Pharmaceutical Effects Research Articles

Adapting to A Warming World: Climate Change and its Effects on Plant Phytochemicals

Climate change is profoundly altering the global environment, impacting ecosystems, biodiversity and the natural processes that sustain life. Among its numerous effects, climate change significantly influences plant phytochemistry. Plant phytochemistry is greatly impacted by climate change, among its many other consequences. Changes or variations in phytochemical composition have a significant impact on crucial ecological processes since these compounds are essential for defence against infections, herbivores and environmental stresses, as well as for luring pollinators and seed dispersers. Rising temperature have the ability to quicken enzymatic processes, which may lead to a rise in the synthesis of some phytochemicals, such as flavonoids, which are recognized for their antioxidant qualities and function in shielding plants from oxidative stress and UV rays. Furthermore, high temperatures can cause heat stress, which can cause the synthesis of chemicals linked to stress, including heat shock proteins, taking resources away from other secondary metabolites. The process referred to as the CO2 fertilization effect can increase biomass output and photosynthesis when CO2 levels are elevated which results in increased concentrations of some phytochemicals, such tannins and phenolics. Osmoprotectants and stress-related substances like anthocyanins, which lessen oxidative damage, can accumulate during drought. On the other hand, an abundance of water can lead to hypoxic conditions, which can impact nutrient intake and root respiration as well as alter the phytochemical composition of plants. Furthermore, the production of phytochemicals has changed due to climate change, which has significant ecological ramifications for interactions between plants and insects as well as microbes and the dynamics of the ecosystem as a whole. Changes in phytochemical concentrations can affect pollination, seed dispersal and herbivory patterns, which can all have an effect on plant fitness and the makeup of communities. From the standpoint of evolution, plants that can produce phytochemicals in variable conditions and maintain or increase their production may have a selective advantage that promotes natural selection and adaptation. Modifications in the phytochemical content and concentration will impact the effectiveness of pharmaceuticals and herbal remedies. Thus, the paper explores the complex interactions between climate change and plant phytochemistry, highlighting key environmental factors and their effects on the production and function of phytochemicals.

The content of cannabinoids in common hemp plants in the conditions of the Republic of Bashkortostan

Cannabis sativa L. – a herbaceous plant. Recently, interest in this fast-growing plant has increased again due to its multipurpose use: It is indeed a treasure trove of phytochemicals and a rich source of both cellulose and wood fibers. The pharmaceutical and construction sectors are equally interested in this plant, since its metabolites have powerful biological activity for human health, and stem outer and inner tissues can be used to manufacture bioplastics and concrete-like materials, respectively. Cannabinoids are the most studied group of compounds, mainly because of their wide range of pharmaceutical effects on the human body, including psychotropic activity. The content of the main cannabinoids in common hemp plants of the Vera, Nadezhda, Surskaya, Omegadar-1 varieties for 2020-2023 has been studied. The predominant cannabinoid in all varieties during the years of the study is CBD. The studied common hemp varieties in the years of research fully comply with the requirements of the law. The THC content did not exceed 0.1%.

Combined effects of climate warming and pharmaceuticals on a tri-trophic freshwater food web

Multiple anthropogenic stressors influence the functioning of lakes and ponds, but their combined effects are often little understood. We conducted two mesocosm experiments to evaluate the effects of warming (+4 °C above ambient temperature) and environmentally relevant concentrations of a mixture of commonly used pharmaceuticals (cardiovascular, psychoactive, antihistamines, antibiotics) on tri-trophic food webs representative of communities in ponds and other small standing waters. Communities were constituted of phyto- and zooplankton and macroinvertebrates (molluscs and insects) including benthic detritivores, grazers, omnivorous scrapers, omnivorous piercers, water column predators, benthic predators, and phytophilous predators. We quantified the main and interactive effects of warming and pharmaceuticals on each trophic level in the pelagic community and attributed them to the direct effects of both stressors and the indirect effects arising through biotic interactions. Warming and pharmaceuticals had stronger effects in the summer experiment, altering zooplankton community composition and causing delayed or accelerated emergence of top insect predators (odonates). In the summer experiment, both stressors and top predators reduced the biomass of filter-feeding zooplankton (cladocerans), while warming and pharmaceuticals had opposite effects on phytoplankton. In the winter experiment, the effects were much weaker and were limited to a positive effect of warming on phytoplankton biomass. Overall, we show that pharmaceuticals can exacerbate the effects of climate warming in freshwater ecosystems, especially during the warm season. Our results demonstrate the utility of community-level studies across seasons for risk assessment of multiple emerging stressors in freshwater ecosystems.

Intestinal Membrane Function in Inflammatory Bowel Disease.

Inflammatory bowel disease is a set of chronic inflammatory diseases that mainly develop in the gastrointestinal mucosa, including ulcerative colitis and Crohn's disease. Gastrointestinal membrane permeability is an important factor influencing the pharmacological effects of pharmaceuticals administered orally for treating inflammatory bowel disease and other diseases. Understanding the presence or absence of changes in pharmacokinetic properties under a disease state facilitates effective pharmacotherapy. In this paper, we reviewed the gastrointestinal membrane function in ulcerative colitis and Crohn's disease from the perspective of in vitro membrane permeability and electrophysiological parameters. Information on in vivo permeability in humans is summarized. We also overviewed the inflammatory bowel disease research using gut-on-a-chip, in which some advances have recently been achieved. It is expected that these findings will be exploited for the development of therapeutic drugs for inflammatory bowel disease and the optimization of treatment options and regimens.

Biological activity spectra of the main phytochemicals of Silybum marianum L. Gaertn. by in silico study

The main objective of bioinformatics is to augment the perception of biological data. Bioinformatics gains information from computer analysis of biological practices. Biologically active principles have both pharmaceutical and adverse effects on the organisms. PASS (Prediction of Activity Spectra for Substances) software is used to estimate the general efficacy and safety of the phytochemicals. PASS simultaneously predicts several hundreds of biological activities of natural and synthetic chemical compounds. The average precision of prediction is about 90%. The extract from the seed of Silybum marianum contains silymarin, which is a complex mixture of polyphenolic molecules, including seven closely related flavonolignans, namely, silybin A, silybin B, isosilybin A, isosilybin B, silychristin, isosilychristin, silydianin and one flavonoid namely taxifolin. Silymarin has been used to treat various hepatic diseases, including chronic and acute liver diseases in canines and felines. It is used as a nutritional supplement to treat liver diseases and toxicities and prevent certain cancers in companion animals. In the present study, the main phytochemicals reported from Silybum marianum L. Gaertn. were subjected to in-silico evaluation using PASS software. The methods, biological activity spectra and significance of the in-silico study are discussed. Keywords: Efficacy, In Silico, PASS, Phytochemicals, Silybum marianum, Toxicity

Chrysin, The Flavonoid Molecule of Antioxidant Interest

AbstractChrysin, the natural bioactive flavone compound, has been identified in several edible materials such as honey, propolis, and passionflower with numerous biological potentials and pharmaceutical effects including antitumor, anti‐inflammatory, antiviral and antioxidant. The compound has been reported to have lower in vitro antioxidant activity compared to other flavone‐based structures such as quercetin, luteolin, and myricetin, which is mostly attributed to the higher hydroxylation and the presence of conjugated en‐diol structures in these flavonoids and the lack of these structural features in chrysin. On the contrary to the in vitro antioxidant effect of chrysin, the compound has exerted remarkable in vivo antioxidant activities in several models related to the liver, brain, heart, kidneys, and other soft tissues. The current review includes a discussion of the in vivo and in vitro antioxidant activity of chrysin compared to other common flavonoids. The study also covers subjects linked to chrysin antioxidants, such as its metabolism, bioavailability, and current formulations that aim to increase chrysin antioxidant impact and overcome its low bioavailability.

Quercetin: A Potential Polydynamic Drug.

The study of natural products as potential drug leads has gained tremendous research interest. Quercetin is one of those natural products. It belongs to the family of flavonoids and, more specifically, flavonols. This review summarizes the beneficial pharmaceutical effects of quercetin, such as its anti-cancer, anti-inflammatory, and antimicrobial properties, which are some of the quercetin effects described in this review. Nevertheless, quercetin shows poor bioavailability and low solubility. For this reason, its encapsulation in macromolecules increases its bioavailability and therefore pharmaceutical efficiency. In this review, a brief description of the different forms of encapsulation of quercetin are described, and new ones are proposed. The beneficial effects of applying new pharmaceutical forms of nanotechnology are outlined.

Production and characterization of an Fv-clasp of rheumatoid factor, a low-affinity human autoantibody.

Rheumatoid factor (RF) is an autoantibody against IgG that affects autoimmune diseases and inhibits the effectiveness of pharmaceuticals and diagnostic agents. Although RFs derived from various germline genes have been identified, little is known about their molecular recognition mechanisms. In this study, the Fv-clasp format was used to prepare YES8c, an RF. We developed an Escherichia coli secretion expression system capable of producing milligram-scale of YES8c Fv-clasp per 1L of culture. Although YES8c is an autoantibody with very low affinity, the produced Fv-clasp maintained specific binding to IgG. Interestingly, the molecules prepared by E. coli secretion had a higher affinity than those prepared by refolding. In the structure of the YES8c-Fc complex, the N-terminus of the light chain is close to Fc; therefore, it is suggested that the addition of the N-terminal methionine may cause collisions with Fc, resulting in reduced affinity. Our findings suggest that the Fv-clasp, which provides sufficient stability and a high bacterial yield, is a useful format for studying RFs with very low affinity. Furthermore, the Fv-clasp produced from a secretion expression system, which can properly process the N-terminus, would be suitable for analysis of RFs in which the N-terminus may be involved in interactions.

Myasthenia Gravis: A Systematic Review.

Myasthenia gravis (MG), a rare disease, is the most common neuromuscular junction problem. It's the quintessential autoimmune disease with ocular, bulbar, respiratory, axial, and limb muscles exhibiting a typical fatigable weakening due to the development of antibodies against the acetylcholine receptor (AChR). Infections, stress, surgeries, thymus gland anomalies, and pharmaceutical side effects can also cause it. Ocular symptoms are initially experienced by most of the sufferers. The majority of the sufferers will go through at least one episode of symptom exacerbation during their illness. The immune system in MG interferes with nerve-muscle communication, causing muscles to become weak and tired quickly. The actual cause is not yet known, but a problem in the thymus gland may be the cause. In a person suffering from this disease, the size of the thymus becomes larger than normal, which is also called thymic hyperplasia. It is more common for women to have early-onset MG (EOMG) than for males to have late-onset MG (LOMG). Merely clinical evidence, encompassing the patients' medical history and physical indications of fluctuating muscle weakness in a specific region, is utilized to diagnose MG. Complementary diagnostic procedures and lab techniques aid in confirming the synaptic dysfunction and characterizing its kind and degree. Early diagnosis and the availability of effective treatments have reduced the burden of severe impairment and high mortality previously associated with MG. Current immunomodulation-based therapies come with side effects brought on by persistent immune suppression. Improved knowledge of this relatively uncommon but curable condition is required among primary carers. The objective of this review is to provide information about MG and to help people recognize its symptoms and start treatment without panic so that the progression of this disease can be stopped and complications can be avoided.

Evaluation of Endocrine Related Adverse Effects of Non-Endocrine Targeted Pharmaceuticals in Cellular Systems.

Prenatal period is a critical developmental phase that is sensitive to hormonal disruption by natural and/or exogenous hormones. Some pharmaceuticals frequently prescribed and used safely during pregnancy are shown to interact with the developmental programming of fetus, resulting in endocrine-related adverse effects. In this research, we aimed to determine the endocrine disrupting potential of paracetamol, indomethacin, alpha-methyldopa and pantoprazole which are frequently prescribed pharmaceuticals during pregnancy. In vitro aromatase inhibitory, estrogen receptor (ER) agonist/antagonist (E-Screen assay) and hormone biosynthesis modulatory effects (H295R steroidogenesis assay) of the selected pharmaceuticals were evaluated. Furthermore, their effects on viability of MCF-7/BUS and H295R cells were also evaluated by MTT assay. None of the pharmaceuticals affected H295R cell viability. Only indomethacin reduced MCF-7/BUS cell viability at 100µM and 300µM. Among the tested pharmaceuticals, only paracetamol and indomethacin showed aromatase inhibitory activity with IC 50 values of 14.7 x 10 -5 M and 57.6 x 10 -5 M, respectively. Moreover, indomethacin displayed a biphasic ER agonist effect. ER antagonist effects of indomethacin and pantoprazole were confirmed by performing two stepped E-Screen assay. After the partial validation of the H295R steroidogenesis assay with forskolin and prochloraz, the effects of pharmaceuticals on synthesis of testosterone (T) and estradiol (E2) levels were tested. Alpha-methyldopa increased E2 at all tested concentrations and T at 1.48 and 4.4µM. Contrarily other tested pharmaceuticals did not affect steroidogenesis. Present data suggest that all tested pharmaceuticals may have potential endocrine disrupting effect, which should be considered when used in pregnancy.

First identification of potential bioactive compounds from ethanol extracts of Lepista sordida from Indonesia

Mushrooms species are well known to have a high potential for bioactive compounds for decades. In the era of modern technologies, it is possible to uncover and explore the hidden ethnopharmacological values, comprising complex bioactive compounds of substantial health benefits. Lepista sordida is an edible and medicinal mushroom, and its distributed from Europe to Southeast Asia. However, there was no prior study on the bioactive compounds of L. sordida from Indonesia. In this present study, ethanol extracts of L. sordida were obtained and their extract properties were determined by gas chromatography-mass spectrometry (GC-MS). A total of 13 different chemical compounds were found in L. sordida ethanol extracts through GC-MS analysis. 4-O-Methylmannose, n-Hexadecanoic acid, and cis-13-Octadecenoic acid were noted as the major compounds with area percentages of 10.09%, 8.19%, and 6.49%, respectively. The result of PASS Server analysis suggested that the ethanolic extract of L. sordida has the pharmaceutical effect to treat phobic disorder and skin damage, preventing blood clotting, anti-inflammatory, and treating several infections which cause by bacteria, protozoa, and viruses. Therefore, it is strongly suggested to conduct further bioassay to confirm the pharmaceutical properties of this mushroom.

Synthesis of hydroxyethyl starch 200/0.5-loaded albumin nanoparticles: biocompatibility and interaction mechanism.

We aimed to synthesize hydroxyethyl starch (HES) 200/0.5-loaded bovine serum albumin nanoparticles (HBNs) and investigate the compatibility and binding mechanism in simulated physiological environments. Here, to elucidate the morphology, biocompatibility, and formation mechanism of HBNs, techniques such as scanning electron microscopy, haemolysis test, fluorescence, and circular dichroism spectroscopy were applied. The thermodynamic parameters at body temperature (ΔS° = -26.7J·mol-1 ·K-1 , ΔH° = -3.20 × 104 J·mol-1 , and ΔG = -2.35 × 104 J·mol-1 ) showed a 1:1 binding stoichiometry, which was formed by hydrogen bonds and van der Waals interactions. In addition, the conformational analysis showed that the microenvironment of fluorophores was altered with the adaptational protein secondary structural changes. Energy transfer occurred from the fluorophores to HES with a high possibility. All these results provided accurate and complete primary data for demonstrating the interaction mechanisms of HES with BSA, which helps to understand its pharmaceutical effects in blood.

From mundane to classic: Sinomenine as a multi-therapeutic agent.

Sinomenine is an active substance extracted from the traditional Chinese medicine Sinomenium acutum. Sinomenine has been shown to mediate a wide range of pharmacological actions and is known to possess good anti-inflammatory, immunosuppressive, antitumor, neuroprotective, antiarrhythmic and other pharmacological effects. Understanding the underlying mechanisms and the association between the targets and the pharmaceutical effects on different diseases is crucial to the discovery and design of new treatment strategies. In this review, we aim to give a systematic and comprehensive overview of the research progress of sinomenine over the past 20 years. We first describe the metabolism of sinomenine in vivo and then summarize the pharmacological actions of sinomenine on different diseases. Furthermore, the potential binding properties of sinomenine and the potential of developing new sinomenine-based drugs are also reviewed.

Design, synthesis and biological evaluation of novel cationic liposomes loaded with melphalan for the treatment of cancer

Therapeutically active lipids in drug delivery systems offer customization for enhanced pharmaceutical and biological effects, improving safety and efficacy. Biologically active N, N-didodecyl-3,4-dimethoxy-N-methylbenzenaminium lipid (Q) was synthesized and employed to create a liposome formulation (FQ) encapsulating melphalan (M) through a thin film hydration method. Synthesized cationic lipids and their liposomal formulation underwent characterization and assessment for additive anti-cancer effects on myeloma and melanoma cancer cell lines. These effects were evaluated through various studies, including cytotoxicity assessments, cell cycle arrest analysis, apoptosis measurements, mitochondrial membrane potential depolarization, DNA fragmentation, and a significant reduction in tumorigenic potential, as evidenced by a decrease in both the number and percentage area of cancer spheroids.

Intrathecal Therapy Options for Meningeal Carcinomatosis.

Around 5 percent of all patients with metastatic breast cancer go on to develop distant metastases in the meninges, also known as meningeal carcinomatosis. The median survival of these patients is between 3.5 and 4.5 months. Current treatment approaches are based on radiotherapy, systemic and intrathecal therapy. Methotrexate, liposomal cytarabine and trastuzumab are the most common substances used for intrathecal therapy. The aim of this review was to provide an overview of these intrathecal therapy options for meningeal carcinomatosis. A systematic search of the literature was carried out in PubMed using the following search terms: "meningeal metastases", "meningeal carcinomatosis", "leptomeningeal metastasis", "leptomeningeal carcinomatosis", "leptomeningeal disease", "breast cancer", "MTX", "methotrexate", "DepoCyte", "liposomal cytarabine", "trastuzumab" and "anti-HER2". This search resulted in 75 potentially relevant studies, 11 of which were included in this review after meeting the previously determined inclusion and exclusion criteria. The studies differ considerably with regards to study design, cohort size, and dosages of administered drugs. In principle, intrathecal therapy has a tolerable side-effects profile and offers promising results in terms of the median overall survival following treatment with trastuzumab for HER2-positive primary tumors. The focus when treating meningeal carcinomatosis must be on providing a multimodal individual therapeutic approach. However, comprehensive studies which compare the efficacy and side effects of individual pharmaceuticals are lacking. Because of the poor prognosis associated with meningeal carcinomatosis, an approach which treats only the symptoms (best supportive care) should always be considered and discussed with affected patients.

Epiberberine induced p53/p21-dependent G2/M cell cycle arrest and cell apoptosis in gastric cancer cells by activating γ-aminobutyric acid receptor- β3

Background and PurposeEpiberberine (EPI) is one of the most important bioalkaloid found in the rhizome of Coptis chinensis, which has been observed to exhibit pharmaceutical effects against gastric cancer (GC). Nevertheless, the potential mechanism of EPI against GC cells still remains unclear. This study aimed to identify the core receptor on GC cells through which EPI inhibited the growth of GC cells and to explore the underlying inhibitory mechanisms. MethodsTo identify hub receptor targets that respond to EPI treatment, RNA sequencing (RNA-Seq) data from a tumor-bearing mouse model were analyzed using bioinformatics method and molecular docking. The binding interaction between EPI and GABRB3 was validated through western blotting based-cellular thermal shift assay (WB-CETSA). To further verify the binding region between EPI and GABRB3 through circular dichroism (CD) chromatography, fragments of the extracellular and transmembrane domains of the GABRB3 protein were expressed and purified in vitro. Stable cell lines with the overexpression or knockdown of GABRB3 were established using the recombinant lentivirus system. MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide)) assay, colony formation assay, invasion and migration experiments, and flow cytometry were conducted to validate the inhibitory effect of EPI on the GC cells via GABRB3. Additionally, western blotting was utilized to explore the potential inhibitory mechanisms. ResultsThrough the combination of multiple bioinformatics methods and molecular docking, we found that the γ-aminobutyric acid type A receptor subunit -β3 (GABRB3) might be the critical receptor target in response to EPI treatment. The results of WB-CETSA analysis indicated that EPI significantly promoted the thermostability of the GABRB3 protein. Importantly, EPI could directly bind to GABRB3 and alter the secondary structure of GABRB3 fragments similar to the natural agonist, γ-aminobutyric acid (GABA). The EPI-induced suppression of the malignant phenotype of GC cells was dependent on the presence of GABRB3. GABRB3 expression was positively correlated with TP53 in patients with GC. The binding of EPI to GABRB3 stimulated p53 accumulation in GC cells. This activated the p21/CDK1/cyclinB1 pathway, resulting in G2/M cell cycle arrest, and induced the Bcl-2/BAX/Caspase axis-dependent cell apoptosis. ConclusionThis study revealed the target receptor for EPI in GC cells and provided new insights into its anticancer mechanisms.

Insights in Pharmaceutical Pollution: The Prospective Role of eDNA Metabarcoding.

Environmental pollution is a growing threat to natural ecosystems and one of the world's most pressing concerns. The increasing worldwide use of pharmaceuticals has elevated their status as significant emerging contaminants. Pharmaceuticals enter aquatic environments through multiple pathways related to anthropogenic activity. Their high consumption, insufficient waste treatment, and the incapacity of organisms to completely metabolize them contribute to their accumulation in aquatic environments, posing a threat to all life forms. Various analytical methods have been used to quantify pharmaceuticals. Biotechnology advancements based on next-generation sequencing (NGS) techniques, like eDNA metabarcoding, have enabled the development of new methods for assessing and monitoring the ecotoxicological effects of pharmaceuticals. eDNA metabarcoding is a valuable biomonitoring tool for pharmaceutical pollution because it (a) provides an efficient method to assess and predict pollution status, (b) identifies pollution sources, (c) tracks changes in pharmaceutical pollution levels over time, (d) assesses the ecological impact of pharmaceutical pollution, (e) helps prioritize cleanup and mitigation efforts, and (f) offers insights into the diversity and composition of microbial and other bioindicator communities. This review highlights the issue of aquatic pharmaceutical pollution while emphasizing the importance of using modern NGS-based biomonitoring actions to assess its environmental effects more consistently and effectively.

Engineered therapeutic proteins for sustained-release drug delivery systems.

Proteins play a vital role in diverse biological processes in the human body, and protein therapeutics have been applied to treat different diseases such as cancers, genetic disorders, autoimmunity, and inflammation. Protein therapeutics have demonstrated their advantages, such as specific pharmaceutical effects, low toxicity, and strong solubility. However, several disadvantages arise in clinical applications, including short half-life, immunogenicity, and low permeation, leading to reduced drug effectiveness. The structure of protein therapeutics can be modified to increase molecular size, leading to prolonged stability and increased plasma half-life. Notably, the controlled-release delivery systems for the sustained release of protein drugs and preserving the stability of cargo proteins are envisioned as a potential approach to overcome these challenges. In this review, we summarize recent research progress related to structural modifications (PEGylation, glycosylation, poly amino acid modification, and molecular biology-based strategies) and promising long-term delivery systems, such as polymer-based systems (injectable gel/implants, microparticles, nanoparticles, micro/nanogels, functional polymers), lipid-based systems (liposomes, solid lipid nanoparticles, nanostructured lipid carriers), and inorganic nanoparticles exploited for protein therapeutics. STATEMENT OF SIGNIFICANCE: In this review, we highlight recent advances concerning modifying proteins directly to enhance their stability and functionality and discuss state-of-the-art methods for the delivery and controlled long-term release of active protein therapeutics to their target site. In terms of drug modifications, four widely used strategies, including PEGylation, poly amino acid modification, glycosylation, and genetic, are discussed. As for drug delivery systems, we emphasize recent progress relating to polymer-based systems, lipid-based systems developed, and inorganic nanoparticles for protein sustained-release delivery. This review points out the areas requiring focused research attention before the full potential of protein therapeutics for human health and disease can be realized.

Role of CD44 expressed in renal tubules during maladaptive repair in renal fibrogenesis in an allopurinol-induced rat model of chronic kidney disease.

The kidney is a major target organ for the adverse effects of pharmaceuticals; renal tubular epithelial cells (TECs) are particularly vulnerable to drug-induced toxicity. TECs have regenerative capacity; however, maladaptive repair of TECs after injury leads to renal fibrosis, resulting in chronic kidney disease (CKD). We previously reported the specific expression of CD44 in failed-repair TECs of rat CKD model induced by ischemia reperfusion injury. Here, we investigated the pathophysiological role of CD44 in renal fibrogenesis in allopurinol-treated rat CKD model. Dilated or atrophic TECs expressing CD44 in fibrotic areas were collected by laser microdissection and subjected to microarray analysis. Gene ontology showed that extracellular matrix (ECM)-related genes were upregulated and differentiation-related genes were downregulated in dilated/atrophic TECs. Ingenuity Pathway Analysis identified CD44 as an upstream regulator of fibrosis-related genes, including Fn1, which encodes fibronectin. Immunohistochemistry demonstrated that dilated/atrophic TECs expressing CD44 showed decreases in differentiation markers of TECs and clear expression of mesenchymal markers during basement membrane attachment. In situ hybridization revealed an increase in Fn1 mRNA in the cytoplasm of dilated/atrophic TECs, whereas fibronectin was localized in the stroma around these TECs, supporting the production/secretion of ECM by dilated/atrophic TECs. Overall, these data indicated that dilated/atrophic TECs underwent a partial epithelial-mesenchymal transition (pEMT) and that CD44 promoted renal fibrogenesis via induction of ECM production in failed-repair TECs exhibiting pEMT. CD44 was detected in the urine and serum of APL-treated rats, which may reflect the expression of CD44 in the kidney.

Reexamining the effects of drug loading on the in vivo performance of PEGylated liposomal doxorubicin.

Higher drug loading employed in nanoscale delivery platforms is a goal that researchers have long sought after. But such viewpoint remains controversial because the impacts that nanocarriers bring about on bodies have been seriously overlooked. In the present study we investigated the effects of drug loading on the in vivo performance of PEGylated liposomal doxorubicin (PLD). We prepared PLDs with two different drug loading rates: high drug loading rate, H-Dox, 12.9% w/w Dox/HSPC; low drug loading rate, L-Dox, 2.4% w/w Dox/HSPC (L-Dox had about 5 folds drug carriers of H-Dox at the same Dox dose). The pharmaceutical properties and biological effects of H-Dox and L-Dox were compared in mice, rats or 4T1 subcutaneous tumor-bearing mice. We showed that the lowering of doxorubicin loading did not cause substantial shifts to the pharmaceutical properties of PLDs such as in vitro and in vivo stability (stable), anti-tumor effect (equivalent effective), as well as tissue and cellular distribution. Moreover, it was even more beneficial for mitigating the undesired biological effects caused by PLDs, through prolonging blood circulation and alleviating cutaneous accumulation in the presence of pre-existing anti-PEG Abs due to less opsonins (e.g. IgM and C3) deposition on per particle. Our results warn that the effects of drug loading would be much more convoluted than expected due to the complex intermediation between nanocarriers and bodies, urging independent investigation for each individual delivery platform to facilitate clinical translation and application.