Phenomenon Of Drug Resistance Research Articles

Coupling the role of lipids to the conformational dynamics of the ABC transporter P-glycoprotein

The ATP-binding cassette transporter P-glycoprotein (P-gp) is a multidrug efflux pump that is overexpressed in a variety of cancers and associated with the drug-resistance phenomenon. P-gp structures were previously determined in detergent and in nanodisks, in which different transmembrane helix conformations were found, “straight” and “kinked,” respectively, indicating a possible role of the lipid environment on the P-gp structural ensemble. Here, we investigate the dynamic conformational ensembles and protein-lipid interactions of two human P-gp inward-open conformers, straight and kinked, employing all-atom molecular dynamics (MD) simulations in asymmetric multicomponent lipid bilayers that mimic the highly specialized hepatocyte membrane in which P-gp is expressed. The two conformers are found to differ in terms of the accessibility of the substrate cavity. The MD simulations show how cholesterol and different lipid species wedge, snorkel, and partially enter within the cavity of the straight P-gp conformer solved in detergent. However, the access to the cavity of kinked P-gp conformer solved in nanodisks is restricted. Furthermore, the volume and dynamic fluctuations of the substrate cavity largely differ between the two P-gp structures and are modulated by the presence (or absence) of cholesterol in the membrane and/or of ATP. From the mechanistic perspective, the findings indicate that the straight conformer likely precedes the kinked conformer in the functional working cycle of P-gp, with the latter conformation representing a post substrate-bound state. The inaccessibility of the main transmembrane cavity in the kinked conformer might be crucial in preventing substrate disengagement and transport withdrawal. Remarkably, in our unbiased MD simulations, one transmembrane helix (TM10) of the straight conformer underwent a spontaneous conformational transition to a kinked conformation, underlining the relevance of both conformations in a native phospholipid environment and revealing structural descriptors defining the transition between two P-gp conformers.

Oestrogen receptor positive breast cancer and its embedded mechanism: breast cancer resistance to conventional drugs and related therapies, a review.

Traditional medication and alternative therapies have long been used to treat breast cancer. One of the main problems with current treatments is that there is an increase in drug resistance in the cancer cells owing to genetic differences such as mutational changes, epigenetic changes and miRNA (microRNA) alterations such as miR-1246, miR-298, miR-27b and miR-33a, along with epigenetic modifications, such as Histone3 acetylation and CCCTC-Binding Factor (CTCF) hypermethylation for drug resistance in breast cancer cell lines. Certain forms of conventional drug resistance have been linked to genetic changes in genes such as ABCB1, AKT, S100A8/A9, TAGLN2 and NPM. This review aims to explore the current approaches to counter breast cancer, the action mechanism, along with novel therapeutic methods endowing potential drug resistance. The investigation of novel therapeutic approaches sheds light on the phenomenon of drug resistance including genetic variations that impact distinct forms of oestrogen receptor (ER) cancer, genetic changes, epigenetics-reported resistance and their identification in patients. Long-term effective therapy for breast cancer includes selective oestrogen receptor modulators, selective oestrogen receptor degraders and genetic variations, such as mutations in nuclear genes, epigenetic modifications and miRNA alterations in target proteins. Novel research addressing combinational therapies including maytansine, photodynamic therapy, guajadiol, talazoparib, COX2 inhibitors and miRNA 1246 inhibitors have been developed to improve patient survival rates.

Anemoside B4 attenuates necrotic enteritis of laying hens induced by Clostridium perfringens via inhibiting NF-κB and PI3K/Akt/mTOR signalling pathways

Poultry necrotic enteritis is an important enteric disease which might be controlled by antibiotics. However, with the excessive use of antibiotics, the phenomenon of drug resistance of Clostridium perfringens is becoming increasingly prominent. Anemoside B4 exhibits important anti-inflammatory, antioxidant and immunomodulatory effects. This study was performed to estimate the effect of Anemoside B4 on chicken necrotic enteritis induced by C. perfringens in vivo and in vitro. In the in vivo experiment we investigated the efficacy of Anemoside B4 on the growth curve, biofilm formation, haemolytic activity, virulence-related gene expression and NF-κB and PI3K/AKT/mTOR activation in Caco-2 cells induced by C. perfringens. The results showed that 12.5–50 μg/mL Anemoside B4 had no antibacterial activity but could inhibit biofilm formation, attenuate haemolytic activity and virulence-related gene expression of C. perfringens and weaken NF-κB and PI3K/Akt/mTOR activation triggered by C. perfringens in Caco-2 cells. In the in vivo experiment, 60 17-day-old healthy White Leghorns were randomly divided into six groups. The growing laying hens of the control group were fed a basic diet, and those of the five challenged groups were fed a basic diet (infection group), added 0.43 g/kg Anemoside B4 (0.43 g/kg Ane group), 0.86 g/kg Anemoside B4 (0.86 g/kg Ane group), 1.72 g/kg Anemoside B4 (1.72 g/kg Ane group) and 40 mg/kg lincomycin (lincomycin group), respectively. All challenged laying hens were infected with 1 × 109 CFU C. perfringens from day 17–20. Blood and intestinal samples were obtained, and the data demonstrated that Anemoside B4 improved the blood biochemical parameters, attenuated jejunum tissue injury, increased the spleen, thymus, bursa of fabricius index, and decreased lesion scores of the jejunum and the ileum. In the jejunum, Anemoside B4 and lincomycin downregulated the expression of IL-1β, IL-6, IL-10, TNF-α and IFN-γ at mRNA levels. Moreover, Anemoside B4 significantly enhanced both mRNA and protein levels of tight junctions ZO-1, Claudin-1 and MUC-2 in the jejunum. Anemoside B4 weakened p-P65, p-PI3K, p-Akt and p-mTOR protein expression in the jejunum infected by C. perfringens. Diets supplemented with Anemoside B4 alleviated C. perfringens-induced necrotic enteritis in laying hens by inhibiting NF-κB and PI3K/Akt/mTOR signalling pathways and improving intestinal barrier functions.

The Phenomenon of Antiretroviral Drug Resistance in the Context of Human Immunodeficiency Virus Treatment: Dynamic and Ever Evolving Subject Matter.

Human immunodeficiency virus (HIV) is a significant global health issue that affects a substantial number of individuals across the globe, with a total of 39 million individuals living with HIV/AIDS. ART has resulted in a reduction in HIV-related mortality. Nevertheless, the issue of medication resistance is a significant obstacle in the management of HIV/AIDS. The unique genetic composition of HIV enables it to undergo rapid mutations and adapt, leading to the emergence of drug-resistant forms. The development of drug resistance can be attributed to various circumstances, including noncompliance with treatment regimens, insufficient dosage, interactions between drugs, viral mutations, preexposure prophylactics, and transmission from mother to child. It is therefore essential to comprehend the molecular components of HIV and the mechanisms of antiretroviral medications to devise efficacious treatment options for HIV/AIDS.

Antimicrobial Activity of Syzygium aromaticum Essential Oil in Human Health Treatment.

The use of natural compounds to prevent and treat infective diseases is increasing its importance, especially in the case of multidrug-resistant (MDR) microorganisms-mediated infections. The drug resistance phenomenon is today a global problem, so it is important to have available substances able to counteract MDR infections. Syzygium aromaticum (L.) Merr. & L.M. Perry (commonly called clove) is a spice characterized by several biological properties. Clove essential oil (EO) consists of numerous active molecules, being eugenol as the principal component; however, other compounds that synergize with each other are responsible for the biological properties of the EO. S. aromaticum is traditionally used for bowel and stomach disorders, cold and flu, oral hygiene, tooth decay, and for its analgesic action. Its EO has shown antioxidant, antimicrobial, anti-inflammatory, neuro-protective, anti-stress, anticancer, and anti-nociceptive activities. This review aims to investigate the role of E. S. aromaticum EO in the counteraction of MDR microorganisms responsible for human disorders, diseases, or infections, such as Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhi, Candida albicans, Giardia lamblia, Streptococcus mutans, Porphyromonas gingivalis, and Klebsiella pneumoniae. This study might orient clinical researchers on future therapeutic uses of S. aromaticum EO in the prevention and treatment of infectious diseases.

Use of Essential Oils to Counteract the Phenomena of Antimicrobial Resistance in Livestock Species.

Antimicrobial resistance is an increasingly widespread phenomenon that is of particular concern because of the possible consequences in the years to come. The dynamics leading to the resistance of microbial strains are diverse, but certainly include the incorrect use of veterinary drugs both in terms of dosage and timing of administration. Moreover, the drug is often administered in the absence of a diagnosis. Many active ingredients in pharmaceutical formulations are, therefore, losing their efficacy. In this situation, it is imperative to seek alternative treatment solutions. Essential oils are mixtures of compounds with different pharmacological properties. They have been shown to possess the antibacterial, anti-parasitic, antiviral, and regulatory properties of numerous metabolic processes. The abundance of molecules they contain makes it difficult for treated microbial species to develop pharmacological resistance. Given their natural origin, they are environmentally friendly and show little or no toxicity to higher animals. There are several published studies on the use of essential oils as antimicrobials, but the present literature has not been adequately summarized in a manuscript. This review aims to shed light on the results achieved by the scientific community regarding the use of essential oils to treat the main agents of bacterial infection of veterinary interest in livestock. The Google Scholar, PubMed, SciELO, and SCOPUS databases were used for the search and selection of studies. The manuscript aims to lay the foundations for a new strategy of veterinary drug use that is more environmentally friendly and less prone to the emergence of drug resistance phenomena.

The role of metal ions in the occurrence, progression, drug resistance, and biological characteristics of gastric cancer.

Metal ions exert pivotal functions within the human body, encompassing essential roles in upholding cell structure, gene expression regulation, and catalytic enzyme activity. Additionally, they significantly influence various pathways implicated in divergent mechanisms of cell death. Among the prevailing malignant tumors of the digestive tract worldwide, gastric cancer stands prominent, exhibiting persistent high mortality rates. A compelling body of evidence reveals conspicuous ion irregularities in tumor tissues, encompassing gastric cancer. Notably, metal ions have been observed to elicit distinct contributions to the progression, drug resistance, and biological attributes of gastric cancer. This review consolidates pertinent literature on the involvement of metal ions in the etiology and advancement of gastric cancer. Particular attention is directed towards metal ions, namely, Na, K, Mg, Ca, Fe, Cu, Zn, and Mn, elucidating their roles in the initiation and progression of gastric cancer, cellular demise processes, drug resistance phenomena, and therapeutic approaches.

High monocytic MDSC signature predicts multi-drug resistance and cancer relapse in non-Hodgkin lymphoma patients treated with R-CHOP.

Non-Hodgkin Lymphoma (NHL) is a heterogeneous lymphoproliferative malignancy with B cell origin. Combinatorial treatment of rituximab, cyclophsphamide, hydroxydaunorubicin, oncovin, prednisone (R-CHOP) is the standard treatment regimen for NHL, yielding a complete remission (CR) rate of 40-50%. Unfortunately, considerable patients undergo relapse after CR or initial treatment, resulting in poor clinical implications. Patient's response to chemotherapy varies widely from static disease to cancer recurrence and later is primarily associated with the development of multi-drug resistance (MDR). The immunosuppressive cells within the tumor microenvironment (TME) have become a crucial target for improving the therapy efficacy. However, a better understanding of their involvement is needed for distinctive response of NHL patients after receiving chemotherapy to design more effective front-line treatment algorithms based on reliable predictive biomarkers. Peripheral blood from 61 CD20+ NHL patients before and after chemotherapy was utilized for immunophenotyping by flow-cytometry at different phases of treatment. In-vivo and in-vitro doxorubicin (Dox) resistance models were developed with murine Dalton's lymphoma and Jurkat/Raji cell-lines respectively and impact of responsible immune cells on generation of drug resistance was studied by RT-PCR, flow-cytometry and colorimetric assays. Gene silencing, ChIP and western blot were performed to explore the involved signaling pathways. We observed a strong positive correlation between elevated level of CD33+CD11b+CD14+CD15- monocytic MDSCs (M-MDSC) and MDR in NHL relapse cohorts. We executed the role of M-MDSCs in fostering drug resistance phenomenon in doxorubicin-resistant cancer cells in both in-vitro, in-vivo models. Moreover, in-vitro supplementation of MDSCs in murine and human lymphoma culture augments early expression of MDR phenotypes than culture without MDSCs, correlated well with in-vitro drug efflux and tumor progression. We found that MDSC secreted cytokines IL-6, IL-10, IL-1β are the dominant factors elevating MDR expression in cancer cells, neutralization of MDSC secreted IL-6, IL-10, IL-1β reversed the MDR trait. Moreover, we identified MDSC secreted IL-6/IL-10/IL-1β induced STAT1/STAT3/NF-κβ signaling axis as a targeted cascade to promote early drug resistance in cancer cells. Our data suggests that screening patients for high titre of M-MDSCs might be considered as a new potential biomarker and treatment modality in overcoming chemo-resistance in NHL patients.

Phylogenetic Aspects of Antibiotic Resistance and Biofilm Formation of P. aeruginosa Isolated from Clinical Samples.

Biofilm production and drug resistance phenomenon play a critical role in P. aeruginosa infections. Several genes, including psl, pel, brlR, and mex, are involved in the phenomenon. The aim of this study was to find the relationship between the mentioned genes and the sources of P. aeruginosa infections. Fifty-nine P. aeruginosa isolates detected from clinical specimens were used to determine antibiotic susceptibility patterns, prevalence of the genes using PCR, biofilm formation, biofilm eradication concentration assay (MBEC), and epidemiological characteristics using pulsed-field gel electrophoresis (PFGE). The results showed that 35.6% and 16.94% of all the samples were isolated from urine and wounds, 81.33% of the isolates were biofilm producers, 27.11% were multidrug-resistant (MDR), and 100% of the main biofilm former genes belonged to pslA. 94.91% of the isolates possessed brlR and mexA, and 91.5% of them expressed pslA. It was also indicated that neither ciprofloxacin nor imipenem could eradicate the formed biofilms. Moreover, we could identify 81.4% distinctive restriction profiles among the isolates, using an 80% similarity cutoff point; brlR and pel genes were significantly (P=0.032; P=0.044) related to phylogenetic pulsotypes. Comparison of the dendrogram in the isolates revealed that the detected isolates from urine were present in 12 different pulsotypes. It was found that there was a relationship between MDR, biofilm production, and brlR and pel genes among the isolates. It is distinguished there were similar genetic patterns between detected isolates from urine and could be concluded that the urinary tract played a critical role in maintaining and transferring biofilm drug-resistant genes of P. aeruginosa in clinical sites. The study highlights the importance of urine in distribution of clinical biofilm formation and drug-resistant P. aeruginosa isolates.

Phytochemical Composition and Pharmacological Efficacy Evaluation of Calamintha nepeta, Calamintha sylvatica, Lavandula austroapennina and Mentha piperita Essential Oils for the Control of Honeybee (Apis mellifera) Varroosis.

Varroa destructor is currently considered the parasite that causes the greatest damage and economic losses to honeybee farms. Its presence is often associated with that of viral and bacterial pathogens, which ultimately leads to colony collapse. Careful control of the parasitic load is therefore necessary to avoid the onset of these events. Although chemical treatments are often in easily and quickly administered formulations, in recent years, there have been increasingly frequent reports of the onset of drug resistance phenomena, which must lead to reconsidering their use. Furthermore, chemical compounds can easily accumulate in the food matrices of the hive, with possible risks for the final consumer. In such a condition, it is imperative to find alternative treatment solutions. Essential oils (EOs) prove to be promising candidates due to their good efficacy and good environmental biodegradability. In this study, the acaricidal efficacy of the EOs of Calamintha sylvatica Bromf., Calamintha nepeta Savi, Lavandula austroapennina N.G. Passal. Tundis & Upson and Mentha piperita L., extracted from botanical species belonging to the Lamiaceae family, was evaluated. The test chosen for the evaluation was residual toxicity by contact. The examined EOs were diluted in Acetone to a concentration of 2, 1 and 0.5 mg/mL. At the highest concentration, the EOs demonstrated an acaricidal activity equal to 52% for C. nepeta, 60% for C. sylvatica, 80% for L. austroapennina and 68% for M. piperita. Of the EOs tested, therefore, Lavender proves to be a good candidate for subsequent evaluations in semi-field and field studies.

The Promise of Metal-Doped Iron Oxide Nanoparticles as Antimicrobial Agent.

Antibiotic resistance (AMR) is one of the pressing global public health concerns and projections indicate a potential 10 million fatalities by the year 2050. The decreasing effectiveness of commercially available antibiotics due to the drug resistance phenomenon has spurred research efforts to develop potent and safe antimicrobial agents. Iron oxide nanoparticles (IONPs), especially when doped with metals, have emerged as a promising avenue for combating microbial infections. Like IONPs, the antimicrobial activities of doped-IONPs are also linked to their surface charge, size, and shape. Doping metals on nanoparticles can alter the size and magnetic properties by reducing the energy band gap and combining electronic charges with spins. Furthermore, smaller metal-doped nanoparticles tend to exhibit enhanced antimicrobial activity due to their higher surface-to-volume ratio, facilitating greater interaction with bacterial cells. Moreover, metal doping can also lead to increased charge density in magnetic nanoparticles and thereby elevate reactive oxygen species (ROS) generation. These ROS play a vital role to disrupt bacterial cell membrane, proteins, or nucleic acids. In this review, we compared the antimicrobial activities of different doped-IONPs, elucidated their mechanism(s), and put forth opinions for improved biocompatibility.

Prevalence and drug susceptibility of clinical Candida species in nasopharyngeal cancer patients in Vietnam

In the nature, Candida species are normal inhabitants and can be observed in a wide variety of vertebrates. In humans, especially for cancer patients who fall prey to opportunistic pathogens, this group of susceptible multi-drug resistant and biofilm-forming yeasts, are among the commonest ones. In this study, Candida species in 76 oral lesion samples from Vietnamese nasopharyngeal-cancer patients were isolated, morphologically identified using CHROMagar™, germ tube formation, and chlamydospore formation tests, and molecularly confirmed by PCR-RFLP. The drug susceptibility of these isolates was then tested, and the gene ERG11 was DNA sequenced to investigate the mechanism of resistance.The results showed that Candida albicans remained the most prevalent species (63.16% of the cases), followed by Candida glabrata, Candida tropicalis, and Candida krusei. The rates of resistance of non-albicans Candida for tested drugs were 85.71%, 53.57%, and 57.14% to fluconazole, clotrimazole, and miconazole, respectively. Although the drug-resistance rate of Candida albicans was lower than that of non-albicans Candida, it was higher than expected, suggesting an emerging drug-resistance phenomenon. Furthermore, ERG11 DNA sequencing revealed different mutations (especially K128T), implying the presence of multiple resistance mechanisms. Altogether, the results indicate an alarming drug-resistance situation in Candida species in Vietnamese cancer patients and emphasize the importance of species identification and their drug susceptibility prior to treatment.

Navigating fungal infections and antifungal stewardship: drug resistance, susceptibility testing, therapeutic drug monitoring and future directions.

Antifungal stewardship refers to the rational use of antifungal agents. Historically, in some instances, the misuse or overuse of antifungal agents has predisposed patients to an elevated risk of systemic side-effects and treatment resistance, as well as increased healthcare costs. Superficial mycoses, such as onychomycosis, are sometimes treated without any diagnostic testing and is associated with a high likelihood of self-diagnosis and self-treatment, potentially leading to the emergence of resistance against commonly used antifungals like terbinafine. Practitioners need to ensure that a proper clinical diagnosis is backed up by appropriate testing. This may include the traditional light microscopy and culture; additionally, molecular techniques (such as polymerase chain reaction, terbinafine gene mutational analysis) and antifungal susceptibility testing are considerations as appropriate. The choice of antifungal agent should be guided by what is the standard of care in the location where the clinician practices as well as more broadly state and national prescription patterns. Recently, reports of treatment resistance concerning both superficial and deep fungal infections have added another layer of difficulty to clinical practice. This review aims to explore the phenomenon of antifungal drug resistance, and highlights the importance of adopting antifungal stewardship programs. We provide an overview of treatment resistance and mechanisms of resistance reported thus far in dermatophytes. Challenges of performing antifungal susceptibility testing and therapeutic drug monitoring are discussed, as well as principles, recommendations and future directions of antifungal stewardship programs.

Factors Influencing the Emergence of Antimicrobial Drug Resistance in Clinical Dental Practice

OBJECTIVE: To investigate the perception of general dentists regarding the over-prescription of antibiotics leading to Antimicrobial drug resistance in their clinical practice. METHODOLOGY: A cross-sectional study encompassing a personalized Likert scale questionnaire on factors influencing anti-microbial resistance in dental general practices was conducted on 196 practitioners. The questionnaire inquired about different factors which tend to affect the over-prescription of antibiotics and influence anti-microbial resistance. It was piloted on 30 participants before dissemination. RESULTS: Factors showing the highest level of agreement were "lack of patient awareness regarding use of antibiotics" (96.9%), "over-the-counter availability" (95.4%), and self-medication" (95.4%). General dental practitioners were overprescribing in their clinical setup due to improper guidelines (24.4%), for their patient's satisfaction (21.2%), and lack of knowledge (19.2%).33.5% of them stated that patients reporting to them were self-medicating and 27.2% found that their patients had a lack of awareness. CONCLUSIONS: This study concluded that all the factors were responsible for the Antimicrobial Drug Resistance phenomenon in clinical dental practice. However, the majority of the dentists were over-prescribing antibiotics due to improper guidelines, lack of knowledge, and for the patient's satisfaction. KEYWORDS: Antimicrobial Drug Resistance; Awareness; Antibiotics; Dental General Practices; Over-the-Counter Drugs.

Biorisk Management and Antibiotic Susceptibility Pattern of Biofilm producing Pseudomonas aeruginosa Isolated from Broiler Chicken: A Public Health Concern

Control of biosecurity and biosecurity within poultry consists of a set of practical measures meant to prevent and control the spread of disease between people and animals. Infections, caused mainly by zoonotic agents, occur frequently due to the lack of safety monitoring regulations, as well as the inappropriate use of antimicrobial products, leading to the emergence of antimicrobial-resistant microorganisms. Pseudomonas aeruginosa, often known as the MDR pathogen has evolved resistance to multiple antibiotics. Because of its propensity to build biofilms in meat and other food products, P. aeruginosa is even more resilient to the phenomenon of drug resistance which is a major public health issue. Standard microbiological and biochemical tests were used to isolate and identify P. aeruginosa from a total of 100 meat samples (20 from each district from broiler chicken meat) gathered from various butcher shops and supermarkets. The Kirby Bauer method was used to identify antibiotic resistance, while the microtiter plate test was used to monitor biofilm formation. It was found that P. aeruginosa was identified from 22% of the broiler chicken meat samples and showed resistance to Cloxacillin, teicoplanin, ciprofloxacin, imipenem, and meropenem, followed by linezolid, streptomycin, amikacin, compound sulphonamide, aztreonam and cefepime which showed intermediate resistance. Multiple Antibiotic Resistance Index (MARI) was calculated as 0.45 for a total of 11 antibiotics. Also, all 22 MDR isolates of P. aeruginosa tested positive for the presence of the biofilm. In conclusion, it was determined that chicken meat was contaminated with Pseudomonas aeruginosa, and these strains that produce biofilms are more resistant to antibiotics. Thus, there is a serious threat to public health from biofilm-forming isolates found in broiler chickens.

Natural Compounds of Fungal Origin with Antimicrobial Activity-Potential Cosmetics Applications.

The phenomenon of drug resistance in micro-organisms necessitates the search for new compounds capable of combating them. Fungi emerge as a promising source of such compounds as they produce a wide range of secondary metabolites with bacteriostatic or fungistatic activity. These compounds can serve as alternatives for commonly used antibiotics. Furthermore, fungi also accumulate compounds with antiviral activity. This review focuses on filamentous fungi and macrofungi as sources of antimicrobial compounds. The article describes both individual isolated compounds and extracts that exhibit antibacterial, antifungal, and antiviral activity. These compounds are produced by the fruiting bodies and mycelium, as well as the biomass of mycelial cultures. Additionally, this review characterizes the chemical compounds extracted from mushrooms used in the realm of cosmetology; specifically, their antimicrobial activity.

ZNACZENIE NOWOTWOROWEJ MACIERZY ZEWNĄTRZKOMÓRKOWEJ W OPORNOŚCI NA LEKI – CHARAKTERYSTYKA WYBRANYCH SKŁADNIKÓW MACIERZY

The phenomenon of drug resistance has been one of the biggest challenges in oncology for many years. Cancer cells develop mechanisms that limit the effectiveness of treatment, affecting the survival rate of cancer patients. Most of those mechanisms are based on higher expression of transmembrane proteins that pump the drug out of the cancer cell. Currently, researchers are focusing more on the interaction between tumor cell and their microenvironment, and the direct involvement of the extracellular matrix in resistance. Many scientific studies have shown that increasing the expression of individual components of the extracellular matrix can limit the availability of the drug to cancer cells. Other mechanisms have also been reported where some drugs become directly bound to individual components of the matrix. Furthermore, cancer cells, by interacting with matrix components, activate transcriptional signals that generate resistance mechanisms. This paper is a review of the knowledge on the participation of selected components of the neoplastic extracellular matrix in the phenomenon of drug resistance. This is a very important issue because a better understanding of this mechanism offers the possibility of developing new therapies that could improve the lives of cancer patients and potentially lead to a cured.

Tocilizumab (monoclonal anti-IL-6R antibody) reverses anlotinib resistance in osteosarcoma.

Anlotinib, a tyrosine kinase inhibitor (TKI) has been in clinical application to inhibit malignant cell growth and lung metastasis in osteosarcoma (OS). However, a variety of drug resistance phenomena have been observed in the treatment. We aim to explore the new target to reverse anlotinib resistance in OS. In this study, we established four OS anlotinib-resistant cell lines, and RNA-sequence was performed to evaluate differentially expressed genes. We verified the results of RNA-sequence by PCR, western blot and ELISA assay. We further explored the effects of tocilizumab (anti- IL-6 receptor), either alone or in combined with anlotinib, on the inhibition of anlotinib-resistant OS cells malignant viability by CCK8, EDU, colony formation, apoptosis, transwell, wound healing, Cytoskeletal stain assays, and xenograft nude mouse model. The expression of IL-6 in 104 osteosarcoma samples was tested by IHC. We found IL-6 and its downstream pathway STAT3 were activated in anlotinib-resistant osteosarcoma. Tocilizumab impaired the tumor progression of anlotinib-resistant OS cells, and combined treatment with anlotinib augmented these effects by inhibiting STAT3 expressions. IL-6 was highly expressed in patients with OS and correlated with poor prognosis. Tocilizumab could reverse anlotinib resistance in OS by IL-6/STAT3 pathway and the combination treatment with anlotinib rationalized further studies and clinical treatment of OS.

PROTAC Pharmaceutical Research and its Applications

At present, there are very few protein targets that can be used as drugs, with approximately 15% of proteins being regulated by small molecules and biomacromolecules, while 85% of proteins currently do not have drug targets and cannot be regulated by small molecules and biomacromolecules. Proteolytic targeting chimeras (protacs) can degrade many non-pharmacological target proteins through proteasomes, thereby regulating their regulatory effects. Protein degradation targeting chimeras is an emerging direction in drug research and development. Traditional inhibitors have a blocking effect, leading to drug resistance and off target phenomena. However, this technology degrades the target protein through a 26S protease system. Structurally, PROTAC consists of three parts: the left end is a ligand that binds to the target protein, the right end is a ligand that connects to ubiquitin ligase, and the middle is connected through a "Linker". In the patient's body, one end of PROTAC is connected to E3 ubiquitin ligase, and the other end is connected to the target protein to be degraded. Through multiple rounds of ubiquitination, a ubiquitin chain is formed, achieving the UPS system to degrade the target protein. PROTAC small molecules have great prospects in the treatment of diseases. Unlike traditional small molecule drugs, they do not destroy the function of proteins, but completely degrade them. And PROTAC can be recycled, and the proteins of interest are polyubiquitinated and degraded through proteasomes. The dissociated PROTAC can also initiate new degradation, which is an important breakthrough in the fight against cancer cells. For example, we can design a PROTAC to hijack the protein required for unlimited proliferation of cancer cells, so that it can be degraded and inhibit the growth of cancer cells. Further exploration is needed for the development and clinical application of PROTAC drugs.

Expanding Opportunities in Viral Oncolysis.

Expanding Opportunities in Viral Oncolysis.