening the putative E3 ligases for interaction with LYK5 identified PLANT U-BOX13 (PUB13), which complexed with LYK5, but this complex dissociated upon addition of chitooctaose. Consistent with these results, LYK5 protein abundance was higher in pub13 mutants compared with the wild type without chitooctaose treatment, while similar abundance was detected with the addition of chitooctaose. The pub13 mutants showed hypersensitivity to chitooctaose-induced rapid responses, such as the production of reactive oxygen species (ROS) and mitogen-activated protein (MAP) kinase phosphorylation, but exhibited normal responses to subsequent long-term chitooctaose treatment, such as gene expression and callose deposition. In addition, PUB13 could ubiquitinate the LYK5 kinase domain in vitro. Taken together, our results suggest an important regulatory function for the turnover of LYK5 mediated by the E3 ligase PUB13.

Polycystic ovary syndrome is associated with anogenital distance, a marker of prenatal androgen exposure.

Study question: Is the presence of polycystic ovary syndrome (PCOS) associated with anogenital distance (AGD), a biomarker for the prenatal hormonal environment? Summary answer: The presence of PCOS is associated with longer AGD. What is known already: Although the aetiology of PCOS is unclear, emerging data suggest that the natural history of PCOS may originate from intrauterine life. Prenatal exposure to androgen hormones is considered an important factor of PCOS. AGD is the distance measured from the anus to the genital tubercle and there is considerable evidence in humans and animals to support AGD as a sensitive biomarker of prenatal androgen activity. Study design, size, duration: This case-control study of 156 PCOS patients and 180 reproductively healthy women (control subjects) was performed from October 2015 to July 2016. Participants/materials, setting, methods: The patients and controls were recruited from the out-patient Department of Gynecology of Sun Yat-sen Memorial Hospital. Participants completed health questionnaires and provided a blood sample for evaluation of serum reproductive hormone profiles. Anthropometric indices of AGDAF (anus-fourchette) and AGDAC (anus-clitoris) were measured in all subjects. We used logistic regression to estimate the association between the presence of PCOS and AGD measurements while accounting for important confounders, including age and BMI. Multiple linear regression was used to analyse the relationships between PCOS characteristics (e.g. polycystic ovaries and total testosterone (T)) and two measurements of AGD in the PCOS group and controls. Main results and the role of chance: Overall, logistic regression showed that women with AGDAF in the highest tertile were 18.8 times (95% CI 9.6-36.6; P < 0.001) more likely to have PCOS compared with those in the lowest tertile. Women with AGDAC in the highest tertile were 6.7 times (95% CI 3.7-12.1; P < 0.001) more likely to have PCOS than those in the lowest tertile. In the PCOS group, multiple linear regression analyses revealed that both AGD measurements were positively associated with T levels (ß = 0.246 for AGDAC, ß = 0.368 for AGDAF; P = 0.003 and P < 0.001, respectively), and AGDAF was positively associated with the presence of polycystic ovaries (ß = 0.279; P < 0.001). In the controls, a positive association was found only between T levels with AGDAF (ß = 0.177, P = 0.020), whereas no associations were found between the remaining covariates and AGD measurements. Limitations, reasons for caution: As this was an observational study, causal inference cannot be obtained. Wider implications of the findings: This study suggests that PCOS may originate in intrauterine life, and be affected by prenatal exposure to androgens. Study funding/competing interest(s): This study was supported by funds obtained from the Science Technology Research Project of Guangdong Province (2010B031600058 and 2015A030310083) and the Major Science Technology Research Project of Guangdong Province (ZKM05602S). The authors have no competing interests to declare. Trial registration number: Not applicable.

The characterization of six auxin-induced tomato GH3 genes uncovers a member, SlGH3.4, strongly responsive to arbuscular mycorrhizal symbiosis.

In plants, the GH3 gene family is widely considered to be involved in a broad range of plant physiological processes, through modulation of hormonal homeostasis. Multiple GH3 genes have been functionally characterized in several plant species; however, to date, limited works to study the GH3 genes in tomato have been reported. Here, we characterize the expression and regulatory profiles of six tomato GH3 genes, SlGH3.2, SlGH3.3, SlGH3.4, SlGH3.7, SlGH3.9 and SlGH3.15, in response to different phytohormone applications and arbuscular mycorrhizal (AM) fungal colonization. All six GH3 genes showed inducible responses to external IAA, and three members were significantly up-regulated in response to AM symbiosis. In particular, SlGH3.4, the transcripts of which were barely detectable under normal growth conditions, was strongly activated in the IAA-treated and AM fungal-colonized roots. A comparison of the SlGH3.4 expression in wild-type plants and M161, a mutant with a defect in AM symbiosis, confirmed that SlGH3.4 expression is highly correlated to mycorrhizal colonization. Histochemical staining demonstrated that a 2,258 bp SlGH3.4 promoter fragment could drive ß-glucuronidase (GUS) expression strongly in root tips, steles and cortical cells of IAA-treated roots, but predominantly in the fungal-colonized cells of mycorrhizal roots. A truncated 654 bp promoter failed to direct GUS expression in IAA-treated roots, but maintained the symbiosis-induced activity in mycorrhizal roots. In summary, our results suggest that a mycorrhizal signaling pathway that is at least partially independent of the auxin signaling pathway has evolved for the co-regulation of the auxin- and mycorrhiza-activated GH3 genes in plants.

Genome-wide investigation and expression analysis suggest diverse roles and genetic redundancy of Pht1 family genes in response to Pi deficiency in tomato.

BACKGROUND: Phosphorus (P) deficiency is one of the major nutrient stresses limiting plant growth. The uptake of P by plants is well considered to be mediated by a number of high-affinity phosphate (Pi) transporters belonging to the Pht1 family. Although the Pht1 genes have been extensively identified in several plant species, there is a lack of systematic analysis of the Pht1 gene family in any solanaceous species thus far. RESULTS: Here, we report the genome-wide analysis, phylogenetic evolution and expression patterns of the Pht1 genes in tomato (Solanum lycopersicum). A total of eight putative Pht1 genes (LePT1 to 8), distributed on three chromosomes (3, 6 and 9), were identified through extensive searches of the released tomato genome sequence database. Chromosomal organization and phylogenetic tree analysis suggested that the six Pht1 paralogues, LePT1/3, LePT2/6 and LePT4/5, which were assigned into three pairs with very close physical distance, were produced from recent tandem duplication events that occurred after Solanaceae splitting with other dicot families. Expression analysis of these Pht1 members revealed that except LePT8, of which the transcript was undetectable in all tissues, the other seven paralogues showed differential but partial-overlapping expression patterns. LePT1 and LePT7 were ubiquitously expressed in all tissues examined, and their transcripts were induced abundantly in response to Pi starvation; LePT2 and LePT6, the two paralogues harboring identical coding sequence, were predominantly expressed in Pi-deficient roots; LePT3, LePT4 and LePT5 were strongly activated in the roots colonized by arbuscular mycorrhizal fungi under low-P, but not high-P condition. Histochemical analysis revealed that a 1250-bp LePT3 promoter fragment and a 471-bp LePT5 promoter fragment containing the two elements, MYCS and P1BS, were sufficient to direct the GUS reporter expression in mycorrhizal roots and were limited to distinct cells harboring AM fungal structures. Additionally, the four paralogues, LePT1, LePT2, LePT6 and LePT7, were very significantly down-regulated in the mycorrhizal roots under low Pi supply condition. CONCLUSIONS: The results obtained from this study provide new insights into the evolutionary expansion, functional divergence and genetic redundancy of the Pht1 genes in response to Pi deficiency and mycorrhizal symbiosis in tomato.

Achilles' Heel of currently approved immune checkpoint inhibitors: immune related adverse events.

Immunotherapy has revolutionized the cancer treatment landscape by opening up novel avenues for intervention. As the use of immune checkpoint inhibitors (ICIs) has exponentially increased, so have immune-related adverse events (irAEs). The mechanism of irAEs may involve the direct damage caused by monoclonal antibodies and a sequence of immune responses triggered by T cell activation. Common side effects include dermatologic toxicity, endocrine toxicity, gastrointestinal toxicity, and hepatic toxicity. While relatively rare, neurotoxicity, cardiotoxicity, and pulmonary toxicity can be fatal. These toxicities pose a clinical dilemma regarding treatment discontinuation since they can result in severe complications and necessitate frequent hospitalization. Vigilant monitoring of irAEs is vital in clinical practice, and the principal therapeutic strategy entails the administration of oral or intravenous glucocorticoids (GSCs). It may be necessary to temporarily or permanently discontinue the use of ICIs in severe cases. Given that irAEs can impact multiple organs and require diverse treatment approaches, the involvement of a multidisciplinary team of experts is imperative. This review aims to comprehensively examine the pathogenesis, clinical manifestations, incidence, and treatment options for various irAEs.

Integrating transcriptomics and metabolomics to elucidate the mechanism by which taurine protects against DOX-induced depression.

Doxorubicin (DOX) is an effective anticancer drug with potent antitumour activity. However, the application of DOX is limited by its adverse reactions, such as depression. Taurine can alleviate depression induced by multiple factors. However, it is still unclear whether and how taurine improves DOX-induced depression. To address this question, the aim of this study was to explore the potential mechanism by which taurine protects against DOX-induced depression. Mice were randomly divided into three groups (n = 8): (1) the control group, (2) the DOX group, and (3) the DOX + taurine group. The open field test (OFT), elevated plus maze test, and forced swim test (FST) were first performed to assess the effects of DOX and taurine on the behaviour of mice. Next, a combined transcriptomic and metabolomic analysis was performed to analyse the possible antidepressive effect of taurine. Taurine pretreatment increased the total distance travelled and speed of mice in the OFT, increased the number of entries into the open arm and the time spent in the open arm, and reduced the immobility time in the FST. In addition, 179 differential genes and 51 differentially abundant metabolites were detected in the DOX + taurine group compared to the DOX group. Furthermore, differential genes and differentially abundant metabolites were found to be jointly involved in 21 pathways, which may be closely related to the antidepressant effect of taurine. Taurine alleviated DOX-induced depressive behaviour. The various pathways identified in this study, such as the serotonergic synapse and the inflammatory mediator regulation of TRP channels, may be key regulatory pathways related to depression and antidepressant effects.

Safe Induction of Acute Inflammation with Enhanced Antitumor Immunity by Hydrogel-Mediated Outer Membrane Vesicle Delivery.

Acute inflammation has the potential for the recruitment of immune cells, inhibiting tumor angiogenesis, metastasis, and drug resistance thereby overcoming the tumor immunosuppressive microenvironment caused by chronic inflammation. Here, an acute inflammation inducer using bacteria outer membrane vesicles (OMVs) loaded in thermal-sensitive hydrogel (named OMVs-gel) for localized and controlled release of OMVs in tumor sites is proposed. OMVs trigger neutrophil recruitment and amplify acute inflammation inside tumor tissues. The hydrogel ensures drastic inflammation is confined within the tumor, addressing biosafety concerns that the direct administration of free OMVs may cause fatal effects. This strategy eradicated solid tumors safely and rapidly. The study further elucidates one of the possible immune mechanisms of OMVs-gel therapy, which involves the assembly of antitumor neutrophils and elastase release for selective tumor killing. Additionally, tumor vascular destruction induced by OMVs-gel results in tumor darkening, allowing for combinational photothermal therapy. The findings suggest that the use of OMVs-gel can safely induce acute inflammation and enhance antitumor immunity, representing a promising strategy to promote acute inflammation application in tumor immunotherapy.

Anticoagulant-related nephropathy induced by direct-acting oral anticoagulants: Clinical characteristics, treatments and outcomes.

INTRODUCTION: There is a scarcity of data on anticoagulation-related nephropathy (ARN) caused by direct-acting oral anticoagulants (DOACs) in recent years. MATERIALS AND METHODS: We collected literatures on DOACs-induced ARN to October 1, 2022, without language restrictions for retrospective analysis. RESULTS: Twenty events were included with a median onset time of 28 days among which fourteen were caused by dabigatran. Patients accompanied by chronic kidney disease (85 %) seemed more easily to have an ARN. Clinical symptoms associated with ARN were mostly presented as hematuria and acute decline of renal function (100 %), then abnormal coagulation function (75 %) but only one with an INR over 3. Renal biopsies were performed in 14 patients, with thirteen showing occlusive intratubular red blood cell casts and ten showing acute tubular injury of varying intensity or even tubular necrosis. Extensive changes in interstitial compartment like hemorrhage, fibrosis or inflammation were also presented in eight biopsies. IgA nephropathy as a latent or undiagnosed disease was demonstrated in eight biopsies. Treatments of ARN were mainly supportive with all patients discontinuing DOACs and 35 % initiating dialysis for acute deterioration of renal function. Steroids were used in 9 patients with a severe ARN verified by biopsy. 60 % of patients did not recover baseline renal function and some even deteriorated. CONCLUSIONS: In conclusion, DOACs-induced ARN is a rare but serious adverse reaction. A prompt diagnosis of ARN and supportive treatments are necessary for patients receiving DOACs concurrent with an acute renal injury.

The safety profile of EGFR/ALK-TKIs administered immediately before or after ICIs in advanced NSCLC.

BACKGROUND: As more therapeutic targets are being discovered in advanced non-small cell lung cancer (NSCLC), it is pivotal for clinicians to correctly sequence immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for delivery of safe and effective treatment. Our present study aimed to assess the safety profile of sequential treatment of TKIs and ICIs in advanced NSCLC. METHODS: We retrospectively analyzed the data of 64 patients who underwent sequential treatment of EGFR/ALK-TKIs and ICIs, including all the EGFR/ALK-TKIs and ICIs approved by National Medical Products Administration (NMPA) in China. RESULTS: The decrease in hemoglobin was the most common adverse event (54.5 % and 44.4 %) for all patients. For TKIs post-treatment with ICIs group, the incidence rate of decrease in white blood cells was 32.7 %. Liver toxicity was also common for this sequential therapy: treatment-related elevation in ALT (30.9 %) and AST (25.5 %). In addition, grade 3 or higher skin toxicity occurred in 2 patients, and grade 3 or higher neuritis was observed in 1 patient. Interstitial pneumonia was also observed in 1 patient. For patients within the group of TKIs pre-treatment with ICIs, the most common adverse event was hepatic toxicity, the elevation in ALT and AST was 33.3 % and 22.2 % respectively. It was worth noting that the incidence rate of grade 3 or higher elevation in ALT and AST was 22.2 %. Other adverse events such as blood toxicity, skin rash, and diarrhea were also observed in this sequential treatment, but most of which was slight. CONCLUSION: Although the adverse event did not significantly increase in the sequential treatment pattern of our study, careful consideration should be given to the possibility of an increased risk of some adverse event when TKIs were pre/post-treated with ICIs.

Recent advances in immune checkpoint inhibitor-induced type 1 diabetes mellitus.

As a new group of anticancer drugs, immune checkpoint inhibitors (ICIs) have exhibited favorable antitumor efficacy in numerous malignant tumors. Anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4), anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) are three kinds of ICIs widely used in clinical practice. However, ICI therapy (monotherapy or combination therapy) is always accompanied by a unique toxicity profile known as immune-related adverse events (irAEs) affecting multiple organs. The endocrine glands are common targets of irAEs induced by ICIs, which cause type 1 diabetes mellitus (T1DM) when the pancreas is affected. Although the incidence rate of ICI-induced T1DM is rare, it will always lead to an irreversible impairment of ß-cells and be potentially life-threatening. Hence, it is vital for endocrinologists and oncologists to obtain a comprehensive understanding of ICI-induced T1DM and its management. In our present manuscript, we have reviewed the epidemiology, pathology and mechanism, diagnosis, management, and treatments of ICI-induced T1DM.

Recent Advances in the Management of Adverse Events Associated with Lorlatinib.

As a novel third-generation ALK tyrosine kinase inhibitor (TKI), lorlatinib has shown excellent systemic and intracranial activity in non-small cell lung cancer (NSCLC) patients who carry sensitizing ALK-activating mutations and progress on first- and second-generation TKIs. In comparison with other ALK-TKIs, lorlatinib has a unique safety profile for hyperlipidemia and central nervous system adverse events. Lorlatinib-induced adverse events are well tolerated, permanent discontinuations are rarely reported, and dose modifications and/or standard medical therapy are useful for the management of adverse events. Our present study reviews the safety profile of lorlatinib as well as the relevant management strategies. Our present study aims to provide a practical guide for the scientific management and application of lorlatinib.

Curcumin protects against doxorubicin induced oxidative stress by regulating the Keap1-Nrf2-ARE and autophagy signaling pathways.

BACKGROUND: Doxorubicin (DOX)-induced neurotoxicity is widely reported in previous studies. Oxidative stress has been validated as a critical event involved in DOX-induced neurotoxicity. As a selective autophagy adaptor protein, p62 is reported to regulate Keap1-Nrf2-ARE antioxidant pathway in response to oxidative stress. Curcumin (CUR) relieves depressive-like state through the mitigation of oxidative stress and the activation of Nrf2-ARE signaling pathway. However, the exact mechanism of CUR in alleviating DOX-induced neurotoxicity is still unknown. MATERIALS AND METHODS: The rats were randomly divided into three groups: control group, DOX group, and DOX + CUR group. At the end of 3 weeks, the behavior tests as sucrose preference test (SPT), forced swimming test (FST), and novelty-suppressed feeding test (NSFT) were performed to assess anxiety- and depression-like behaviors. The rats were sacrificed after behavior tests, and the brain tissues were collected for biochemical analysis. RESULTS: It was observed that the administration of CUR could effectively reverse DOX-induced depressive-like behaviors. The exposure of DOX activated autophagy and increased oxidative stress levels, and the administration of CUR could significantly inhibit DOX-induced autophagy and suppress oxidative stress. More importantly, we also found that Keap1-Nrf2-ARE signaling pathway was involved in DOX-induced neurotoxicity and oxidative stress regulated by autophagy. CONCLUSION: Our study demonstrated that CUR could effectively reverse DOX-induced neurotoxicity through suppressing autophagy and mitigating oxidative stress and endoplasmic reticulum (ER) stress.