Advantages of nanocarriers for basic research in the field of traumatic brain injury

A major challenge for the efficient treatment of traumatic brain injury is the need for therapeutic molecules to cross the blood-brain barrier to enter and accumulate in brain tissue.To overcome this problem,researchers have begun to focus on nanocarriers and other brain-targeting drug delivery systems.In this review,we summarize the epidemiology,basic pathophysiology,current clinical treatment,the establishment of models,and the evaluation indicators that are commonly used for traumatic brain injury.We also report the current status of traumatic brain injury when treated with nanocarriers such as liposomes and vesicles.Nanocarriers can overcome a variety of key biological barriers,improve drug bioavailability,increase intracellular penetration and retention time,achieve drug enrichment,control drug release,and achieve brain-targeting drug delivery.However,the application of nanocarriers remains in the basic research stage and has yet to be fully translated to the clinic.

Molecular Mechanisms of Intracellular Delivery of Nanoparticles Monitored by an Enzyme‑Induced Proximity Labeling

Achieving increasingly finely targeted drug delivery to organs,tissues,cells,and even to intracellular biomacromolecules is one of the core goals of nanomedicines.As the delivery destination is refined to cellular and subcellular targets,it is essential to explore the delivery of nanomedicines at the molecular level.However,due to the lack of technical methods,the molecular mechanism of the intracellular delivery of nanomedicines remains unclear to date.Here,we develop an enzyme-induced proximity labeling technology in nanoparticles(nano-EPL)for the real-time monitoring of proteins that interact with intracellular nanomedicines.Poly(lactic-co-glycolic acid)nanoparticles coupled with horseradish peroxidase(HRP)were fabricated as a model(HRP(+)-PNPs)to evaluate the molecular mechanism of nano delivery in macrophages.By adding the labeling probe biotin-phenol and the catalytic substrate H_(2)O_(2)at different time points in cellular delivery,nano-EPL technology was validated for the real-time in situ labeling of proteins interacting with nanoparticles.Nano-EPL achieves the dynamic molecular profiling of 740 proteins to map the intracellular delivery of HRP(+)-PNPs in macrophages over time.Based on dynamic clustering analysis of these proteins,we further discovered that different organelles,including endosomes,lysosomes,the endoplasmic reticulum,and the Golgi apparatus,are involved in delivery with distinct participation timelines.More importantly,the engagement of these organelles differentially affects the drug delivery efficiency,reflecting the spatial–temporal heterogeneity of nano delivery in cells.In summary,these findings highlight a significant methodological advance toward understanding the molecular mechanisms involved in the intracellular delivery of nanomedicines.

Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Advances in the development of amorphous solid dispersions:The role of polymeric carriers

Amorphous solid dispersion(ASD)is one of the most effective approaches for delivering poorly soluble drugs.In ASDs,polymeric materials serve as the carriers in which the drugs are dispersed at the molecular level.To prepare the solid dispersions,there are many polymers with various physicochemical and thermochemical characteristics available for use in ASD formulations.Polymer selection is of great importance because it influences the stability,solubility and dissolution rates,manufacturing process,and bioavailability of the ASD.This review article provides a comprehensive overview of ASDs from the perspectives of physicochemical characteristics of polymers,formulation designs and preparation methods.Furthermore,considerations of safety and regulatory requirements along with the studies recommended for characterizing and evaluating polymeric carriers are briefly discussed.

Application of Nano-Delivery Systems in Lymph Nodes for Tumor Immunotherapy

Immunotherapy has become a promising research“hotspot”in cancer treatment.“Soldier”immune cells are not uniform throughout the body;they accumulate mostly in the immune organs such as the spleen and lymph nodes(LNs),etc.The unique structure of LNs provides the microenvironment suitable for the survival,activation,and proliferation of multiple types of immune cells.LNs play an important role in both the initiation of adaptive immunity and the generation of durable anti-tumor responses.Antigens taken up by antigen-presenting cells in peripheral tissues need to migrate with lymphatic fluid to LNs to activate the lymphocytes therein.Meanwhile,the accumulation and retaining of many immune functional compounds in LNs enhance their efficacy significantly.Therefore,LNs have become a key target for tumor immunotherapy.Unfortunately,the nonspecific distribution of the immune drugs in vivo greatly limits the activation and proliferation of immune cells,which leads to unsatisfactory anti-tumor effects.The efficient nano-delivery system to LNs is an effective strategy to maximize the efficacy of immune drugs.Nano-delivery systems have shown beneficial in improving biodistribution and enhancing accumulation in lymphoid tissues,exhibiting powerful and promising prospects for achieving effective delivery to LNs.Herein,the physiological structure and the delivery barriers of LNs were summarized and the factors affecting LNs accumulation were discussed thoroughly.Moreover,developments in nano-delivery systems were reviewed and the transformation prospects of LNs targeting nanocarriers were summarized and discussed.

Role of p53 suppression in the pathogenesis of hepatocellular carcinoma

In the world,hepatocellular carcinoma(HCC)is among the top 10 most prevalent malignancies.HCC formation has indeed been linked to numerous etiological factors,including alcohol usage,hepatitis viruses and liver cirrhosis.Among the most prevalent defects in a wide range of tumours,notably HCC,is the silencing of the p53 tumour suppressor gene.The control of the cell cycle and the preservation of gene function are both critically important functions of p53.In order to pinpoint the core mechanisms of HCC and find more efficient treatments,molecular research employing HCC tissues has been the main focus.Stimulated p53 triggers necessary reactions that achieve cell cycle arrest,genetic stability,DNA repair and the elimination of DNA-damaged cells’responses to biological stressors(like oncogenes or DNA damage).To the contrary hand,the oncogene protein of the murine double minute 2(MDM2)is a significant biological inhibitor of p53.MDM2 causes p53 protein degradation,which in turn adversely controls p53 function.Despite carrying wt-p53,the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway.High p53 in-vivo expression might have two clinical impacts on HCC:(1)Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways;and(2)Exogenous p53 makes HCC susceptible to various anticancer drugs.This review describes the functions and primary mechanisms of p53 in pathological mechanism,chemoresistance and therapeutic mechanisms of HCC.

Smart stimuli-responsive drug delivery systems in spotlight of COVID-19

The world has been dealing with a novel severe acute respiratory syndrome(SARS-CoV-2)since the end of 2019,which threatens the lives of many peopleworldwide.COVID-19 causes respiratory infection with different symptoms,from sneezing and coughing to pneumonia and sometimes gastric symptoms.Researchers worldwide are actively developing novel drug delivery systems(DDSs),such as stimuli-responsive DDSs.The ability of these carriers to respond to external/internal and even multiple stimuli is essential in creating“smart”DDS that can effectively control dosage,sustained release,individual variations,and targeted delivery.To conduct a comprehensive literature survey for this article,the terms“Stimuli-responsive”,“COVID-19”and“Drug delivery”were searched on databases/search engines like“Google Scholar”,“NCBI”,“PubMed”,and“Science Direct”.Many different types of DDSs have been proposed,including those responsive to various exogenous(light,heat,ultrasound andmagnetic field)or endogenous(microenvironmental changes in pH,ROS and enzymes)stimuli.Despite significant progress in DDS research,several challenging issues must be addressed to fill the gaps in the literature.Therefore,this study reviews the drug release mechanisms and applications of endogenous/exogenous stimuli-responsive DDSs while also exploring their potential with respect to COVID-19.

Sericin alleviates pentylenetetrazole kindling epilepsy and associated comorbidities via modulation of GABA-T enzyme and mitochondrial activity

Objective:To assess the effect of sericin against pentylenetetrazole(PTZ)kindling epilepsy and its associated comorbidities.Methods:Epilepsy was induced with PTZ at the dose of 30 mg/kg i.p.on alternative days for 25 days in rats.Sericin was administered orally at the doses of 250,500,and 1000 mg/kg for 35 days.The behavioral activities were performed using an elevated plus maze,forced swim test,and Morris water maze test.A PTZ challenge test was conducted on day 32.On day 35,rats were sacrificed to perform oxidative stress,mitochondrial dysfunction,neuroinflammation,neurotransmitters,GABA-T activity,and histopathological analyses.Results:Sericin at 500 and 1000 mg/kg significantly reduced behavioral changes and neuroinflammatory cytokines,as well as improved oxidative stress,mitochondrial enzyme complex activity,neurotransmitter level,and GABA-T enzymatic activity(P<0.05).Moreover,sericin improved the neuronal survival altered by PTZ kindling in rat hippocampus.Conclusions:Sericin mitigates epilepsy-associated secondary complications possibly by the modulation of mitochondrial enzyme complexes and GABA-T enzymatic activity.

Effect of hydroalcoholic leaf extract of Cassia fistula L.on typeⅡcollagen-induced arthritis in rats

Objective:To explore the effect of Cassia fistula on collagenⅡ-induced arthritis in rats.Methods:The effect of 250 and 500 mg/kg chloroform and hydroalcoholic extract of Cassia fistula leaf on collagenⅡ-induced arthritis was investigated by evaluating paw volume,arthritis index,spleen index,and biochemical parameters.Histopathological analysis and docking study were also performed.Results:A dose-dependent reduction in paw volume,arthritic index,and spleen index was observed following oral administration of the chloroform and hydroalcoholic extracts.Treatment with Cassia fistula extracts reduced tumor necrosis factor-α,interleukin(IL)-1β,IL-6,prostaglandin E_(2),aspartate aminotransferase,alanine aminotransferase,total leucocyte count,and erythrocyte sedimentation rate while increasing IL-10 level.In addition,Cassia fistula extracts improved joint architecture,and prevented cartilage and bone destruction.Docking analysis demonstrated that the physcion,1-octacosanol,5,3’,4’-trihydroxy-6-methoxy-7-O-α-Lrhamnopyranosyl-(1,2)-O-β-D-galactopyranoside and scopoletin may be responsible for the anti-arthritic effect of Cassia fistula.Conclusions:Cassia fistula suppresses the progression of collagenⅡ-induced arthritis by lowering the inflammatory factors,decreasing paw volume and arthritic index,and alleviating joint architecture.However,further studies are required to confirm the bioactive molecule responsible for the anti-arthritic potential of Cassia fistula.

CD71-mediated liposomal arsenic-nickel complex combined with all-trans retinoic acid for the efficacy of acute promyelocytic leukemia

Clinically,arsenic trioxide(ATO)was applied to the treatment of acute promyelocytic leukemia(APL)as a reliable and effective frontline drug.However,the administration regimen of AsⅢwas limited due to its fast clearance,short therapeutic window and toxicity as well.Based on CD71 overexpressed on APL cells,in present study,a transferrin(Tf)-modified liposome(LP)was established firstly to encapsulate AsⅢin arsenic-nickel complex by nickel acetate gradient method.The AsⅢ-loaded liposomes(AsLP)exhibited the feature of acid-sensitive release in vitro.Tf-modified AsLP(Tf-AsLP)were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release AsⅢwhich stimulated reactive oxygen species level and caspase-3 activity.Tf-AsLP prolonged half-life of AsⅢin blood circulation,lowered systemic toxicity,and promoted apoptosis and induced cell differentiation at lesion site in vivo.Considering that ATO combined with RA is usually applied as the first choice in clinic for APL treatment to improve the therapeutic effect,accordingly,a Tf-modified RA liposome(Tf-RALP)was designed to reduce the severe side effects of free RA and assist Tf-AsLP for better efficacy.As expected,the tumor inhibition rate of Tf-AsLP was improved significantly with the combination of Tf-RALP on subcutaneous tumor model.Furthermore,APL orthotopic NOD/SCID mice model was established by 60CO irradiation and HL-60 cells intravenously injection.The effect of co-administration(Tf-AsLP+Tf-RALP)was also confirmed to conspicuous decrease the number of leukemia cells in the circulatory system and prolong the survival time of APL mice by promoting the APL cells’apoptosis and differentiation in peripheral blood and bone marrow.Collectively,Tf-modified acid-sensitive AsLP could greatly reduce the systemic toxicity of free drug.Moreover,Tf-AsLP combined with Tf-RALP could achieve better efficacy.Thus,transferrinmodified AsⅢliposome would be a novel clinical strategy to improve patient compliance,with promising translation prospects.

Depilatory double-disc mouse model for evaluation of vesicant dermal injury pharmacotherapy countermeasures

Background:Sulfur mustard(SM)is a chemical warfare vesicant that severely injures exposed eyes,lungs,and skin.Mechlorethamine hydrochloride(NM)is widely used as an SM surrogate.This study aimed to develop a depilatory double-disc(DDD)NM skin burn model for investigating vesicant pharmacotherapy countermeasures.Methods:Hair removal method(clipping only versus clipping followed by a depilatory),the effect of acetone in the vesicant administration vehicle,NM dose(0.5-20μmol),vehicle volume(5-20μl),and time course(0.5-21 days)were investigated using male and female CD-1 mice.Edema,an indicator of burn response,was assessed by biopsy skin weight.The ideal NM dose to induce partial-thickness burns was assessed by edema and histopathologic evaluation.The optimized DDD model was validated using an established reagent,NDH-4338,a cyclooxygenase,inducible nitric oxide synthase,and acetylcholinesterase inhibitor prodrug.Results:Clipping/depilatory resulted in a 5-fold higher skin edematous response and was highly reproducible(18-fold lower%CV)compared to clipping alone.Acetone did not affect edema formation.Peak edema occurred 24-48 h after NM administra-tion using optimized dosing methods and volume.Ideal partial-thickness burns were achieved with 5μmol of NM and responded to treatment with NDH-4338.No dif-ferences in burn edematous responses were observed between males and females.Conclusion:A highly reproducible and sensitive partial-thickness skin burn model was developed for assessing vesicant pharmacotherapy countermeasures.This model pro-vides clinically relevant wound severity and eliminates the need for organic solvents that induce changes to the skin barrier function.

Fixed-Dose Combination (FDC) Formulation of Quinine Sulphate-Doxycycline (Qidox) for Malaria Therapy

Background: One of the deadliest parasite infections is malaria. A combination of quinine sulphate and doxycycline is another therapeutic option for malaria that is resistant to chloroquine and is anticipated to be able to both combat the issue of anti-malarial medication resistance as well as the compliance to malaria therapy that is still raging in certain locations of Indonesia. Aim: This study will focus on evaluating the possibility of interaction between quinine sulphate and doxycycline followed by formulating the fixed-dose combination of both active pharmaceutical ingredients. Method: The study was designed as a laboratory experiment and applied some examinations. The examination from the organoleptic test of active pharmaceutical ingredients powder, crystallography analysis, and physical analysis of fixed-dose tablet including hardness, friability, and disintegration time testing. Result: The crystallography study reported there was no physical interaction found between quinine sulphate and doxycycline. The formula found excellent tablet printability with a composition of Quinine sulphate and doxycycline (Qidox). Conclusion: quinine sulphate with doxycycline can be combined into one tablet as Fixed-Dose Combination (FDC).

Profiling the effects of microwave-assisted and soxhlet extraction techniques on the physicochemical attributes of Moringa oleifera seed oil and proteins

There is a constant search for biomaterials from natural products like plants for food and industrial applications.The work embodied in this report aimed at investigating the effects of microwave-assisted and soxhlet extraction(MAE and SE) techniques on the functional physicochemical quality characteristics of Moringa oleifera seed oil and proteins extracts. M. oleifera seeds were ground to fine powders and oil was extracted by microwave-assisted and soxhlet extraction techniques using petroleum ether. Quality attributes including yield percent, moisture content,iodine, saponification, specific gravity, viscosity, p H, thiobarbituric acid, acid and peroxide values were measured. Mineral and vitamin contents, chemical/functional groups, fatty acid(FA) composition, and reducing power of the oil were evaluated. Metabolomics of protein extracted from the defatted powders were analyzed by nuclear magnetic resonance(NMR). M. oleifera oil from MAE and SE methods had good yield(34.25 ± 0.0%,28.75 ± 0.0%), low moisture content(0.008 ± 0.0%, 0.011 ± 0.0%), non-drying and unsaturated, moderately saponified, less dense(0.91 ± 0.01, 0.92 ± 0.02 g m L^(-1)), had Newtonian flow, were weakly acidic, showed good content of FAs, recorded strong potential for long shelf-life, showed stability against oxidative rancidity and enzymatic hydrolysis, had very rich deposits of micro-and macro-nutrients as well as water-soluble and lipidsoluble vitamins, and functional groups in the oil were reflective of its content of long-and medium-chain triglycerides(LCT and MCT). Monounsaturated and saturated fatty acids(MUFA and SFA) were detected and the oil has excellent ferric ion reducing power. NMR metabolomic assay revealed the presence of nine essential amino acids(EAAs) in the protein extract. MAE technique is a feasible and acceptable alternative for high throughput extraction of M. oleifera oil with high yield and excellent quality attributes. The study revealed that MAE did not impart any remarkable advantage(s) on the physicochemical properties of M. oleifera seed oil and protein compared to SE technique.

Attitudes and understanding of complementary and alternative medicine in cancer care:An exploratory study of patients’perspectives in Karachi,Pakistan

Objective:To evaluate the prevalence and types of complementary and alternative medicine(CAM)modalities among patients with cancer in Karachi,Pakistan.Methods:This descriptive cross-sectional study was conducted from March 2021 to December 2021.Five hundred patients with cancer were invited to participate in the study.Electronic databases,namely,Google scholar,Publons,EMBASE,PubMed,Chinese National Knowledge Infrastructure Database,and ResearchGate was used for questionnaire designed.The self-administered survey included questions on demographic characteristics,education level,socio-economic conditions and information about CAM therapies,prevalence,effectiveness,and common CAM modalities.Statistical analysis was conducted using SPSS software version 22.Results:Out of the 500 invited patients,433(86.6%)successfully completed and returned the questionnaires.In contrast to patients who were with younger,highly educated,professionally active,higher income,and had advanced cancer,time since diagnosis,type of treatment,cancer types and family history are significantly associated with CAM use.The results showed that 59.8%of the participants were acquainted with complementary and/or alternative medicine and considered safe owing to its natural ingredients.The prevalence of CAM usage among cancer patients was 40.9%and the most widely used CAM modality was herbal medicine(27.7%)and dietary supplements(28.8%).Patients used CAM as a complementary therapy to improve the morphological parameter(28.2%),strengthen the immune system(6.8%),and to decrease the side effects of conventional treatment(18.1%).Most of the respondents get the information regarding CAM therapy from the electronic media(43.2%)and the family members(48%)rather than healthcare personnel.Conclusions:Participants used CAM modalities along with the conventional health care practices.Further multicentre studies should be conducted to provide information regarding the usage of CAM therapies and their eventual benefits in patients with cancer.

Recurrent ciprofloxacin induced hypoglycemia in a non-diabetic patient:A case report

BACKGROUND Fluoroquinolones are a class of broad-spectrum antimicrobials used for various bacterial infections.Frequent use of fluoroquinolones has been questioned due to severe associated adverse effects,including dysglycemia(hypoglycemia or hyperglycemia)due to an alternation in glucose metabolism.Recent clinical trials showed the association of poor clinical outcomes with hypoglycemia in critically ill patients without diabetes.Many predisposing factors worsen fluoroquinolone-induced hypoglycemia,including diabetes,concomitant medication use like sulfonylureas or insulin,renal disease,and the elderly.CASE SUMMARY We report a case of recurrent hypoglycemia after ciprofloxacin initiation for a 71-year-old,non-diabetic,critically ill patient despite the presence of total parenteral nutrition and nasogastric tube feeding.The adverse drug reaction probability(Naranjo)scale was completed with a probable adverse drug reaction.The hypoglycemia resolved entirely after ciprofloxacin discontinuation.CONCLUSION Although ciprofloxacin-induced hypoglycemia is rare,special consideration is needed for the elderly due to their higher susceptibility to adverse side effects.

Pharmacognostic and phytochemical studies as an invaluable approach for correct identification of medicinal plants:The case of Artemisia vulgaris L.substituted for Artemisia annua L.in Western Uganda

Background:Different parts of Artemisia vulgaris L.(A.vulgaris)are ethno-medicinally used as an emmenagogue and for the treatment of ailments such as malaria fever,ulcers,and cancer.However,anecdotal evidence shows that the plant is often substituted for Artemisia annua L.(A.annua)by herbalists in Western Uganda due to similarities in their morphology.Misidentification of medicinal plants and mislabelling of herbal products have been incriminated in toxicity and adverse health outcomes in traditional medicine practise.Because safety continues to be a major issue with the use of herbal remedies,it becomes imperative therefore that medicinal plants should be correctly identified.Methods:This study focused on investigating the macroscopic,microscopic,physicochemical characteristics and phytochemical composition of A.vulgaris leaves compared to A.annua to ease its correct identification.Results:The results showed that there are some colour differences between the leaves of the two species,with a close arrangement of microscopic features but different leaf constants.The leaves of the two Artemisia species had similar tastes,but their shapes and colours(greenish-yellow for A.annua and dark green for A.vulgaris)can be used by the local community to distinguish between them.The artemisinin content was higher in A.vulgaris leaves(1.72%)than in A.annua(1.43%),but the reverse was observed for the total flavonoid content.Conclusion:This observation could justify the change in the use of A.vulgaris by the indigenous community in western Uganda.Further studies should consider the pharmacognostic comparison of A.annua with other species in the genus Artemisia and the use of molecular techniques such as DNA barcoding.

Recent advances in zwitterionic nanoscale drug delivery systems to overcome biological barriers

Nanoscale drug delivery systems(nDDS)have been employed widely in enhancing the therapeutic efficacy of drugs against diseases with reduced side effects.Although several nDDS have been successfully approved for clinical use up to now,biological barriers between the administration site and the target site hinder the wider clinical adoption of nDDS in disease treatment.Polyethylene glycol(PEG)-modification(or PEGylation)has been regarded as the gold standard for stabilising nDDS in complex biological environment.However,the accelerated blood clearance(ABC)of PEGylated nDDS after repeated injections becomes great challenges for their clinical applications.Zwitterionic polymer,a novel family of antifouling materials,have evolved as an alternative to PEG due to their super-hydrophilicity and biocompatibility.Zwitterionic nDDS could avoid the generation of ABC phenomenon and exhibit longer blood circulation time than the PEGylated analogues.More impressively,zwitterionic nDDS have recently been shown to overcome multiple biological barriers such as nonspecific organ distribution,pressure gradients,impermeable cell membranes and lysosomal degradation without the need of any complex chemical modifications.The realization of overcoming multiple biological barriers by zwitterionic nDDS may simplify the current overly complex design of nDDS,which could facilitate their better clinical translation.Herein,we summarise the recent progress of zwitterionic nDDS at overcoming various biological barriers and analyse their underlyingmechanisms.Finally,prospects and challenges are introduced to guide the rational design of zwitterionic nDDS for disease treatment.

Identifying and validating MMP family members(MMP2,MMP9,MMP12,and MMP16)as therapeutic targets and biomarkers in kidney renal clear cell carcinoma(KIRC)

Kidney Renal Clear Cell Carcinoma(KIRC)is a malignant tumor that carries a substantial risk of morbidity and mortality.The MMP family assumes a crucial role in tumor invasion and metastasis.This study aimed to uncover the mechanistic relevance of the MMP gene family as a therapeutic target and diagnostic biomarker in Kidney Renal Clear Cell Carcinoma(KIRC)through a comprehensive approach encompassing both computational and molecular analyses.STRING,Cytoscape,UALCAN,GEPIA,OncoDB,HPA,cBioPortal,GSEA,TIMER,ENCORI,DrugBank,targeted bisulfite sequencing(bisulfite-seq),conventional PCR,Sanger sequencing,and RT-qPCR based analyses were used in the present study to analyze MMP gene family members to accurately determine a few hub genes that can be utilized as both therapeutic targets and diagnostic biomarkers for KIRC.By performing STRING and Cytohubba analyses of the 24 MMP gene family members,MMP2(matrix metallopeptidase 2),MMP9(matrix metallopeptidase 9),MMP12(matrix metallopeptidase 12),and MMP16(matrix metallopeptidase 16)genes were denoted as hub genes having highest degree scores.After analyzing MMP2,MMP9,MMP12,and MMP16 via various TCGA databases and RT-qPCR technique across clinical samples and KIRC cell lines,interestingly,all these hub genes were found significantly overexpressed at mRNA and protein levels in KIRC samples relative to controls.The notable effect of the up-regulated MMP2,MMP9,MMP12,and MMP16 was also documented on the overall survival(OS)of the KIRC patients.Moreover,targeted bisulfite-sequencing(bisulfite-seq)analysis revealed that promoter hypomethylation pattern was associated with up-regulation of hub genes(MMP2,MMP9,MMP12,and MMP16).In addition to this,hub genes were involved in various diverse oncogenic pathways.The MMP gene family members(MMP2,MMP9,MMP12,and MMP16)may serve as therapeutic targets and prognostic biomarkers in KIRC.

Insulin therapy in type 2 diabetes: Insights into clinical efficacy, patient-reported outcomes, and adherence challenges

Insulin therapy plays a crucial role in the management of type 2 diabetes as the disease progresses.Over the past century,insulin formulations have undergone significant modifications and bioengineering,resulting in a diverse range of available insulin products.These products show distinct pharmacokinetic and pharmacodynamic profiles.Consequently,various insulin regimens have em-erged for the management of type 2 diabetes,including premixed formulations and combinations of basal and bolus insulins.The utilization of different insulin regimens yields disparate clinical outcomes,adverse events,and,notably,patient-reported outcomes(PROs).PROs provide valuable insights from the patient’s perspective,serving as a valuable mine of information for enhancing healthcare and informing clinical decisions.Adherence to insulin therapy,a critical patient-reported outcome,significantly affects clinical outcomes and is influenced by multiple factors.This review provides insights into the clinical effectiveness of various insulin preparations,PROs,and factors impacting insulin therapy adherence,with the aim of enhancing healthcare practices and informing clinical decisions for individuals with type 2 diabetes.