Apigenin ameliorates diabetic neuropathy in rats by modulating the TLR4/MyD88 signaling pathway

Objective:To determine the neuroprotective effects of apigenin against streptozotocin(STZ)-induced diabetic neuropathy(DN).Methods:To induce DN,Wistar rats(150-200 g)were administered with STZ(55 mg/kg,i.p.).Then they were randomly assigned to various groups,viz.,normal,diabetic control,insulin(10 IU/kg,s.c.),apigenin(5,10,and 20 mg/kg,p.o.),and insulin(10 IU/kg)plus apigenin(20 mg/kg,p.o.).Various behavioral,biochemical,and molecular markers[tumor necrosis factor-alpha(TNF-α),interleukin(IL)-1β,IL-6,Toll-like receptor 4(TLR4),myeloid differentiation primary response 88(MyD88),and nuclear factor erythroid 2-related factor 2(Nrf2)]were assessed.Results:Apigenin(10 and 20 mg/kg,p.o.)substantially reduced plasma glucose levels,lipid profile,aspartate transaminase,alanine transaminase,glycated hemoglobin,and neural advanced glycation end products in STZ-induced DN rats(P<0.05).After apigenin intervention,STZ-induced changes in food and water intake,body weight,urine output,allodynia,hyperalgesia,and insulin levels were markedly improved(P<0.05).Neural antioxidant enzymes(superoxide dismutase and glutathione)and Na+K+ATPase activity were also considerably elevated(P<0.05)while the level of lipid peroxidation was diminished following apigenin therapy(P<0.05).Furthermore,apigenin markedly upregulated the Nrf2 mRNA level while downregulating the mRNA expressions of TNF-αand ILs and the protein expressions of TLR4 and MyD88(P<0.05).STZ-induced histological abnormalities in the sciatic nerve were also improved by apigenin treatment.Conclusions:Apigenin exerts its neuroprotective effect by modulating the inflammatory and oxidative stress pathways via regulating the TLR4-MyD88 signaling pathway.

Issues and challenges in diabetic neuropathy management:A narrative review

Diabetic neuropathy(DN)is a devastating disorder with an increasing prevalence globally.This epidemic can pose a critical burden on individuals and communities,subsequently affecting the productivity and economic output of a country.With more people living a sedentary lifestyle,the incidence of DN is escalating worldwide.Many researchers have relentlessly worked on ways to combat this devastating disease.Their efforts have given rise to a number of commercially available therapies that can alleviate the symptoms of DN.Unfortunately,most of these therapies are only partially effective.Worse still,some are associated with unfavorable side effects.This narrative review aims to highlight current issues and challenges in the management of DN,especially from the perspective of molecular mechanisms that lead to its progression,with the hope of providing future direction in the management of DN.To improve the approaches to diabetic management,the suggested resolutions in the literature are also discussed in this review.This review will provide an in-depth understanding of the causative mechanisms of DN,apart from the insights to improve the quality and strategic approaches to DN management.

Diabetic neuropathy results in vasomotor dysfunction of medium sized peripheral arteries

BACKGROUND The effect of the sympathetic nervous system on peripheral arteries causes vasoconstriction when smooth muscle cells in the walls of blood vessels contract,which leads to narrowing of arteries and reduction of the blood flow.AIM To compare sympathetic vasomotor activation of the brachial arteries in healthy subjects and patients with painful diabetic neuropathy;and therefore,to assess whether there is significant vasomotor dysfunction of medium sized arteries in diabetic neuropathy.METHODS The study included 41 diabetic neuropathy patients and 41 healthy controls.Baseline diameter and flow rate of the brachial arteries were measured.Then,using a bipolar stimulus electrode,a 10 mA,1 Hz electrical stimulus was administered to the median nerve at the wrist level for 5 s.The brachial artery diameter and blood flow rate were re-measured after stimulation.RESULTS In the control group,the median flow rate was 70.0 mL/min prior to stimulation and 35.0 mL/min after stimulation,with a statistically significant decrease(P<0.001),which is consistent with sympathetic nervous system functioning(vasoconstriction).In the diabetic neuropathy group,median flow rate before the stimulation was 35.0 mL/min.After stimulation,the median flow rate was 77.0 mL/min;thus,no significant decrease in the flow rate was detected.In the control group,the median brachial artery diameter,which was 3.6 mm prior to stimulation,decreased to 3.4 mm after stimulation,and this decrease was also statistically significant(P=0.046).In the diabetic neuropathy group,the median brachial artery diameter increased from 3.4 mm to 3.6 mm following nerve stimulation.Once again,no narrowing was observed.CONCLUSION Our research suggests that diabetic neuropathy results in significant vasomotor dysfunction of medium sized peripheral arteries.Physiological vasoconstriction in response to sympathetic activation is impaired in diabetic neuropathy.

Sitagliptin,sitagliptin and metformin,or sitagliptin and amitriptyline attenuate streptozotocin-nicotinamide induced diabetic neuropathy in rats

Diabetic neuropathies are a family of nerve disorders caused by diabetes. Symptoms of the disease include nerve palsy, mononeuropathy, mononeuropathy multiplex, diabetic amyotrophy, painful polyneuropathy, autonomic neu- ropathy, and thoracoabdominal neuropathy. In this study, type 2 diabetes in rats was induced with nicotinamide- streptozotocin. Drug treatment was initiated on the d 15, with the combination regimen of metformin, pioglitazone and glimipiride or metformin and sitagliptin or sitagliptin, amitriptyline and sitagliptin and led to significantly im- proved glycemic control, increased grip strength and paw jumping response on d 21, 28 and 35 （P 〈 0.001）. Signif- icant increases in blood protein levels and decreases in urinary protein levels were observed in the animals treated with the different regimens on d 21, 28 and 35 （P 〈 0.001）. Combined treatment of streptozotocin and nicotinamide caused marked degeneration of nerve cells, while administration of metformin and sitagliptin showed tissue regen- eration and no body weight gain. In conclusion, treatment with sitagliptin and sitagliptin combined with metformin or amitriptyline results in no body weight gain, but causes an increase in grip strength and pain sensitivity, exhibits neural protection, and reverses the alteration of biochemical parameters in rats with streptozotocin-nicotinamide induced type 2 diabetes.

THERAPEUTIC EFFECTS OF ACUPUNCTURE COMBINED WITH MEDICINE ON DIABETIC NEUROPATHY

Objective To search for a good therapeutic method for treating diabetic neuropathy. Methods Patients were randomly divided into an acupuncture group （n =30） and a control group （n =26）. In the control group, gliclazide, at the dose of 80 mg/d, for lowering blood sugar, and adenosine coenzyme B12, at the dose of 0.75 mg, for improving nutrition of nerves were orally administered. In the acupuncture group, acupuncture at bilateral Yishu point was added. Three weeks of treatments were given for both groups. Therapeutic effects and changes in fasting blood sugar, fasting glucose in urine and blood fat were observed. Results The total effective rate was 93.3% and 67.3% in the acupuncture and control group, respectively. Fasting blood sugar, fasting glucose in urine, total cholesterol and triglyceride were obviously lowered, and high density lipoprotein markedly elevated in the acupuncture group with significant differences, compared with those in the control group （P〈0.05）. Conclusion Acupuncture combined with medicine can improve disorder of fat metabolism in diabetic patients at the early and intermediate stages and depress and stabilize blood glucose to improve neural functions.

Symptomatic and pathogenetic treatment of diabetic neuropathy Role of alpha-lipoic acid

Diabetic neuropathy, the most common form of peripheral neuropathy, presents as different forms of focal or diffuse neuropathy, including the disabling, or potentially life-threatening clinical entities of painful diabetic neuropathy, autonomic neuropathy, and diabetic foot. The pathogenesis of diabetic neuropathy results from the concurrent action of various intersecting factors of nerve damage, such as oxidative stress and mitochondrial dysfunction, inflammation, microangiopathy and ischemia, triggered by hyperglycemia and related biochemical changes. Symptomatic treatment of diabetic neuropathy mainly concerns therapies for neuropathic pain, interventions targeted at the organ systems involved in autonomic neuropathy, and management of diabetic foot. Therapeutic approaches to the pathogenesis of diabetic neuropathy have focused on the different components of the causes of nerve damage, particularly oxidative stress, which has been demonstrated to play a central role. Alpha-lipoic acid, a potent lipophilic free radical scavenger, has been used in treatment of patients with diabetic neuropathy, displaying efficacy on the chief symptoms, including neuropathic pain, and showing that neuropathic deficits may be improved by treatment. Current evidence suggests a possible efficacy of alpha-lipoic acid not only for neuropathic symptoms, but also for reducing the risk factors for diabetic neuropathy.

The potential effects of Caper (Capparis spinosa L.) in the treatment of diabetic neuropathy

Diabetic neuropathy(DN)is the most common form of neuropathy worldwide,with its prevalence rising alongside diabetes,and being characterized by sensory,motor or autonomic symptoms.DN is considered to be an incurable complication of diabetes,the management of which mainly consists of improving glycemic control,managing pain relief and ensuring continuous foot care.Although gabapentin,duloxetine and tricyclic antidepressants are commonly used to reduce patient symptoms,they do not affect the pathophysiology and progression of neuropathy.Furthermore,these drugs can have various side effects including insomnia,decreased appetite,arrhythmia,heart failure,and suicidal behavior.According to traditional Persian medicine,DN is recognized as a type of“Khadar”or“Esterkha”(a sensory or motor disorder,respectively)that occurs due to the accumulation of sugars in the peripheral nerves.Capparis spinosa L.,commonly known as the caper plant,has been recommended in authentic sources of traditional Persian medicine to treat such disorders.In this study,we reviewed the pharmacological properties of C.spinosa using the Web of Science,PubMed,Scopus and Google Scholar databases,and found that Capparis spinosa L.could affect several pathways involved in DN pathogenesis,including aldose reductase activity,the secretion of inflammatory mediators(IL-17,TNF-α,IL-1β,IL-6),oxidative stress,hyperlipidemia,hyperglycemia and advanced glycation end product formation.Based on these findings,we hypothesize that Capparis spinosa L.,may prevent the progression and reduce the symptoms of diabetic neuropathy,and so can be considered as a complementary treatment in this disorder.This hypothesis should be evaluated in well-designed in vitro and in vivo studies,and through clinical trials.

Treatment of Painful Diabetic Neuropathy With Catgut-Embedding in Acupoints

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Molecular Analysis of Clerodendrum formicarum Effects in Painful Diabetic Neuropathy in Rat

The pathophysiology of diabetic neuropathic pain is due to primarily metabolic and vascular factors. There is an increase in sorbitol and fructose, glycated end products, reactive oxygen species and activation of protein kinase C in the diabetic state. All these factors lead to direct damage to the nerves. Taking effective clinical management of neuropathic pain is based on a pharmacological treatment that has shown their limits and many side effects. The hypothesis of central sensitization inhibited by Clerodendrum formicarum, an African pharmacopoeia plant used to treat headaches, arthritis, epilepsy and chronic pain could act on astrocytes and microglial cells. The objective of this work is to study the effect of Clerodendrum formicarum (100, 150 and 200 mg/kg body weight) on astrocytes and microglial cells in a model of diabetic neuropathic pain induced by alloxan monohydrate (150 mg/kg). We noted a suppression of mechanical allodynia and mechanical hyperalgesia respectively by the Von Frey filaments test and the pressure test on the paw by the Clerodendrum formicarumextracts (ECF) at different doses from 2 h at the first injection of the ECF. After 5 days of treatment, we expressed by Western Blot bands of different proteins and by quantitative RT-PCR, we determined inhibition of the expression of GFAP, CD11b and isoforms 1 and 2 of cyclooxygenase. These results suggest that ECF inhibits the activation of astrocytes, microglial cells and cyclooxygenase signaling pathway.

Fuzzy expert system for diagnosing diabetic neuropathy

AIM To design a fuzzy expert system to help detect and diagnose the severity of diabetic neuropathy. METHODS The research was completed in 2014 and consisted of two main phases. In the first phase, the diagnostic parameters were determined based on the literature review and by investigating specialists' perspectives(n= 8). In the second phase, 244 medical records related to the patients who were visited in an endocrinology and metabolism research centre during the first six months of 2014 and were primarily diagnosed with diabetic neuropathy, were used to test the sensitivity, specificity, and accuracy of the fuzzy expert system.RESULTS The final diagnostic parameters included the duration of diabetes, the score of a symptom examination based on the Michigan questionnaire, the score of a sign examination based on the Michigan questionnaire, the glycolysis haemoglobin level, fasting blood sugar, blood creatinine, and albuminuria. The output variable was the severity of diabetic neuropathy which was shown as a number between zero and 10, had been divided into four categories: absence of the disease,(the degree of severity) mild, moderate, and severe. The interface of the system was designed by ASP.Net(Active Server Pages Network Enabled Technology) and the system function was tested in terms of sensitivity(true positive rate)(89%), specificity(true negative rate)(98%), and accuracy(a proportion of true results, both positive and negative)(93%).CONCLUSION The system designed in this study can help specialistsand general practitioners to diagnose the disease more quickly to improve the quality of care for patients.

Treatment of Diabetic Neuropathy——Principles and Methods

Diabetic neuropathy (DN) is one of the common complications of diabetes mellitus (DM), its incidence can be as high as over 90%. The lesion can involve the sensory, motor and vegetative nerves. As a whole, the lesion can be divided into symmetric multiple neuropathy and asymmetric single neuropathy. Because the pathogenesis of the disease is not clear, no specific therapy is available so far. Besides control of blood sugar level, vitamin B, vasodilators and analgesics are often used in Western medicine for expectant treatment. Basic studies on chronic complications of DM show that aldose reductase and non-enzymatic glycosylation of protein are factors initiating the pathological changes, inhibitors against them have been tested in experimental studies and proved effective. Unfortunately, they are not used clinically due to severe side effects. Screening for herbal drugs to treat DN is still a popular trend in the TCM circle.

ADVANCES IN TREATMENT OF DIABETIC NEUROPATHY BY TRADITIONAL CHINESE MEDICINE

Diabetic neuropathy (DN) is the most commonly seen complication in diabetes mellitus (DM), and can occur in its early stage. With the prolongation of the course of the disease, the incidence of DN can reach 90％. The lesion can involve any location of neural system, it can occur

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.

Interconnections between diabetic corneal neuropathy and diabetic retinopathy:diagnostic and therapeutic implications

Diabetic corneal neuropathy and diabetic retinopathy are ocular complications occurring in the context of diabetes mellitus.Diabetic corneal neuropathy refers to the progressive damage of corneal nerves.Diabetic retinopathy has traditionally been considered as damage to the retinal microvasculature.However,growing evidence suggests that diabetic retinopathy is a complex neurovascular disorder resulting from dysfunction of the neurovascular unit,which includes both the retinal vascular structures and neural tissues.Diabetic retinopathy is one of the leading causes of blindness and is frequently screened for as part of diabetic ocular screening.However,diabetic corneal neuropathy is commonly overlooked and underdiagnosed,leading to severe ocular surface impairment.Several studies have found that these two conditions tend to occur together,and they share similarities in their pathogenesis pathways,being triggered by a status of chronic hyperglycemia.This review aims to discuss the interconnection between diabetic corneal neuropathy and diabetic retinopathy,whether diabetic corneal neuropathy precedes diabetic retinopathy,as well as the relation between the stage of diabetic retinopathy and the severity of corneal neuropathy.We also endeavor to explore the relevance of a corneal screening in diabetic eyes and the possibility of using corneal nerve measurements to monitor the progression of diabetic retinopathy.

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.

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.

Corneal subepithelial nerve fibers in type 2 diabetes:potential biomarker of diabetic neuropathy

AIM:To observe the changes in corneal subepithelial nerve fibers(CNFs)and Langerhans cells(LCs)in patients with type 2 diabetes using corneal laser confocal microscopy(CLCM).METHODS:A total of 60 patients(64 eyes),including 40 patients with type 2 diabetes(DM group)and 20 subjects without diabetes(control group)were included with CLCM.Neuron J plugin of Image J software were used for quantitative analysis of CNF length(CNFL),CNF density(CNFD),corneal nerve branch fiber density(CNBD),main branch length density,branch length density,corneal nerve fiber tortuosity(NT)score,and LCs density.An independent samples t-test to analyze the variability between the two groups was performed,and Pearson correlation analysis was used to analyze the relationships between CNF and multiple biochemical indicators in the DM group.The predictive power of CNF for type 2 diabetes was assessed using the receiver operating characteristic(ROC)curve.RESULTS:There were significant differences in the CNFL,CNFD,and main branch length density between two groups.The results of Pearson correlation analysis showed a significant negative correlation between CNFD and the duration of diabetes as well as triglyceride levels and total cholesterol,and a significant positive correlation between CNFD and serum albumin.In addition,the NT score showed a positive correlation and urea nitrogen,similar to the positive correlation observed between LC density and glycosylated hemoglobin(HbA1c)levels.CNFD showed the highest area under the curve(AUC of ROC)value,followed by main branch length density and CNFL.The AUC of the ROC curve under the logistic regression model also demonstrated good predictive values.The cut-off values of CNFD,CNFL,and main branch length density for diabetes showed 31.25,18.85,and 12.56,respectively.CONCLUSION:In patients with type 2 diabetes,there is a notable reduction in both CNFL and CNFD.These measurements can be influenced by various blood biochemical factors.However,the compromised nerve fibers can serve as valuable indicators for predicting the onset of type 2 diabetes and also as biomarkers for detecting diabetic neuropathy and its related complications.

Non-pharmacological interventions for diabetic peripheral neuropathy:Are we winning the battle?

Despite the advent of relatively reliable modalities of diagnosing diabetic peripheral neuropathy(DPN),such as nerve conduction studies,there is still a knowledge gap about the pathophysiology,and thus limited available in-terventions for symptom control and curtailing disease progression.The pharma-cologic aspect of management is mainly centred on pain control,however,there are several important aspects of DPN such as loss of vibration sense,pressure sense,and proprioception which are associated with risks to lower limb health,which pharmacotherapy does not address.Furthermore,published evidence suggests non-pharmacologic interventions such as glycaemic control through dietary modification and exercise need to be combined with other measures such as psychotherapy,to reach a desired,however modest effect.Acupuncture is emerging as an important treatment modality for several chronic medical conditions including neuropathic and other pain syndromes.In their study published in the World Journal of Diabetes on the potential of acupuncture to reduce DPN symptoms and enhance nerve conduction parameters,Hoerder et al have been able to demonstrate that acupuncture improves sensory function and that this effect is likely sustained two months after treatment cessation.Although previous studies also support these findings,larger multi-center randomized control trials including a sham-controlled arm accounting for a placebo effect are required.Overall,given the satisfactory safety profile and the positive results found in these studies,it is likely that acupuncture may become an important aspect of the repertoire of effective DPN management.

Systematic investigation of Radix Salviae for treating diabetic peripheral neuropathy disease based on network Pharmacology

BACKGROUND Diabetic peripheral neuropathy(DPN)is a debilitating complication of diabetes mellitus with limited available treatment options.Radix Salviae,a traditional Chinese herb,has shown promise in treating DPN,but its therapeutic mech-anisms have not been systematically investigated.AIM Radix Salviae(Danshen in pinin),a traditional Chinese medicine(TCM),is widely used to treat DPN in China.However,the mechanism through which Radix Salviae treats DPN remains unclear.Therefore,we aimed to explore the mechanism of action of Radix Salviae against DPN using network pharmacology.METHODS The active ingredients and target genes of Radix Salviae were screened using the TCM pharmacology database and analysis platform.The genes associated with DPN were obtained from the Gene Cards and OMIM databases,a drug-com-position-target-disease network was constructed,and a protein–protein inter-action network was subsequently constructed to screen the main targets.Gene Ontology(GO)functional annotation and pathway enrichment analysis were performed via the Kyoto Encyclopedia of Genes and Genomes(KEGG)using Bioconductor.RESULTS A total of 56 effective components,108 targets and 4581 DPN-related target genes of Radix Salviae were screened.Intervention with Radix Salviae for DPN mainly involved 81 target genes.The top 30 major targets were selected for enrichment analysis of GO and KEGG pathways.CONCLUSION These results suggested that Radix Salviae could treat DPN by regulating the AGE-RAGE signaling pathway and the PI3K-Akt signaling pathway.Therefore,Danshen may affect DPN by regulating inflammation and apoptosis.

Clinical Efficacy of Pentoxifylline Combined with Thioctic Acid in the Treatment of Painful Diabetic Peripheral Neuropathy

Objective:To observe the efficacy of pentoxifylline+thioctic acid in the treatment of patients with painful diabetic peripheral neuropathy(PDPN).Methods:70 patients with PDPN admitted from October 2019 to October 2022 were selected and randomly grouped,with pentoxifylline+thioctic acid treatment in Group A and thioctic acid treatment in Group B,and the treatment efficacy was compared.Results:The treatment efficacy in Group A was higher than that of Group B,P<0.05;the points of each symptom of PDPN in Group A were lower than that of Group B,P<0.05;the C-reactive protein and electromyography indexes of PDPN patients in Group A were better than that of Group B,P<0.05.Conclusion:PDPN patients treated with pentoxifylline+thioctic acid can optimize nerve function,inhibit inflammation progression,and reduce PDPN symptoms,which is an efficient and feasible treatment option.