Cell metabolism pathways involved in the pathophysiological changes of diabetic peripheral neuropathy

Diabetic peripheral neuropathy is a common complication of diabetes mellitus.Elucidating the pathophysiological metabolic mechanism impels the generation of ideal therapies.However,existing limited treatments for diabetic peripheral neuropathy expose the urgent need for cell metabolism research.Given the lack of comprehensive understanding of energy metabolism changes and related signaling pathways in diabetic peripheral neuropathy,it is essential to explore energy changes and metabolic changes in diabetic peripheral neuropathy to develop suitable treatment methods.This review summarizes the pathophysiological mechanism of diabetic peripheral neuropathy from the perspective of cellular metabolism and the specific interventions for different metabolic pathways to develop effective treatment methods.Various metabolic mechanisms(e.g.,polyol,hexosamine,protein kinase C pathway)are associated with diabetic peripheral neuropathy,and researchers are looking for more effective treatments through these pathways.

Neutrophil peptide 1 accelerates the clearance of degenerative axons during Wallerian degeneration by activating macrophages after peripheral nerve crush injury

Macrophages play an important role in peripheral nerve regeneration,but the specific mechanism of regeneration is still unclear.Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide closely involved in peripheral nerve regeneration.However,the mechanism by which neutrophil peptide 1 enhances nerve regeneration remains unclear.This study was designed to investigate the relationship between neutrophil peptide 1 and macrophages in vivo and in vitro in peripheral nerve crush injury.The functions of RAW 264.7 cells we re elucidated by Cell Counting Kit-8 assay,flow cytometry,migration assays,phagocytosis assays,immunohistochemistry and enzyme-linked immunosorbent assay.Axonal debris phagocytosis was observed using the CUBIC(Clear,Unobstructed Brain/Body Imaging Cocktails and Computational analysis)optical clearing technique during Wallerian degeneration.Macrophage inflammatory factor expression in different polarization states was detected using a protein chip.The results showed that neutrophil peptide 1 promoted the prolife ration,migration and phagocytosis of macrophages,and CD206 expression on the surfa ce of macrophages,indicating M2 polarization.The axonal debris clearance rate during Wallerian degeneration was enhanced after neutrophil peptide 1 intervention.Neutrophil peptide 1 also downregulated inflammatory factors interleukin-1α,-6,-12,and tumor necrosis factor-αin invo and in vitro.Thus,the results suggest that neutrophil peptide 1 activates macrophages and accelerates Wallerian degeneration,which may be one mechanism by which neutrophil peptide 1 enhances peripheral nerve regeneration.

Role of transforming growth factor-βin peripheral nerve regeneration

Injuries caused by trauma and neurodegenerative diseases can damage the peripheral nervous system and cause functional deficits.Unlike in the central nervous system,damaged axons in peripheral nerves can be induced to regenerate in response to intrinsic cues after reprogramming or in a growth-promoting microenvironment created by Schwann cells.However,axon regeneration and repair do not automatically result in the restoration of function,which is the ultimate therapeutic goal but also a major clinical challenge.Transforming growth factor(TGF)is a multifunctional cytokine that regulates various biological processes including tissue repair,embryo development,and cell growth and differentiation.There is accumulating evidence that TGF-βfamily proteins participate in peripheral nerve repair through various factors and signaling pathways by regulating the growth and transformation of Schwann cells;recruiting specific immune cells;controlling the permeability of the blood-nerve barrier,thereby stimulating axon growth;and inhibiting remyelination of regenerated axons.TGF-βhas been applied to the treatment of peripheral nerve injury in animal models.In this context,we review the functions of TGF-βin peripheral nerve regeneration and potential clinical applications.

Artificial intelligence-assisted repair of peripheral nerve injury: a new research hotspot and associated challenges

Artificial intelligence can be indirectly applied to the repair of peripheral nerve injury.Specifically,it can be used to analyze and process data regarding peripheral nerve injury and repair,while study findings on peripheral nerve injury and repair can provide valuable data to enrich artificial intelligence algorithms.To investigate advances in the use of artificial intelligence in the diagnosis,rehabilitation,and scientific examination of peripheral nerve injury,we used CiteSpace and VOSviewer software to analyze the relevant literature included in the Web of Science from 1994–2023.We identified the following research hotspots in peripheral nerve injury and repair:(1)diagnosis,classification,and prognostic assessment of peripheral nerve injury using neuroimaging and artificial intelligence techniques,such as corneal confocal microscopy and coherent anti-Stokes Raman spectroscopy;(2)motion control and rehabilitation following peripheral nerve injury using artificial neural networks and machine learning algorithms,such as wearable devices and assisted wheelchair systems;(3)improving the accuracy and effectiveness of peripheral nerve electrical stimulation therapy using artificial intelligence techniques combined with deep learning,such as implantable peripheral nerve interfaces;(4)the application of artificial intelligence technology to brain-machine interfaces for disabled patients and those with reduced mobility,enabling them to control devices such as networked hand prostheses;(5)artificial intelligence robots that can replace doctors in certain procedures during surgery or rehabilitation,thereby reducing surgical risk and complications,and facilitating postoperative recovery.Although artificial intelligence has shown many benefits and potential applications in peripheral nerve injury and repair,there are some limitations to this technology,such as the consequences of missing or imbalanced data,low data accuracy and reproducibility,and ethical issues(e.g.,privacy,data security,research transparency).Future research should address the issue of data collection,as large-scale,high-quality clinical datasets are required to establish effective artificial intelligence models.Multimodal data processing is also necessary,along with interdisciplinary collaboration,medical-industrial integration,and multicenter,large-sample clinical studies.

Chemokine platelet factor 4 accelerates peripheral nerve regeneration by regulating Schwann cell activation and axon elongation

Schwann cells in peripheral nerves react to traumatic nerve injury by attempting to grow and regenerate.Howeve r,it is unclear what factors play a role in this process.In this study,we searched a GEO database and found that expression of platelet factor 4 was markedly up-regulated after sciatic nerve injury.Platelet factor is an important molecule in cell apoptosis,diffe rentiation,survival,and proliferation.Further,polymerase chain reaction and immunohistochemical staining confirmed the change in platelet factor 4 in the sciatic nerve at different time points after injury.Enzyme-linked immunosorbent assay confirmed that platelet factor 4 was secreted by Schwann cells.We also found that silencing platelet factor 4 decreased the proliferation and migration of primary cultured Schwann cells,while exogenously applied platelet factor 4 stimulated Schwann cell prolife ration and migration and neuronal axon growth.Furthermore,knocking out platelet factor 4 inhibited the prolife ration of Schwann cells in injured rat sciatic nerve.These findings suggest that Schwann cell-secreted platelet factor 4 may facilitate peripheral nerve repair and regeneration by regulating Schwann cell activation and axon growth.Thus,platelet factor 4 may be a potential therapeutic target for traumatic peripheral nerve injury.

Runx2 regulates peripheral nerve regeneration to promote Schwann cell migration and re-myelination

Runx2 is a major regulator of osteoblast differentiation and function;however,the role of Runx2 in peripheral nerve repair is unclea r.Here,we analyzed Runx2expression following injury and found that it was specifically up-regulated in Schwann cells.Furthermore,using Schwann cell-specific Runx2 knocko ut mice,we studied peripheral nerve development and regeneration and found that multiple steps in the regeneration process following sciatic nerve injury were Runx2-dependent.Changes observed in Runx2 knoc kout mice include increased prolife ration of Schwann cells,impaired Schwann cell migration and axonal regrowth,reduced re-myelination of axo ns,and a block in macrophage clearance in the late stage of regeneration.Taken together,our findings indicate that Runx2 is a key regulator of Schwann cell plasticity,and therefore peripheral nerve repair.Thus,our study shows that Runx2 plays a major role in Schwann cell migration,re-myelination,and peripheral nerve functional recovery following injury.

One-year results for myopia control of orthokeratology with different back optic zone diameters: a randomized trial using a novel multispectral-based topographer

AIM:To present the 1-year results of a prospective cohort study investigating the efficacy,potential mechanism,and safety of orthokeratology(ortho-k)with different back optic zone diameters(BOZD)for myopia control in children.METHODS:This randomized clinical study was performed between Dec.2020 and Dec.2021.Participants were randomly assigned to three groups wearing ortho-k:5 mm BOZD(5-MM group),5.5 mm BOZD(5.5-MM group),and 6 mm BOZD(6-MM group).The 1-year data were recorded,including axial length,relative peripheral refraction(RPR,measured by multispectral refractive topography,MRT),and visual quality.The contrast sensitivity(CS)was evaluated by CSV-1000 instrument with spatial frequencies of 3,6,12,and 18 cycles/degree(c/d);the corneal higher-order aberrations(HOAs)were measured by iTrace aberration analyzer.The one-way ANOVA was performed to assess the differences between the three groups.The correlation between the change in AL and RPR was calculated by Pearson’s correlation coefficient.RESULTS:The 1-year results of 20,21,and 21 subjects in the 5-MM,5.5-MM,and 6-MM groups,respectively,were presented.There were no statistical differences in baseline age,sex,or ocular parameters between the three groups(all P>0.05).At the 1-year visit,the 5-MM group had lower axial elongation than the 6-MM group(0.07±0.09 vs 0.18±0.11 mm,P=0.001).The 5-MM group had more myopic total RPR(TRPR,P=0.014),with RPR in the 15°–30°(RPR 15–30,P=0.015),30°–45°(RPR 30–45,P=0.011),temporal(RPR-T,P=0.008),and nasal area(RPR-N,P<0.001)than the 6-MM group.RPR 15–30 in the 5.5-MM group was more myopic than that in the 6-MM group(P=0.002),and RPR-N in the 5-MM group was more myopic than that in the 5.5-MM group(P<0.001).There were positive correlations between the axial elongation and the change in TRPR(r=0.756,P<0.001),RPR 15–30(r=0.364,P=0.004),RPR 30–45(r=0.306,P=0.016),and RPR-N(r=0.253,P=0.047).The CS decreased at 3 c/d(P<0.001),and the corneal HOAs increased in the 5-MM group(P=0.030).CONCLUSION:Ortho-k with 5 mm BOZD can control myopia progression more effectively.The mechanism may be associated with greater myopic shifts in RPR.

Human umbilical cord mesenchymal stem cell-derived exosomes loaded into a composite conduit promote functional recovery after peripheral nerve injury in rats

Complete transverse injury of peripheral nerves is challenging to treat.Exosomes secreted by human umbilical cord mesenchymal stem cells are considered to play an important role in intercellular communication and regulate tissue regeneration.In previous studies,a collagen/hyaluronic acid sponge was shown to provide a suitable regeneration environment for Schwann cell proliferation and to promote axonal regeneration.This three-dimensional(3D)composite conduit contains a collagen/hyaluronic acid inner sponge enclosed in an electrospun hollow poly(lactic-co-glycolic acid)tube.However,whether there is a synergy between the 3D composite conduit and exosomes in the repair of peripheral nerve injury remains unknown.In this study,we tested a comprehensive strategy for repairing long-gap(10 mm)peripheral nerve injury that combined the 3D composite conduit with human umbilical cord mesenchymal stem cell-derived exosomes.Repair effectiveness was evaluated by sciatic functional index,sciatic nerve compound muscle action potential recording,recovery of muscle mass,measuring the cross-sectional area of the muscle fiber,Masson trichrome staining,and transmission electron microscopy of the regenerated nerve in rats.The results showed that transplantation of the 3D composite conduit loaded with human umbilical cord mesenchymal stem cell-derived exosomes promoted peripheral nerve regeneration and restoration of motor function,similar to autograft transplantation.More CD31-positive endothelial cells were observed in the regenerated nerve after transplantation of the loaded conduit than after transplantation of the conduit without exosomes,which may have contributed to the observed increase in axon regeneration and distal nerve reconnection.Therefore,the use of a 3D composite conduit loaded with human umbilical cord mesenchymal stem cell-derived exosomes represents a promising cell-free therapeutic option for the treatment of peripheral nerve injury.

Establishment and validation of a predictive model for peripherally inserted central catheter-related thrombosis in patients with liver cancer

BACKGROUND Peripherally inserted central catheters(PICCs)are commonly used in hospitalized patients with liver cancer for the administration of chemotherapy,nutrition,and other medications.However,PICC-related thrombosis is a serious complication that can lead to morbidity and mortality in this patient population.Several risk factors have been identified for the development of PICC-related thrombosis,including cancer type,stage,comorbidities,and catheter characteristics.Understanding these risk factors and developing a predictive model can help healthcare providers identify high-risk patients and implement preventive measures to reduce the incidence of thrombosis.AIM To analyze the influencing factors of PICC-related thrombosis in hospitalized patients with liver cancer,construct a predictive model,and validate it.METHODS Clinical data of hospitalized patients with liver cancer admitted from January 2020 to December 2023 were collected.Thirty-five cases of PICC-related thrombosis in hospitalized patients with liver cancer were collected,and 220 patients who underwent PICC placement during the same period but did not develop PICC-related thrombosis were randomly selected as controls.A total of 255 samples were collected and used as the training set,and 77 cases were collected as the validation set in a 7:3 ratio.General patient information,case data,catheterization data,coagulation indicators,and Autar Thrombosis Risk Assessment Scale scores were analyzed.Univariate and multivariate unconditional logistic regression analyses were performed on relevant factors,and the value of combined indicators in predicting PICC-related thrombosis in hospitalized patients with liver cancer was evaluated using receiver operating characteristic(ROC)curve analysis.RESULTS Univariate analysis showed statistically significant differences(P<0.05)in age,sex,Karnofsky performance status score(KPS),bedridden time,activities of daily living impairment,parenteral nutrition,catheter duration,distant metastasis,and bone marrow suppression between the thrombosis group and the non-thrombosis group.Other aspects had no statistically significant differences(P>0.05).Multivariate regression analysis showed that age≥60 years,KPS score≤50 points,parenteral nutrition,stage III to IV,distant metastasis,bone marrow suppression,and activities of daily living impairment were independent risk factors for PICC-related thrombosis in hospitalized patients with liver cancer(P<0.05).Catheter duration of 1-6 months and catheter duration>6 months were protective factors for PICC-related thrombosis(P<0.05).The predictive model for PICC-related thrombosis was obtained as follows:P predictive probability=[exp(Logit P)]/[1+exp(Logit P)],where Logit P=age×1.907+KPS score×2.045+parenteral nutrition×9.467+catheter duration×0.506+tumor-node-metastasis(TNM)staging×2.844+distant metastasis×2.065+bone marrow suppression×2.082+activities of daily living impairment×13.926.ROC curve analysis showed an area under the curve(AUC)of 0.827(95%CI:0.724-0.929,P<0.001),with a corresponding optimal cut-off value of 0.612,sensitivity of 0.755,and specificity of 0.857.Calibration curve analysis showed good consistency between the predicted occurrence of PICC-related thrombosis and actual occurrence(P>0.05).ROC analysis showed AUCs of 0.888 and 0.729 for the training and validation sets,respectively.CONCLUSION Age,KPS score,parenteral nutrition,TNM staging,distant metastasis,bone marrow suppression,and activities of daily living impairment are independent risk factors for PICC-related thrombosis in hospitalized patients with liver cancer,while catheter duration is a protective factor for the disease.The predictive model has an AUC of 0.827,indicating high predictive accuracy and clinical value.

Lower extremity peripherally inserted central catheter placement ectopic to the ascending lumbar vein:A case report

BACKGROUND Peripherally inserted central catheters(PICCs)are an essential infusion route for oncology patients receiving intravenous treatments,but lower extremity veni-puncture is the preferred technique for patients with superior vena cava syndrome(SVCS).We report the case of a patient with a lower extremity PICC ectopic to the ascending lumbar vein,to indicate and verify PICC catheterisation in the lower extremity is safe and feasible.And hope to provide different per-spectives for clinical PICC venipuncture to get the attention of peers.CASE SUMMARY On 24 August 2022,a 58-year-old male was admitted to our department due to an intermittent cough persisting for over a month,which worsened 10 d prior.Imaging and laboratory investigations suggested the patient with pulmonary malignancy and SVCS.Chemotherapy was not an absolute contraindication in this patient.Lower extremity venipuncture is the preferred technique because administering upper extremity venous transfusion to patients with SVCS can exacerbate oedema in the head,neck,and upper extremities.The patient and his family were informed about the procedure,and informed consent was obtained.After successful puncture and prompt treatment,the patient was discharged,experiencing some relief from symptoms.CONCLUSION Inferior vena cava catheterisation is rare and important for cancer patients with SVCS,particularly in complex situations involving ectopic placement.

Autophagy-targeting modulation to promote peripheral nerve regeneration

Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms.Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration.However,recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration,particularly in the context of traumatic injuries.Consequently,autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration.Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths,thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation.These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration.A range of autophagyinducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries.This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration,summarizing the potential drugs and interventions that can be harnessed to promote this process.We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.

A genetic variant study of bortezomib-induced peripheral neuropathy in Chinese multiple myeloma patients

Background:Bortezomib results in peripheral neuropathy(PN)in approximately 50%of patients,during multiple myeloma(MM)treatment,a complication known as Bortezomib-induced peripheral neuropathy(BIPN).The drug response varies among individuals.Genetic factor may play an important role in BIPN.Methods:A nextgeneration sequencing(NGS)panel containing 1659 targets from 233 genes was used to identify risk variants for developing BIPN in 204 MM patients who received bortezomib therapy.mRNA expression of MTHFR and ALDH1A1 in 62 peripheral blood samples was detected by real-time quantitative PCR(RT-qPCR).Serum homocysteine(Hcy)levels were detected in 40 samples by chemiluminescent microparticle immunoassay(CMIA).Results:Compared with the non-BIPN group(n=89),a total of 8 significantly associated single nucleotide polymorphisms(SNPs)were identified in the BIPN group(n=115):MTHFR(rs1801131,rs1801133,rs17421511),EPHX1(rs1051740),MME(rs2016848),ALDH1A1(rs6151031),HTR7(rs1935349)and CYP2A6(rs8192720).The mRNA expression level of MTHFR in newly diagnosed patients with peripheral neuritis after treatment(NP group)was lower than that of newly diagnosed patients without peripheral neuritis after treatment(NnP group)(1.70±0.77 vs.2.81±0.97,p=0.009).Serum Hcy levels were significantly higher in BIPN group than in non-BIPN group(11.66±1.79μmol/L vs.8.52±3.29μmol/L,p=0.016)and healthy controls(11.66±1.79μmol/L vs.8.55±2.13μmol/L,p≤0.001).Conclusion:CYP2A6,EPHX1,MTHFR,ALDH1A1,HTR7,MME and BIPN are linked in Chinese MM patients.BIPN is more likely to occur in patients with lower MTHFR mRNA expression,which might result in higher serum Hcy levels.

Hydralazine represses Fpn ubiquitination to rescue injured neurons via competitive binding to UBA52

A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death distinguished by imbalance in iron and thiol metabolism, leading to lethal lipid peroxidation. However, the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear. Ferroportin (Fpn), the only known mammalian nonheme iron export protein, plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis. Here, we explored in vitro and in vivo the involvement of Fpn in neuronal ferroptosis. We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn, and stimulation of lipid peroxidation. Early administration of the potent arterial vasodilator, hydralazine (HYD), decreases the ubiquitination of Fpn after PNI by binding to UBA52, leading to suppression of neuronal cell death and significant acceleration of axon regeneration and motor function recovery. HYD targeting of ferroptosis is a promising strategy for clinical management of PNI.

Millimetric devices for nerve stimulation:a promising path towards miniaturization

Nerve stimulation is a rapidly developing field,demonstrating positive outcomes across several conditions.Despite potential benefits,current nerve stimulation devices are large,complicated,and are powered via implanted pulse generators.These facto rs necessitate invasive surgical implantation and limit potential applications.Reducing nerve stimulation devices to millimetric sizes would make these interventions less invasive and facilitate broader therapeutic applications.However,device miniaturization presents a serious engineering challenge.This review presents significant advancements from several groups that have overcome this challenge and developed millimetricsized nerve stimulation devices.These are based on antennas,mini-coils,magneto-electric and optoelectronic materials,or receive ultrasound power.We highlight key design elements,findings from pilot studies,and present several considerations for future applications of these devices.

Diabetic peripheral neuropathy and neuromodulation techniques:a systematic review of progress and prospects

Neuromodulation for diabetic peripheral neuropathy represents a significant area of interest in the management of chronic pain associated with this condition.Diabetic peripheral neuropathy,a common complication of diabetes,is characterized by nerve damage due to high blood sugar levels that lead to symptoms,such as pain,tingling,and numbness,primarily in the hands and feet.The aim of this systematic review was to evaluate the efficacy of neuromodulatory techniques as potential therapeutic interventions for patients with diabetic peripheral neuropathy,while also examining recent developments in this domain.The investigation encompassed an array of neuromodulation methods,including frequency rhythmic electrical modulated systems,dorsal root ganglion stimulation,and spinal cord stimulation.This systematic review suggests that neuromodulatory techniques may be useful in the treatment of diabetic peripheral neuropathy.Understanding the advantages of these treatments will enable physicians and other healthcare providers to offer additional options for patients with symptoms refractory to standard pharmacologic treatments.Through these efforts,we may improve quality of life and increase functional capacity in patients suffering from complications related to diabetic neuropathy.

Mutations in Ras homolog family member A in patients with peripheral T-cell lymphoma and implications for personalized medicine

Genome sequencing has revealed frequent mutations in Ras homolog family member A(RHOA)among various cancers with unique aberrant profiles and pathogenic effects,especially in peripheral T-cell lymphoma(PTCL).The discrete positional distribution and types of RHOA amino acid substitutions vary according to the tumor type,thereby leading to different functional and biological properties,which provide new insight into the molecular pathogenesis and potential targeted therapies for various tumors.However,the similarities and discrepancies in characteristics of RHOA mutations among various histologic subtypes of PTCL have not been fully elucidated.Herein we highlight the inconsistencies and complexities of the type and location of RHOA mutations and demonstrate the contribution of RHOA variants to the pathogenesis of PTCL by combining epigenetic abnormalities and activating multiple downstream pathways.The promising potential of targeting RHOA as a therapeutic modality is also outlined.This review provides new insight in the field of personalized medicine to improve the clinical outcomes for patients.

FK506 contributes to peripheral nerve regeneration by inhibiting neuroinflammatory responses and promoting neuron survival

FK506(Tacrolimus)is a systemic immunosuppressant approved by the U.S.Food and Drug Administration.FK506 has been shown to promote peripheral nerve regeneration,however,its precise mechanism of action and its pathways remain unclear.In this study,we established a rat model of sciatic nerve injury and found that FK506 improved the morphology of the injured sciatic nerve,increased the numbers of motor and sensory neurons,reduced inflammatory responses,markedly improved the conduction function of the injured nerve,and promoted motor function recovery.These findings suggest that FK506 promotes peripheral nerve structure recovery and functional regeneration by reducing the intensity of inflammation after neuronal injury and increasing the number of surviving neurons.

Early peripheral perfusion index predicts 28-day outcome in patients with septic shock

BACKGROUND:To investigate the prognostic value of the peripheral perfusion index(PPI)in patients with septic shock.METHODS:This prospective cohort study,conducted at the emergency intensive care unit of Peking University People's Hospital,recruited 200 patients with septic shock between January 2023 and August 2023.These patients were divided into survival(n=84)and death(n=116)groups based on 28-day outcomes.Clinical evaluations included laboratory tests and clinical scores,with lactate and PPI values assessed upon admission to the emergency room and at 6 h and 12 h after admission.Risk factors associated with mortality were analyzed using univariate and multivariate Cox regression analyses.Receiver operator characteristic(ROC)curve was used to assess predictive performance.Mortality rates were compared,and Kaplan-Meier survival plots were created.RESULTS:Compared to the survival group,patients in the death group were older and had more severe liver damage and coagulation dysfunction,necessitating higher norepinephrine doses and increased fl uid replacement.Higher lactate levels and lower PPI levels at 0 h,6 h,and 12 h were observed in the death group.Multivariate Cox regression identifi ed prolonged prothrombin time(PT),decreased 6-h PPI and 12-h PPI as independent risk factors for death.The area under the curves for 6-h PPI and 12-h PPI were 0.802(95%CI 0.742-0.863,P<0.001)and 0.945(95%CI 0.915-0.974,P<0.001),respectively,which were superior to Glasgow Coma Scale(GCS),Sequential Organ Failure Assessment(SOFA)scores(0.864 and 0.928).Cumulative mortality in the low PPI groups at 6 h and 12 h was signifi cantly higher than in the high PPI groups(6-h PPI:77.52%vs.22.54%;12-h PPI:92.04%vs.13.79%,P<0.001).CONCLUSION:PPI may have value in predicting 28-day mortality in patients with septic shock.

Targeted metabolomics reveals the aberrant energy status in diabetic peripheral neuropathy and the neuroprotective mechanism of traditional Chinese medicine JinMaiTong

Diabetic peripheral neuropathy (DPN) is a common and devastating complication of diabetes, for which effective therapies are currently lacking. Disturbed energy status plays a crucial role in DPN pathogenesis. However, the integrated profile of energy metabolism, especially the central carbohydrate metabolism, remains unclear in DPN. Here, we developed a metabolomics approach by targeting 56 metabolites using high-performance ion chromatography-tandem mass spectrometry (HPIC-MS/MS) to illustrate the integrative characteristics of central carbohydrate metabolism in patients with DPN and streptozotocin-induced DPN rats. Furthermore, JinMaiTong (JMT), a traditional Chinese medicine (TCM) formula, was found to be effective for DPN, improving the peripheral neurological function and alleviating the neuropathology of DPN rats even after demyelination and axonal degeneration. JMT ameliorated DPN by regulating the aberrant energy balance and mitochondrial functions, including excessive glycolysis restoration, tricarboxylic acid cycle improvement, and increased adenosine triphosphate (ATP) generation. Bioenergetic profile was aberrant in cultured rat Schwann cells under high-glucose conditions, which was remarkably corrected by JMT treatment. In-vivo and in-vitro studies revealed that these effects of JMT were mainly attributed to the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and downstream peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Our results expand the therapeutic framework for DPN and suggest the integrative modulation of energy metabolism using TCMs, such as JMT, as an effective strategy for its treatment.

Manufacturing CAR-NK against tumors: Who is the ideal supplier?

Chimeric antigen receptor-natural killer(CAR-NK) cells have emerged as another prominent player in the realm of tumor immunotherapy following CAR-T cells. The unique features of CAR-NK cells make it possible to compensate for deficiencies in CAR-T therapy, such as the complexity of the manufacturing process, clinical adverse events, and solid tumor challenges. To date, CAR-NK products from different allogeneic sources have exhibited remarkable anti-tumor effects on preclinical studies and have gradually been applied in clinical practice.However, each source has advantages and disadvantages. Selecting a suitable source may help maximize CAR-NK cell efficacy and increase the feasibility of clinical transformation. Therefore, this review discusses the development and challenges of CAR-NK cells from different sources to provide a reference for future exploration.