Cooperative Sentinel Surveillance of Malaria in Laiza and Nearby Areas of Myanmar and Importation Threat Monitoring - China, 2019-2023.

Introduction: Laiza and nearby areas (LNA) in Myanmar are identified as the primary malaria hotspots in the bordering regions of Yunnan Province, China. Methods: Six sentinel surveillance sites were established at the China-Myanmar border in LNA to monitor malaria. Data from 2019 was used as a baseline to analyze malaria incidence and trends in LNA and Myanmar, as well as the importation of malaria cases into China from 2019 to 2023. Results: Plasmodium vivax was the predominant species, representing 99.95% (14,060/14,066) of confirmed malaria cases in LNA. A total of 8,356 malaria cases were identified in 2023, with an annual parasite incidence (API) of 19.78 per 100 person-years. Compared to 2019, the incidence rate ratio was 21.47 (95% confidence interval: 18.84, 24.48), indicating that the API in 2023 was 21.47 times higher than that in 2019. In Yunnan, out of 1,016 reported cases, 545 imported cases (53.64%) originated from LNA and spread to 18 (13.95%) out of 129 counties. Ten provinces in China, including Yunnan, reported imported malaria cases from LNA in Myanmar. Conclusions: The increase in population, particularly among internally displaced persons, along with inadequate healthcare services, has led to a notable resurgence of malaria in LNA. This resurgence poses a risk to preventing the re-emergence of malaria transmission in China. There is an urgent need for novel collaborative policies, as well as financial and technical assistance, to enhance malaria control efforts in LNA, Myanmar.

Development of a precision tumor bone metastasis model by a magnetic micro-living-motor system.

An ideal bone metastasis animal model is critical and fundamental for mechanistic research and following development of new drug and treatment. Caudal artery (CA) injection allows bone metastasis in the hindlimb, while in-depth targeted and quantitative studies of bone metastasis require a new model to overcome its limitations. Here, we developed a targeted, quantitative, and highly consistent method for the modeling of bone metastasis with cell-based magnetic micro-living-motor (MLM) system created by effectively combining Fe3O4-PDA-Au with biosafety. The MLM system can achieve efficient migration, target site colonization and control tumorigenesis in bone precisely with the application of a magnetic field. In vivo, day 3 post cell injection, tumor bone metastasis signals were observed locally in the injected femur among 82.76% mice of the MLM group as compared to the 56.82% in the CA group, and the signal intensity was 45.1 and 95.9 times stronger than that in the left and right lower limbs of the CA group, respectively. Post-injection day 28, metastasis in vital organs was reduced by approximately 90% in the MLM group compared to the CA group. Our innovative use of the MLM system in the field of tumor modeling opens a new avenue for exploring the mechanisms of tumor bone metastasis, recurrence and drug resistance.

MAGL protects against renal fibrosis through inhibiting tubular cell lipotoxicity.

Rationale: Renal fibrosis, with no therapeutic approaches, is a common pathological feature in various chronic kidney diseases (CKD). Tubular cell injury plays a pivotal role in renal fibrosis. Commonly, injured tubular cells exhibit significant lipid accumulation. However, the underlying mechanisms remain poorly understood. Methods: 2-arachidonoylglycerol (2-AG) levels in CKD patients and CKD model specimens were measured using mass spectrometry. 2-AG-loaded nanoparticles were infused into unilateral ureteral obstruction (UUO) mice. Lipid accumulation and renal fibrosis were tested. Furthermore, monoacylglycerol lipase (MAGL), the hydrolyzing enzyme of 2-AG, was assessed in CKD patients and models. Tubular cell-specific MAGL knock-in mice were generated. Moreover, MAGL recombination protein was also administered to unilateral ischemia reperfusion injury (UIRI) mice. Besides, a series of methods including RNA sequencing, metabolomics, primary cell culture, lipid staining, etc. were used. Results: 2-AG was increased in the serum or kidneys from CKD patients and models. Supplement of 2-AG further induced lipid accumulation and fibrogenesis through cannabinoid receptor type 2 (CB2)/ß-catenin signaling. ß-catenin knockout blocked 2-AG/CB2-induced fatty acid ß-oxidation (FAO) deficiency and lipid accumulation. Remarkably, MAGL significantly decreased in CKD, aligning with lipid accumulation and fibrosis. Specific transgene of MAGL in tubular cells significantly preserved FAO, inhibited lipid-mediated toxicity in tubular cells, and finally retarded fibrogenesis. Additionally, supplementation of MAGL in UIRI mice also preserved FAO function, inhibited lipid accumulation, and protected against renal fibrosis. Conclusion: MAGL is a potential diagnostic marker for kidney function decline, and also serves as a new therapeutic target for renal fibrosis through ameliorating lipotoxicity.

Emergence of ST1193 Clone in Maternal and Neonatal ESBL-Producing E. coli Isolates.

Objective: The emerging epidemic of extended-spectrum ß-lactamase-producing E. coli (ESBL-EC) is a global public health crisis. ESBL-EC infections are increasing worldwide and contribute to morbidity and mortality among newborn infants. However, the antimicrobial resistance characteristics and clonal transmission of maternal and neonatal ESBL-EC isolates need to be further deciphered. Materials and Methods: We performed phenotypic and genotypic characterization of 33 ESBL-EC isolates from pregnant women and newborn during 2019-2020. Results: Minimum inhibitory concentrations of 17 antimicrobial agents showed that all isolates were multidrug-resistant (MDR) and had a resistance rate of 100% to ampicillin, and mild resistance to florfenicol, gentamicin, ceftazidime, and amoxicillin-clavulanate. Additionally, imipenem, meropenem, polymyxin, and tigecycline exhibited good activity against the tested ESBL-EC isolates with low MIC50 (0.06-1 µg/mL) and MIC90 (0.06-1 µg/mL). Whole genome sequencing indicated that ESBL-EC isolates contained diverse antimicrobial resistant genes (blaCTX-M, blaTEM, blaSHV, tetA, etc.) and toxin genes (ompA, csg, fimH, hybtA, etc.). blaCTX-M genes were the main ESBL genotype. ST1193 (18.2%) was the second most abundant ST among the ESBL-EC isolates (ST131 was the most common, with 30.3%), and this is the first report of its mother-to-infant colonization transmission in China. Conclusion: These findings revealed the occurrence of high-risk ST1193 clone among ESBL-EC isolates from pregnant women and newborn colonization in China. Further national or regional multicenter studies are needed to assess the dissemination and evolution of ESBL-EC ST1193 clone as a nosocomial pathogen in China.

The E3 ligase Trim63 promotes podocyte injury and proteinuria by targeting PPARα to inhibit fatty acid oxidation.

Podocyte injury is a hallmark of glomerular disease and one of the leading causes of chronic kidney disease (CKD). Peroxisome proliferator-activated receptor α (PPARα) plays a key role in podocyte fatty acid oxidation (FAO). However, the underlying regulatory mechanisms remain unresolved. Trim63 is an E3 ubiquitin ligase that has been shown to inhibit PPARα activity; however, its role in fatty acid metabolism in the kidney has not been elucidated to date. In this study, we investigated the effects of overexpression and knockdown of Trim63 in Adriamycin (ADR)-induced nephropathy and diabetic nephropathy models and a podocyte cell line. In both rodents and human patients with proteinuric CKD, Trim63 was upregulated, particularly in the podocytes of injured glomeruli. In the ADR-induced nephropathy model, ectopic Trim63 application aggravated FAO deficiency and mitochondrial dysfunction and triggered intense lipid deposition, podocyte injury, and proteinuria. Notably, Trim63 inhibition alleviated FAO deficiency and mitochondrial dysfunction, and markedly restored podocyte injury and renal fibrosis in ADR-induced and diabetic nephropathy (DN) models. Additionally, Trim63 was observed to mediate PPARα ubiquitination and degradation, leading to podocyte injury. We demonstrate the pathological role of Trim63, which was previously unrecognized in kidney tissue, in FAO deficiency and podocyte injury. Targeting Trim63 may represent a viable therapeutic strategy for podocyte injury and proteinuria.

Implementing a novel capture and ligation probe-PCR method in mass screen and treatment to support malaria elimination efforts in the China-Myanmar border region.

BACKGROUND: Mass screening and treatment (MSAT) for malaria elimination lacks an ideal diagnostic tool to allow sensitive and affordable test of the target population in the field. This study evaluated whether Capture and Ligation Probe-PCR (CLIP-PCR) could be used in a field MSAT in Laiza City, Myanmar. METHODS: On day 0, two dried blood spots were collected from each participant. On day 1, all samples were screened for Plasmodium in a 20 m2 laboratory with workbench, a biosafety cabinet, a refrigerator, a benchtop shaking incubator and a qPCR machine, by four technicians using CLIP-PCR with sample pooling, at a health clinic of the Chinese bordering town of Nabang. On day 2, all positives were followed up and treated. RESULTS: Of 15,038 persons (65% of the total population) screened, 204 (1.36%) were CLIP-PCR positives. Among them, 188, 14, and 2 were infected with Plasmodium vivax, Plasmodium falciparum, and P. vivax/P. falciparum mix, respectively. The testing capacity was 538 persons/day, with a cost of US$0.92 /person. The proportion of submicroscopic infection was 64.7%. All positive individuals received treatment within 72 h after blood collection. CONCLUSION: Using CLIP-PCR in MSAT in low transmission settings can support the malaria elimination efforts in the China-Myanmar border region.

The AreA Nitrogen Catabolite Repression Activator Balances Fungal Nutrient Utilization and Virulence in the Insect Fungal Pathogen Beauveria bassiana.

In many fungi, the AreA GATA-type transcription factor mediates nitrogen catabolite repression affecting fungal development and, where applicable, virulence. Here, we investigated the functions of AreA in the fungal entomopathogen and plant endophyte Beauveria bassiana using knockdown of gene expression. The antiAreA mutants were impaired in nitrogen utilization and showed increased sensitivities to osmotic stressors but increased tolerances to oxidative/hypoxia stresses. Repression of BbAreA caused overall minimal effects on fungal virulence. The minor effects on virulence appeared to be due in part to competing secondary effects where host defense phenoloxidase activity was significantly decreased, but production of the fungal metabolite oosporein was increased and hyphal body development was impaired. Knockdown of BbAreA expression also resulted in impairment in ability of the fungus to associate with host plants. These data implicate that BbAreA likely acts as a regulator to balance fungal nutrient utilization, pathogenicity, and mutualism, facilitating the fungal occupation of host niches.

KYA1797K, a Novel Small Molecule Destabilizing ß-Catenin, Is Superior to ICG-001 in Protecting against Kidney Aging.

Introduction: Aged kidney is characterized by mitochondrial dysfunction, cellular senescence, and fibrogenesis. The activation of Wnt/ß-catenin signaling plays an important role in the initiation of kidney aging. However, the inhibiting strategies have not been discovered in detail. Here, we compared the therapeutic effects of two ß-catenin inhibitors, KYA1797K and ICG-001, to assess their superiority. Methods: Two-month-old male C57BL/6 mice which had undergone unilateral nephrectomy and received D-galactose (D-gal) injection were co-treated with KYA1797K or ICG-001 at 10 mg/kg/day for 4 weeks. Human proximal renal tubular cells were treated with D-gal and KYA1797K/ICG-001 to compare their effects. Results: Compared with ICG-001, which inhibits ß-catenin pathway through blocking the binding of ß-catenin and cAMP response element-binding protein (CREB)-binding protein (CBP), KYA1797K, a novel small molecule destabilizing ß-catenin through activating Axin-GSK3ß complex, possesses the superior effects on protecting against kidney aging. In D-gal-treated accelerated aging mice, KYA1797K could greatly inhibit ß-catenin pathway, preserve mitochondrial homeostasis, repress cellular senescence, and retard age-related kidney fibrosis. In cultured proximal tubular cells, KYA1797K shows a better effect on inhibiting cellular senescence and could better suppress mitochondrial dysfunction and ameliorate the fibrotic changes, at the same dose as that in ICG-001. Conclusion: These results show that effectively eliminating ß-catenin is a necessity to target against age-related kidney injury, suggesting the multiple transcriptional regulation of ß-catenin in kidney aging besides T-cell factor/lymphoid enhancer-binding factor family of transcription factors (TCF/LEF-1).

Pan-cancer analysis of oncogenic TNFAIP2 identifying its prognostic value and immunological function in acute myeloid leukemia.

BACKGROUND: Tumor necrosis factor alpha-induced protein 2 (TNFAIP2), a TNFα-inducible gene, appears to participate in inflammation, immune response, hematopoiesis, and carcinogenesis. However, the potential role of TNFAIP2 in the development of acute myeloid leukemia (AML) remains unknow yet. Therefore, we aimed to study the biological role of TNFAIP2 in leukemogenesis. METHODS: TNFAIP2 mRNA level, prognostic value, co-expressed genes, differentially expressed genes, DNA methylation, and functional enrichment analysis in AML patients were explored via multiple public databases, including UALCAN, GTEx portal, Timer 2.0, LinkedOmics, SMART, MethSurv, Metascape, GSEA and String databases. Data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Beat AML database were used to determine the associations between TNFAIP2 expression and various clinical or genetic parameters of AML patients. Moreover, the biological functions of TNFAIP2 in AML were investigated through in vitro experiments. RESULTS: By large-scale data mining, our study indicated that TNFAIP2 was differentially expressed across different normal and tumor tissues. TNFAIP2 expression was significantly increased in AML, particularly in French-American-British (FAB) classification M4/M5 patients, compared with corresponding control tissues. Overexpression of TNFAIP2 was an independent poor prognostic factor of overall survival (OS) and was associated with unfavorable cytogenetic risk and gene mutations in AML patients. DNA hypermethylation of TNFAIP2 at gene body linked to upregulation of TNFAIP2 and inferior OS in AML. Functional enrichment analysis indicated immunomodulation function and inflammation response of TNFAIP2 in leukemogenesis. Finally, the suppression of TNFAIP resulted in inhibition of proliferation by altering cell-cycle progression and increase of cell death by promoting early and late apoptosis in THP-1 and U937AML cells. CONCLUSION: Collectively, the oncogenic TNFAIP2 can function as a novel biomarker and prognostic factor in AML patients. The immunoregulation function of TNFAIP2 warrants further validation in AML.

Characterization of blaNDM-5-and blaCTX-M-199-Producing ST167 Escherichia coli Isolated from Shared Bikes.

Shared bikes as a public transport provide convenience for short-distance travel. Whilst they also act as a potential vector for antimicrobial resistant (AR) bacteria and antimicrobial resistance genes (ARGs). However, the understanding of the whole genome sequence of AR strains and ARGs-carrying plasmids collected from shared bikes is still lacking. Here, we used the HiSeq platform to sequence and analyze 24 Escherichia coli isolated from shared bikes around Metro Stations in Beijing. The isolates from shared bikes showed 14 STs and various genotypes. Two blaNDM-5 and blaCTX-M-199-producing ST167 E. coli have 16 resistance genes, four plasmid types and show >95% of similarities in core genomes compared with the ST167 E. coli strains from different origins. The blaNDM-5- or blaCTX-M-199-carrying plasmids sequencing by Nanopore were compared to plasmids with blaNDM-5- or blaCTX-M-199 originated from humans and animals. These two ST167 E. coli show high similarities in core genomes and the plasmid profiles with strains from hospital inpatients and farm animals. Our study indicated that ST167 E. coli is retained in diverse environments and carried with various plasmids. The analysis of strains such as ST167 can provide useful information for preventing or controlling the spread of AR bacteria between animals, humans and environments.

The application of metagenomic next-generation sequencing for detection of pathogens from dialysis effluent in peritoneal dialysis-associated peritonitis .

BACKGROUND: Metagenomic next-generation sequencing (mNGS) can improve pathogen identification in infectious diseases. METHODS: A prospective parallel control study was undertaken to evaluate the clinical significance of mNGS in identifying pathogens in dialysis effluent of patients with peritoneal dialysis-associated peritonitis (peritonitis). Dialysis effluent specimens were detected both by peritoneal dialysis effluent culture and mNGS. The positive rates and coincidence rates of the two methods were compared. RESULTS: From April 2020 to March 2021, 30 patients presenting with peritonitis were enrolled in this study. The positive pathogen detection rate of mNGS was significantly higher than that of the traditional culture method (86.67% vs. 60.00%; p = 0.039). Fifteen specimens were positive for both of the methods, while 11 specimens were negative for culture but positive for mNGS. Three specimens were positive for culture but negative for mNGS; all of them were streptococcus mitis. One specimen was negative for both methods. The culture method detected one type of pathogen in all specimens; however, two or more types of pathogens were detected in eight specimens by mNGS. In addition to common pathogens, additional pathogens detected by mNGS included Coxiella burnetii, human herpesvirus type 5, human herpesvirus type 6B and Mortierella. CONCLUSION: The pathogen detection rate of mNGS in dialysis effluent of peritonitis patients was significantly higher than that of traditional culture. The mNGS is advantageous in diagnosing the pathogens that are difficult to be cultured. However, mNGS did not demonstrate sensitivity to streptococcus mitis. Results from this study show that mNGS, combined with traditional culture, has potential application for detecting pathogens in peritoneal dialysis patients with peritonitis.

Klotho-derived peptide 6 ameliorates diabetic kidney disease by targeting Wnt/ß-catenin signaling.

Diabetic kidney disease (DKD) is one of the most common and devastating complications of diabetic mellitus, and its prevalence is rising worldwide. Klotho, an anti-aging protein, is kidney protective in DKD. However, its large size, prohibitive cost and structural complexity hamper its potential utility in clinics. Here we report that Klotho-derived peptide 6 (KP6) mimics Klotho function and ameliorates DKD. In either an accelerated model of DKD induced by streptozotocin and advanced oxidation protein products in unilateral nephrectomized mice or db/db mice genetically prone to diabetes, chronic infusion of KP6 reversed established proteinuria, attenuated glomerular hypertrophy, mitigated podocyte damage, and ameliorated glomerulosclerosis and interstitial fibrotic lesions, but did not affect serum phosphorus and calcium levels. KP6 inhibited ß-catenin activation in vivo and blocked the expression of its downstream target genes in glomerular podocytes and tubular epithelial cells. In vitro, KP6 prevented podocyte injury and inhibited ß-catenin activation induced by high glucose without affecting Wnt expression. Co-immunoprecipitation revealed that KP6 bound to Wnt ligands and disrupted the engagement of Wnts with low density lipoprotein receptor-related protein 6, thereby interrupting Wnt/ß-catenin signaling. Mutated KP6 with a scrambled amino acid sequence failed to bind Wnts and did not alleviate DKD in db/db mice. Thus, our studies identified KP6 as a novel Klotho-derived peptide that ameliorated DKD by blocking Wnt/ß-catenin. Hence, our findings also suggest a new therapeutic strategy for the treatment of patients with DKD.

Historical review of malaria control and elimination in the border areas of China: A case study of Yunnan Province.

To understand how malaria could be eliminated in the original hyperendmic area for malaria along international borders in Yunnan Province, malaria situation and control were described on the basis of seven phases. At last the experiences and lessons of the program that reduced border malaria from hyperendmicity to malaria-free status were summarized. Malaria control and elimination area were particularly difficult in the Yunnan border. The achievement can be attributed to high political commitment, strategic and technical innovations based on the actual locality, effective collaboration and communication with neighbouring countries to carry out cross border interventions. Other border areas might perform their own pilot interventions based on their local context, including malaria burden, governing system, health service structure contextualized based on their socioeconomic development and ecology, and then a local decision could be made according to their own trial results.

Analysis of the Therapeutic Effect of Multimode Mechanical Thrombectomy in the Treatment of Acute Ischemic Stroke.

OBJECTIVE: We sought to observe the effectiveness and safety of multimode mechanical thrombectomy in the treatment of acute ischemic stroke. METHODS: The data from patients with acute intracranial artery occlusion treated with multimode mechanical thrombectomy between November 2018 and December 2019 were collected, and the clinical features, imaging data, treatment, and clinical follow-up results 90 days after the operation were analyzed. Postoperative recanalization and the 90-day modified Rankin Scale score were used as clinically effective endpoints. The incidence of symptomatic intracranial hemorrhage within 72 hours and postoperative 90-day mortality were used to evaluate safety. RESULTS: A total of 70 patients were enrolled, including 18 cases with bridging treatment, 11 cases with stent implantation, and 10 cases with balloon dilatation. During the 90 days of follow-up after surgery, 35.7% of (25/70) patients had a good prognosis (modified Rankin Scale score of 0-2). The incidence of postoperative symptomatic intracranial hemorrhage was 11.4% (8/70), and postoperative mortality was 34.3% (24/70). The onset-to-puncture time in the good-prognosis group and the poor-prognosis group was 270 (225-345) versus 330 (270-420) minutes, respectively, and the onset-to-recanalization time in the 2 groups was 350 (295-405) versus 410 (340-470) minutes, respectively. Successful recanalization in the good-prognosis group and the poor-prognosis group was 96.0% versus 57.8%, respectively, and the incidence of symptomatic intracranial hemorrhage in the 2 groups was 0% versus 17.8%, respectively. The difference between the 2 groups was statistically significant (P < 0.05). CONCLUSIONS: Multimode mechanical thrombectomy is a safe and effective therapy for the intracranial occlusion of large vessels in patients with acute ischemic stroke.

Malaria from hyperendemicity to elimination along international borders in Yunnan, China during 2003‒2020: a case study.

BACKGROUND: Border malaria is one of the most intractable problems hindering malaria elimination worldwide. Movement of both the human population and anopheline mosquitoes infected with Plasmodium spp. can cause cross-border malaria transmission. The Yunnan border area was still hyperendemic for malaria in the early part of this century. The objective of this case study was to analyze the strategies, interventions and impacts of malaria control and elimination in the Yunnan border area. MAIN TEXT: A total of 10,349 malaria cases and 17.1 per 10,000 person-years of annual parasite incidence (API) were reported in the border area in 2003. Based on natural village-based stratification, integrated interventions, including mass drug administration for radical cures and preventive treatment, clinically presumptive treatment of all febrile patients for malaria and indoor residual spraying or dipping bed nets with insecticides were successfully carried out from 2003 to 2013. The overall API was reduced to 0.6 per 10,000 person-years by 2013, while effective cross-border collaboration interventions dramatically reduced the malaria burden in the neighbouring border areas of Myanmar. From 2014 forward, the comprehensive strategy, including universal coverage of surveillance to detect malaria cases, a rapid response to possible malaria cases and effective border collaboration with neighbouring areas, successfully eliminated malaria and prevented reintroduction of malaria transmission in the Yunnan border area. CONCLUSIONS: In Yunnan malaria burden has successfully reduced by dynamically accurate stratification and comprehensive interventions; and then the region achieved elimination and prevented reintroduction of malaria transmission through intensive surveillance, rapid response and border collaboration. Other border areas should perform their own intervention trials to develop their own effective strategy.

Macrophage Migration Inhibitory Factor (MIF) as a Stress Molecule in Renal Inflammation.

Renal inflammation is an initial pathological process during progressive renal injury regardless of the initial cause. Macrophage migration inhibitory factor (MIF) is a truly proinflammatory stress mediator that is highly expressed in a variety of both inflammatory cells and intrinsic kidney cells. MIF is released from the diseased kidney immediately upon stimulation to trigger renal inflammation by activating macrophages and T cells, and promoting the production of proinflammatory cytokines, chemokines, and stress molecules via signaling pathways involving the CD74/CD44 and chemokine receptors CXCR2, CXCR4, and CXCR7 signaling. In addition, MIF can function as a stress molecule to counter-regulate the immunosuppressive effect of glucocorticoid in renal inflammation. Given the critical position of MIF in the upstream inflammatory cascade, this review focuses on the regulatory role and molecular mechanisms of MIF in kidney diseases. The therapeutic potential of targeting MIF signaling to treat kidney diseases is also discussed.

AMPK Activator O304 Protects Against Kidney Aging Through Promoting Energy Metabolism and Autophagy.

Aging is an important risk factor for kidney injury. Energy homeostasis plays a key role in retarding aging, and mitochondria are responsible for energy production. In the kidney, renal tubular cells possess high abundance of mitochondria to meet the high energy consumption. AMPK is an evolutionarily conserved serine/threonine kinase which plays a central role in maintaining energy homeostasis and mitochondrial homeostasis. Besides that, AMPK also commands autophagy, a clearing and recycling process to maintain cellular homeostasis. However, the effect of AMPK activators on kidney aging has not been fully elucidated. To this end, we testified the effects of O304, a novel direct AMPK activator, in naturally aging mice model and D-Galactose (D-Gal)-treated renal tubular cell culture. We identified that O304 beneficially protects against cellular senescence and aged-related fibrosis in kidneys. Also, O304 restored energy metabolism, promoted autophagy and preserved mitochondrial homeostasis. Transcriptomic sequencing also proved that O304 induced fatty acid metabolism, mitochondrial biogenesis and ATP process, and downregulated cell aging, DNA damage response and collagen organization. All these results suggest that O304 has a strong potential to retard aged kidney injury through regulating AMPK-induced multiple pathways. Our results provide an important therapeutic approach to delay kidney aging.

Anti-inflammatory effect of Rhein on ulcerative colitis via inhibiting PI3K/Akt/mTOR signaling pathway and regulating gut microbiota.

This study aimed to analyze the therapeutic effect of Rhein on ulcerative colitis (UC) in mice and its possible mechanism. LPS-induced UC cell model and DSS-induced UC mouse model were used to analyze the antiinflammatory effect of Rhein on UC in vitro and in vivo, respectively. Network pharmacology analysis was conducted to identify potential signaling pathways involved in Rhein treating UC, and the results were further confirmed through western blotting assay. 16sRNA sequencing was performed to study the regulatory effect of Rhein on gut microbiota in UC mice. As indicated by the results, Rhein could significantly inhibit the production of pro-inflammatory cytokines (e.g., TNF-α, IL-6 and IL-1ß) in vivo and in vitro, and alleviate DSS-induced UC-associated symptoms in mice (e.g., colon shortening, weight loss, diarrhea and hematochezia). The PI3K/Akt/mTOR signaling pathway was predicted as the potential interacting protein of Rhein in the treatment of UC through network pharmacology analysis. It was found through western blotting assay that the Rhein treatment could significantly inhibit the PI3K/Akt/mTOR signaling pathway by decreasing the phosphorylated protein levels of PI3K, Akt, mTOR and p70S6K1. By 16sRNA gene sequencing analysis, Rhein administration could partially reverse the gut dysbacteriosis of mice induced by DSS and decrease pathogenic bacteria (e.g., Enterobacteriaceae and Turicibacter). It was positively correlated with the production of pro-inflammatory cytokines above, whereas the increase in probiotics (e.g., Unspecified-S24-7 and Rikenellaceae) was negatively correlated with the production of pro-inflammatory cytokines. In conclusion, Rhine had anti-UC efficacy, which was demonstrated by mitigating the UC symptoms and reducing intestinal inflammation by inhibiting the PI3K/Akt/mTOR signaling pathway and modulating gut microbiota.

pH/ROS dual-sensitive and chondroitin sulfate wrapped poly (ß-amino ester)-SA-PAPE copolymer nanoparticles for macrophage-targeted oral therapy for ulcerative colitis.

An oral nanoparticle (NPs) encapsulated in chitosan/alginate hydrogel (CA-Gel) with dual-sensitive in pH and reactive oxygen species (ROS) was developed to load curcumin (CUR) based on the intracellular-specific characteristics of macrophages. Chondroitin sulfate (CS) wrapped PBAE-SA-PAPE with intracellular pH/ROS dual-sensitive characteristics and CUR via a simple nanoprecipitation method to form NPs (CS-CUR-NPs), and mixed CA-Gel to acquire the final preparation (CS-CUR-NPs-Gel). CS-CUR-NPs displayed an ideal average particle size (179.19±5.61nm) and high encapsulating efficiency (94.74±1.15%). CS showed a good targeting ability on macrophages and the CA-Gel contribution in protecting NPs from being destroyed in the upper gastrointestinal tract. As expected, CS-CUR-NPs-Gel could significantly alleviate inflammation in DSS-induced UC mice via TLR4-MAPK/NF-κB pathway. This study is the first to attempt to design a novel pH/ROS dual-stimulated release strategy in helping intracellular CUR delivery and anticipated for efficient anti-UC therapy.

Effectiveness of joint 3 + 1 malaria strategy along China-Myanmar cross border areas.

BACKGROUND: Cross-border malaria in Laiza City of Myanmar seriously affected Yingjiang County of China and compromised reaching the goal of malaria elimination by 2020. Since 2017, a pilot project on 3 + 1 strategy of joint cross-border malaria prevention and control was carried out for building a malaria buffer in these border areas. Here, 3 were the three preventive lines in China where different focalized approaches of malaria elimination were applied and + 1 was a defined border area in Myanmar where the integrated measures of malaria control were adopted. METHODS: A 5-year retrospective analysis (2015 to 2019) was conducted that included case detection, parasite prevalence and vector surveillance. Descriptive statistics was used and the incidence or rates were compared. The annual parasite incidence and the parasite prevalence rate in + 1 area of Myanmar, the annual importation rate in Yingjiang County of China and the density of An. minimus were statistically significant indictors to assess the effectiveness of the 3 + 1 strategy. RESULTS: In + 1 area of Myanmar from 2015 to 2019, the averaged annual parasite incidence was (59.11 ± 40.73)/1000 and Plasmodium vivax accounted for 96.27% of the total confirmed cases. After the pilot project, the annual parasite incidence dropped 89% from 104.77/1000 in 2016 to 12.18/1000 in 2019, the microscopic parasite prevalence rate dropped 100% from 0.34% in 2017 to zero in 2019 and the averaged density of An. Minimus per trap-night dropped 93% from 1.92 in June to 0.13 in September. The submicroscopic parasite prevalence rate increased from 1.15% in 2017 to 1.66% in 2019 without significant difference between the two surveys (P = 0.084). In Yingjiang County of China, neither indigenous nor introduced case was reported and 100% cases were imported from Myanmar since 2017. The averaged annual importation rate from 2015 to 2019 was (0.47 ± 0.15)/1000. After the pilot project, the annual importation rate dropped from 0.59/1000 in 2016 to 0.28/1000 in 2019 with an overall reduction of 53% in the whole county. The reduction was 67% (57.63/1000 to 18.01/1000) in the first preventive line, 52% (0.20/1000 to 0.10/1000) in the second preventive line and 36% (0.32/1000 to 0.22/1000) in the third preventive line. The averaged density of An. Minimus per trap-night in the first preventive line dropped 94% from 2.55 in June to 0.14 in September, without significant difference from that of + 1 area of Myanmar (Z value = - 1.18, P value = 0.24). CONCLUSION: The pilot project on 3 + 1 strategy has been significantly effective in the study areas and a buffer zone of border malaria was successfully established between Laiza City of Myanmar and Yingjiang County of China.