Hepatic drug transporters and nuclear receptors:Regulation by therapeutic agents

The canalicular membrane represents the excretory pole of hepatocytes.Bile is an important route of elimination of potentially toxic endo-and xenobiotics(including drugs and toxins),mediated by the major canalicular transporters:multidrug resistance protein 1(MDR1, ABCB1),also known as P-glycoprotein,multidrug resistance-associated protein 2(MRP2,ABCC2),and the breast cancer resistance protein(BCRP,ABCG2).Their activities depend on regulation of expression and proper localization at the canalicular membrane,as regulated by transcriptional and post-transcriptional events,respectively.At transcriptional level,specific nuclear receptors(NR)s modulated by ligands,co-activators and co-repressors,mediate the physiological requirements of these transporters.This complex system is also responsible for alterations occurring in specific liver pathologies.We briefly describe the major ClassⅡNRs, pregnane X receptor(PXR)and constitutive androstane receptor(CAR),and their role in regulating expression of multidrug resistance proteins.Several therapeutic agents regulate the expression of relevant drug transporters through activation/inactivation of these NRs.We provide some representative examples of the action of therapeutic agents modulating liver drug transporters, which in addition,involve CAR or PXR as mediators.

Current and Future Therapeutic Agents in the Man-agement of Heart Failure

Congestive heart failure is a disease in which initially compensatory changes in cardiac , vascular, and renal functions become detrimental over time. The changes are mediated by a large number of neurohormones and cytokines. Counter-regulatory hormones also play a role, but are generally insufficient to offset the adverse effects of the neurohormones or progression of the disease. Symptoms of heart failure occurs in the 'presence of systolic dysfunction, usually documented by a decrease in ejection fraction, or can present with impaired diastolic function occasionally labeled as heart failure with preserved systolic function of the left ventricle. Heart failure and its treatment represent a medical problem of significant importance because of the high mortality associated with it despite the current therapy , which has substantial evidence of reduction in mortality and morbidity. Prevention or slowing of the progressive deterioration in function of the heart and other organs involved through utilizing new agents that affect more or different neurohormonal pathways may be beneficial and forms the focus of heart failure research and drug development. However , the multiplicity of hormonal effects mandate the use of complex therapy in the management of congestive heart failure(CHF). The new agents in addition to the conventional therapy used in the management of heart failure are; Human B-type nalriuretic peptide (in the treatment of decompensated CHF) , endothelin receptor antagonists, calcium sensitizers, neutral endopeptidase (NEP) and vasopeptidase inhibitors, vasopressin antagonists and cytokine inhibitors.

A review of therapeutic agents for breast cancer with potentially radiosensitizing properties

Breast cancer is the most frequently diagnosed malignant tumor in women worldwide and the leading cause of cancer death.Radiotherapy for breast cancer is readily accepted and widely used in clinical practice.Potential limitations with radiotherapy include treatment resistance,side effects,and complications caused by high doses of irradiation.The search has been on to locate an efficacious radiosensitizer.This review summarizes six currently approved pharmaceuticals that have also been investigated for off-label use as radiosensitizers in breast cancer.

Hydroxyethyl starch and its derivatives as nanocarriers for delivery of diagnostic and therapeutic agents towards cancers

Many types of drugs and agents used for cancer diagnosis and therapy often have low bioavailability and insufficient efficacy,as well as causing various side effects due to their nonspecific delivery.Nanocarriers with purposely-designed compositions and structures have shown varying degrees of abilities to deliver these compounds towards cancers in passive or active manners.Despite the availability of a variety of materials for the construction of nanocarriers,natural polymers with good biocompatibility and biodegradability are preferable for such usage because of their high in vivo safety as well as easy removal of degradation products.Among the natural polymers intended for building nanocarriers,hydroxyethyl starch and its derivatives have gained tremendous attention in the field of drug delivery in the form of nanomedicines over the last decade.There is growing optimism that ever more hydroxyethyl starch-based nanomedicines will be a significant addition to the armoury currently used for cancer diagnosis and therapy.

Activated aggregation-induced emission therapeutics agents for triggering regulated cell death

The induction of regulated cell death(RCD)through photo/ultrasound sensiti-zation therapeutic agents has gained significant attention as a vital approach to combat drug resistance in tumors.Aggregation-induced emission(AIE)therapeutic agents generate reactive oxygen species through photo/ultrasound activation,which can synergize with RCD inducers or directly induce RCD,ultimately resulting in the death of tumor cells.The presented comprehensive review delves into recent advancements in AIE therapeutic agents designed to trigger RCD or synergize with RCD inducers,encompassing apoptosis,necroptosis,pyroptosis,immunogenic cell death,autophagy,ferroptosis,and cuproptosis.Additionally,the intricate regula-tory mechanisms through which activatory-AIE therapeutics influence distinct RCD pathways are examined.A forward-looking perspective on future developments and pertinent challenges within this exciting realm is presented,anticipating the con-tinued evolution of activatable AIE therapeutics as a transformative approach to enhance tumor therapy.

Evolving spectrum of diabetic wound: Mechanistic insights and therapeutic targets

Diabetes mellitus is a chronic metabolic disorder resulting in an increased blood glucose level and prolonged hyperglycemia,causes long term health consequences.Chronic wound is frequently occurring in diabetes patients due to compromised wound healing capability.Management of wounds in diabetic patients remains a clinical challenge despite many advancements in the field of science and technology.Increasing evidence indicates that alteration of the biochemical milieu resulting from alteration in inflammatory cytokines and matrix metalloproteinase,decrease in fibroblast and keratinocyte functioning,neuropathy,altered leukocyte functioning,infection,etc.,plays a significant role in impaired wound healing in diabetic people.Apart from the current pharmacotherapy,different other approaches like the use of conventional drugs,antidiabetic medication,antibiotics,debridement,offloading,platelet-rich plasma,growth factor,oxygen therapy,negative pressure wound therapy,low-level laser,extracorporeal shock wave bioengineered substitute can be considered in the management of diabetic wounds.Drugs/therapeutic strategy that induce angiogenesis and collagen synthesis,inhibition of MMPs,reduction of oxidative stress,controlling hyperglycemia,increase growth factors,regulate inflammatory cytokines,cause NO induction,induce fibroblast and keratinocyte proliferation,control microbial infections are considered important in controlling diabetic wound.Further,medicinal plants and/or phytoconstituents also offer a viable alternative in the treatment of diabetic wound.The focus of the present review is to highlight the molecular and cellular mechanisms,and discuss the drug targets and treatment strategies involved in the diabetic wound.

Stimuli-responsive nanocarriers for therapeutic applications in cancer

Cancer has become a very serious challenge with aging of the human population.Advances in nanotechnology have provided new perspectives in the treatment of cancer.Through the combination of nanotechnology and therapeutics,nanomedicine has been successfully used to treat cancer in recent years.In terms of nanomedicine,nanocarriers play a key role in delivering therapeutic agents,reducing severe side effects,simplifying the administration scheme,and improving therapeutic efficacies.Modulations of the structure and function of nanocarriers for improved therapeutic efficacy in cancer have attracted increasing attention in recent years.Stimuli-responsive nanocarriers penetrate deeply into tissues and respond to external or internal stimuli by releasing the therapeutic agent for cancer therapy.Notably,stimuli-responsive nanocarriers reduce the severe side effects of therapeutic agents,when compared with systemic chemotherapy,and achieve controlled drug release at tumor sites.Therefore,the development of stimuli-responsive nanocarriers plays a crucial role in drug delivery for cancer therapy.This article focuses on the development of nanomaterials with stimuli-responsive properties for use as nanocarriers,in the last few decades.These nanocarriers are more effective at delivering the therapeutic agent under the control of external or internal stimuli.Furthermore,nanocarriers with theranostic features have been designed and fabricated to confirm their great potential in achieving effective treatment of cancer,which will provide us with better choices for cancer therapy.

Fe3O4-based Nanoparticles for pH-responsive Dual-modality Imaging and Photothermal Therapy

The study designed a polyacrylic acid(PAA)modified Fe3O4@MnO2 nanoparticles(Fe3O4@MnO2@PAA)for T1/T2 dualmode imaging.In addition,this nano-drug has pH response and anti-tumor photothermal therapy.First,using Fe3O4 as the core can significantly reduce the signal of Fe3O4@MnO2@PAA nanoparticles.MnO2 nanoshells can be decomposed into paramagnetic Mn2+under the acidic environment in the tumor,which enhanced the T1 signal.The pH-responsive T1/T2 dual-mode magnetic resonance imaging(MRI)contrast agent had good sensitivity and specificity,providing more comprehensive and detailed information for tumor diagnosis.In addition,Fe3O4@MnO2@PAA nanoparticles showed excellent absorption capacity in the near-infrared region(NIR),which could be used as a good photothermal conversion material to mediate photothermal treatment of tumors.Therefore,the pHresponsive dual-mode MRI nanoparticle-mediated photothermal therapy showed good application potential in tumor treatment and diagnosis.

Antioxidants: Friend or foe?

Reactive oxygen species are the intermediates that are formed during the normal metabolic process which are effectively neutralized by the antioxidant system of the body.Any imbalance in this neutralization process causes oxidative stress which has been implicated as one of the cause in diseases such as Alzheimer's disease, cardiovascular disorders, cancer etc. Research has enabled the use of antioxidants as therapeutic agents in the treatment of various diseases. Literature also puts forth the negative effects of using antioxidants in the treatment of diseases. This review is a compilation of both the beneficial and detrimental effects of use of antioxidants in the treatment of diseases such as cancer, cardiovascular diseases, diabetes and oral diseases.

Anti-Recombinant Gametocyte 56 Protein IgY Protected Chickens from Homologous Coccidian Infection

Coccidiosis is caused by intra-cellular infection of Eimeria spp., which goes through a complex life cycle in the intestinal mucosa of infected hosts. Specific immunoglobulins （IgY） could be produced in egg yolk by immunizing hens with specific antigens. In the present study, we cloned the E. maxima gain56 gene, expressed the GST-GAM56 fusion protein and raised IgY to GST-GAM56 in hens. The anti-GST-GAM56 IgY antibody was isolated and used to treat chickens infected with E. maxima oocysts. Intramuscular injection of the antibodies provided minimal protection against parasite infection. However, oral dosing of the IgY 3 or 5 d after oocyst inoculation significantly improved body weight gain, reduced oocyst output and intestinal lesion score were reduced at 3 or 5 d after oocyst challenging, compared to the untreated control group. Our findings suggest that the IgY to gam56 could be an effective prophylactic or therapeutic agent against E. maxima infection in chickens and should have a practical application value.

ADSORPTION OF ^(153)Sm-EDTMP ON HYDROXYAPATITE

Adsorption of a promising bone tumor therapeutic agent 153Sm-EDTMP (ethylene diamine tetramethylene phosphonic acid) and effects of several coexisting substances on adsorption and desorption were investigated using HA (hydroxyapatite) as an in vitro model. The adsorption is quantitative up to total deposition of 40 μmol/g HA, while nonquantitative when the complex concentration is above 40μmol/g HA in the medium of pH=7.0±0.2. The uptake increases significantly with the Ca ions added. Desorption of the adsorped complexes is in the sequence of EDTMP DTPA > EDTA. Two modes of adsorption of 153Sm-EDTMP on HA are suggested, the first one ( 40μmol/g HA) quantitatively covers the available surface and the second, by which, is less efficient, additional complexes are adsorped. Non-qualltitative adsorption is attributed to Coulomb repulsion while the complex concentration ranging from 40 to 80 μmol/g HA.

Anti-aging Related Activities and Health Benefits of Licochalcone A:A Review

Background:Licochalcone A(LCA)is a flavonoid derived from the roots of Glycyrrhiza uralensis Fisch.ex DC and other related plants.Its natural source has been extensively used in complementary medicine,especially traditional Chinese medicine,to treat various ailments.Identified as a phenolic chalcone compound,LCA has gained significant attention in recent years due to its various pharmacological properties.Objective:The objective of this review article is to assess the anti-aging ralated pharmacological properties of LCA.Method:An exhaustive search of several scientific databases was conducted using various relevant keywords to write this review article on LCA,focusing on its therapeutic applications and anti-aging-related pharmacological activities.Some inclusion and exclusion criteria were strictly followed to retrieve updated relevant articles.Results:A collection of 292 papers were screened,and 131 were included in this review for an in-depth analysis of Licochalcone A,focusing on its anti-aging-related pharmacological activities and relevant mechanisms,and its toxicity and side effects.Moreover,the potential of LCA as a pharmacological product is discussed,emphasizing its health benefits and potential as a pharmaceutical product.Conclusion:These findings indicate that Licochalcone A is a promising natural therapeutic agent for anti-aging therapy and other ailments.

The human gut sterolbiome:bile acid-microbiome endocrine aspects and therapeutics

The human body is now viewed as a complex ecosystem that on a cellular and gene level is mainly prokaryotic. The mammalian liver synthesizes and secretes hydrophilic primary bile acids, some of which enter the colon during the enterohepatic circulation, and are converted into numerous hydrophobic metabolites which are capable of entering the portal circulation, returned to the liver, and in humans,accumulating in the biliary pool. Bile acids are hormones that regulate their own synthesis, transport, in addition to glucose and lipid homeostasis, and energy balance. The gut microbial community through their capacity to produce bile acid metabolites distinct from the liver can be thought of as an "endocrine organ"with potential to alter host physiology, perhaps to their own favor. We propose the term "sterolbiome" to describe the genetic potential of the gut microbiome to produce endocrine molecules from endogenous and exogenous steroids in the mammalian gut. The affinity of secondary bile acid metabolites to host nuclear receptors is described, the potential of secondary bile acids to promote tumors, and the potential of bile acids to serve as therapeutic agents are discussed.

Extracellular vesicles:Emerging tools as therapeutic agent carriers

Extracellular vesicles(EVs)are secreted by both eukaryotes and prokaryotes,and are present in all biological fluids of vertebrates,where they transfer DNA,RNA,proteins,lipids,and metabolites from donor to recipient cells in cell-to-cell communication.Some EV components can also indicate the type and biological status of their parent cells and serve as diagnostic targets for liquid biopsy.EVs can also natively carry or be modified to contain therapeutic agents(e.g.,nucleic acids,proteins,polysaccharides,and small molecules)by physical,chemical,or bioengineering strategies.Due to their excellent biocompatibility and stability,EVs are ideal nanocarriers for bioactive ingredients to induce signal transduction,immunoregulation,or other therapeutic effects,which can be targeted to specific cell types.Herein,we review EV classification,intercellular communication,isolation,and characterization strategies as they apply to EV therapeutics.This review focuses on recent advances in EV applications as therapeutic carriers from in vitro research towards in vivo animal models and early clinical applications,using representative examples in the fields of cancer chemotherapeutic drug,cancer vaccine,infectious disease vaccines,regenerative medicine and gene therapy.Finally,we discuss current challenges for EV therapeutics and their future development.

Plant-derived nanovesicles: Further exploration of biomedical function and application potential

Extracellular vesicles(EVs)are phospholipid bilayer vesicles actively secreted by cells,that contain a variety of functional nucleic acids,proteins,and lipids,and are important mediums of intercellular communication.Based on their natural properties,EVs can not only retain the pharmacological effects of their source cells but also serve as natural delivery carriers.Among them,plant-derived nanovesicles(PNVs)are characterized as natural disease therapeutics with many advantages such as simplicity,safety,eco-friendliness,low cost,and low toxicity due to their abundant resources,large yield,and low risk of immunogenicity in vivo.This review systematically introduces the biogenesis,isolation methods,physical characterization,and components of PNVs,and describes their administration and cellular uptake as therapeutic agents.We highlight the therapeutic potential of PNVs as therapeutic agents and drug delivery carriers,including anti-inflammatory,anticancer,wound healing,regeneration,and antiaging properties as well as their potential use in the treatment of liver disease and COVID-19.Finally,the toxicity and immunogenicity,the current clinical application,and the possible challenges in the future development of PNVs were analyzed.We expect the functions of PNVs to be further explored to promote clinical translation,thereby facilitating the development of a new framework for the treatment of human diseases.

Chemical and structural biology of nucleic acids and protein-nucleic acid complexes for novel drug discovery

Since nucleic acids(DNA and RNA) play very important roles in cells,they are molecular targets of many clinically used drugs,such as anticancer drugs and antibiotics.Because of clinical demands for treating various deadly cancers and drug-resistant strains of pathogens,there are urgent needs to develop novel therapeutic agents.Targeting nucleic acids hasn’t been the mainstream of drug discovery in the past,and the lack of 3D structural information for designing and developing drug specificity is one of the main reasons.Fortunately,many important structures of nucleic acids and their protein complexes have been determined over the past decade,which provide novel platforms for future drug design and discovery.In this review,we describe some useful nucleic acid structures,particularly their interactions with the ligands and therapeutic candidates or even drugs.We summarize important information for designing novel potent drugs and for targeting nucleic acids and protein-nucleic acid complexes to treat cancers and overcome the drug-resistant problems.

Molecular and cellular bases of chronic myeloid leukemia

Chronic myeloid leukemia(CML)is a myeloproliferative disease characterized by the overproduction of granulocytes,which leads to high white blood cell counts and splenomegaly in patients.Based on clinical symptoms and laboratory findings,CML is classified into three clinical phases,often starting with a chronic phase,progressing to an accelerated phase and ultimately ending in a terminal phase called blast crisis.Blast crisis phase of CML is clinically similar to an acute leukemia;in particular,B-cell acute lymphoblastic leukemia(B-ALL)is a severe form of acute leukemia in blast crisis,and there is no effective therapy for it yet.CML is induced by the BCR-ABL oncogene,whose gene product is a BCR-ABL tyrosine kinase.Currently,inhibition of BCR-ABL kinase activity by its kinase inhibitor such as imatinib mesylate(Gleevec)is a major therapeutic strategy for CML.However,the inability of BCR-ABL kinase inhibitors to completely kill leukemia stem cells(LSCs)indicates that these kinase inhibitors are unlikely to cure CML.In addition,drug resistance due to the development of BCRABL mutations occurs before and during treatment of CML with kinase inhibitors.A critical issue to resolve this problem is to fully understand the biology of LSCs,and to identify key genes that play significant roles in survival and self-renewal of LSCs.In this review,we will focus on LSCs in CML by summarizing and discussing available experimental results,including the original studies from our own laboratory.

Dendrimer-based strategies for cancer therapy:Recent advances and future perspectives

This review reports some recent advances on the use of dendrimer-based systems for cancer therapy. Dendrimers are emerging as promising carriers or stabilizers for drugs and nanoparticles（NPs） due to their highly branched 3-dimensional globular shape, internal hydrophobic cavity and multiple peripheral functional groups. The fabricated nanoplatforms loaded with therapeutic agents such as drugs,siRNAs or NPs can be further modified to have targeting specificity, antifouling properties and good biocompatibility.In particular, recent advances in the surface modifications of dendrimers and the application of dendrimers as versatile platforms for different therapeutic treatments to cancer including chemotherapy, radiotherapy, photothermal therapy,photodynamic therapy, gene therapy, and combination therapy will be introduced in detail.

An endoplasmic reticulum-targeted organic photothermal agent for enhanced cancer therapy

Developing selectively targeted photothermal agents to reduce side effects in photothermal therapy remains a great challenge. Inspired by the key role of endoplasmic reticulum in the protein synthesis and intracellular signal transduction, particularly for the immunogenic cell death induced by endoplasmic reticulum stress, we developed an endoplasmic reticulum-targeted organic photothermal agent(Ts-PTRGD) for enhancing photothermal therapy of tumor. The photothermal agent was covalently attached with 4-methylbenzenesulfonamide and cyclic Arg-Gly-Asp(c RGD) peptide for realizing the targeting of endoplasmic reticulum and tumor cell. Owing to its amphiphilic properties, it readily self-assembles in water to form nanoparticles. The photothermal agent possesses excellent photophysical properties and biological compatibility. In vitro and in vivo experiments demonstrate that it can actively target endoplasmic reticulum and effectively ablate tumor with near-infrared laser.

Cellular senescence is a promising target for chronic wounds:a comprehensive review

Chronic wounds include,but are not limited to,radiation ulcers,pressure ulcers,vascular ulcers and diabetic foot ulcers.These chronic wounds can persist for years without healing and severe ulcers may lead to amputation.Unfortunately,the underlying pathologies of refractory chronic wounds are not fully characterized,and new treatments are urgently needed.Recently,increasing evidence has indicated that cell senescence plays an important role in the development of chronic wounds,and preventing cell senescence or removing senescent cells holds promise as a new therapeutic strategy.In this review,we aim to probe these latest findings to promote the understanding of cellular senescence in the pathological process and potential management of chronic wounds.