Simultaneous Administration Research Articles

Recombinant vaccine candidates with integrated adjuvants provide stimulation of an effective immune response against bacterial infections

The use of recombinant proteins as vaccine preparations is limited by their weak immunogenicity, which can be enhanced by the use of adjuvants, the development of which is an important and urgent problem of modern vaccinology. Significantly, adjuvants as additives to vaccine preparations are of concern to clinicians. From this point of view, the idea of including an internal adjuvant into the structure of a recombinant protein molecule is of undoubted interest. Previously, we synthesized and studied two recombinant vaccine preparations specific for S. agalactiae (Su4) and S. pneumoniae (PSPF). Each of them was a tandem of immunogenic bacterial surface proteins in combination with an additional adjuvant site. The amino acid sequence identical to flagellin acted as an internal adjuvant. In this work, we investigated the possibility of additional enhancement of the body’s immune response to immunization with recombinant Su4 and PSPF proteins due to the simultaneous administration of an external adjuvant, carboxymethylchitosan or Imject Alum.Studies have shown that the additional introduction of these adjuvants into the composition of the vaccine preparation did not affect the immunogenicity of the Su4 and PSPF proteins, which included the internal adjuvant flagellin. The protective efficacy of the immune response to all immunization options was comparable.Thus, the inclusion of a flagellin insert as an internal adjuvant into the composition of recombinant proteins ensures the development of the highest possible level of the immune response and its protective efficacy against the corresponding pathogens of a bacterial infection.

EIF4A1 Is a Prognostic Marker and Actionable Target in Human Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a primary liver tumor with high lethality and increasing incidence worldwide. While tumor resection or liver transplantation is effective in the early stages of the disease, the therapeutic options for advanced HCC remain limited and the benefits are temporary. Thus, novel therapeutic targets and more efficacious treatments against this deadly cancer are urgently needed. Here, we investigated the pathogenetic and therapeutic role of eukaryotic initiation factor 4A1 (eIF4A1) in this tumor type. We observed consistent eIF4A1 upregulation in HCC lesions compared with non-tumorous surrounding liver tissues. In addition, eIF4A1 levels were negatively correlated with the prognosis of HCC patients. In HCC lines, the exposure to various eIF4A inhibitors triggered a remarkable decline in proliferation and augmented apoptosis, paralleled by the inhibition of several oncogenic pathways. Significantly, anti-growth effects were achieved at nanomolar concentrations of the eIF4A1 inhibitors and were further increased by the simultaneous administration of the pan mTOR inhibitor, Rapalink-1. In conclusion, our results highlight the pathogenetic relevance of eIF4A1 in HCC and recommend further evaluation of the potential usefulness of pharmacological combinations based on eIF4A and mTOR inhibitors in treating this aggressive tumor.

Combinational antitumor strategies of exosomes as drug carriers: Mini review.

Cancer therapies have made tremendous progress in the last decade, but monotherapy still has apparent limitations and lacks therapeutic efficacy. Thus, the simultaneous administration of multiple drugs has been widely explored and has shown better outcomes. Exosomes, deriving from almost all living cells, are natural nanocarriers designed to deliver drugs to tumor sites. Therefore, combinational antitumor therapies based on exosomes, such as engineered exosomes and different combinations of chemotherapeutic agents, therapeutic nucleic acids, photosensitizers, immunotherapy and phytochemicals, have considerable prospects and potential for clinical translation. Here, we summarize current strategies of cancer combination therapy in exosomes and propose opportunities and challenges in the future.

Effect of the anxiolytic fabomotizol on the time parameters of atrial depolarization in the acute phase of myocardial infarction

The aim of the work is to study the effect of the anxiolytic fabomotizole (15 mg/kg, i.v.) on atrial depolarization in the acute phase of myocardial infarction using the method of synchronous multichannel cardioelectrochronotopography. Synchronous multichannel cardioelectrochronotopography was used to study the sequence of depolarization of the atrial epicardium in outbred rats during the acute phase of myocardial infarction caused by ligation of the anterior branch of the left coronary artery with simultaneous administration of the σ1-receptor agonist fabomotizole. Significant differences in the temporal characteristics of atrial depolarization in the acute phase of myocardial infarction were revealed in control animals and animals treated with fabomotizol. In rats against the background of fabomotizol, changes in the time of the onset of epicardial depolarization, the transition of the excitation wave from the right to the left atrium, and the end of depolarization, compared with the initial state, occur by the 5th minute after the ligation of the coronary vessel; in the process of further development of acute myocardial infarction, changes in time parameters are not observed .In animals of the control group, changes in the time parameters of atrial depolarization after coronary vessel ligation develop by 10 minutes after ligation and continue to change as acute myocardial infarction develops. Anxiolytic fabomotizol in the most acute phase of myocardial infarction changes the time parameters of atrial depolarization, preventing the development of atrial fibrillation.

Simultaneous administration of EZH2 and BET inhibitors inhibits proliferation and clonogenic ability of metastatic prostate cancer cells

Androgen deprivation therapy (ADT) is a common treatment for recurrent prostate cancer (PC). However, after a certain period of responsiveness, ADT resistance occurs virtually in all patients and the disease progresses to lethal metastatic castration-resistant prostate cancer (mCRPC). Aberrant expression and function of the epigenetic modifiers EZH2 and BET over activates c-myc, an oncogenic transcription factor critically contributing to mCRPC. In the present work, we tested, for the first time, the combination of an EZH2 inhibitor with a BET inhibitor in metastatic PC cells. The combination outperformed single drugs in inhibiting cell viability, cell proliferation and clonogenic ability, and concomitantly reduced both c-myc and NF-kB expression. Although these promising results will warrant further in vivo validation, they represent the first step to establishing the rationale that the proposed combination might be suitable for mCRPC treatment, by exploiting molecular targets different from androgen receptor.

Effects of simultaneous versus post exposure epigallocatechin-3-gallate treatment on aluminum induced neurotoxicity in rat hippocampus: A multi-approach study

Chronic aluminium(Al) exposure can affect the antioxidant and glutaminergic systems through N-methyl-D-aspartate receptors (NMDAR). This study was aimed to investigate the neurotoxic effect of Al through different mechanisms in rat hippocampus and to evaluate the protective role of epigallocatechin gallate (EGCG), a well-known antioxidant, with simultaneous administration of Al,as well as post-treatment after Al exposure.For this purpose, aluminum chloride(AlCl3) was administered simultaneously with two different EGCG doses for 8 weeks as the first part of the study.In the second part of the study, after 4 weeks of AlCl3 pre-administration, two different EGCG doses were also administered during four additional weeks as post-treatment.Al administration led to oxidative stress and increased acetylcholinesterase levels.NMDAR subunit mRNA expressions were down-regulated by Al, which was apparent in NMDAR1/2B subunits.Simultaneous EGCG treatment has shown a better neuroprotective effect in terms of these mechanisms and represents novel approach for the prevention of neurodegenerative diseases likely to be induced by Al.

Eutectic Mixture Formation and Relaxation Dynamics of Coamorphous Mixtures of Two Benzodiazepine Drugs

The formation of coamorphous mixtures of pharmaceuticals is an interesting strategy to improve the solubility and bioavailability of drugs, while at the same time enhancing the kinetic stability of the resulting binary glass and allowing the simultaneous administration of two active principles. In this contribution, we describe kinetically stable amorphous binary mixtures of two commercial active pharmaceutical ingredients, diazepam and nordazepam, of which the latter, besides being administered as a drug on its own, is also the main active metabolite of the other in the human body. We report the eutectic equilibrium-phase diagram of the binary mixture, which is found to be characterized by an experimental eutectic composition of 0.18 molar fraction of nordazepam, with a eutectic melting point of Te = 395.4 ± 1.2 K. The two compounds are barely miscible in the crystalline phase. The mechanically obtained mixtures were melted and supercooled to study the glass-transition and molecular-relaxation dynamics of amorphous mixtures at the corresponding concentration. The glass-transition temperature was always higher than room temperature and varied linearly with composition. The Te was lower than the onset of thermal decomposition of either compound (pure nordazepam decomposes upon melting and pure diazepam well above its melting point), thus implying that the eutectic liquid and glass can be obtained without any degradation of the drugs. The eutectic glass was kinetically stable against crystallization for at least a few months. The relaxation processes of the amorphous mixtures were studied by dielectric spectroscopy, which provided evidence for a single structural (α) relaxation, a single Johari-Goldstein (β) relaxation, and a ring-inversion conformational relaxation of the diazepinic ring, occurring on the same timescale in both drugs. We further characterized both the binary mixtures and pure compounds by FTIR spectroscopy and first-principles density functional theory (DFT) simulations to analyze intermolecular interactions. The DFT calculations confirm the presence of strong attractive forces within the heteromolecular dimer, leading to large dimer interaction energies of the order of -0.1 eV.

Large yellow croaker (Lrimichthys crocea) IL-2 modulates humoral immunity via the conserved JAK-STAT5 signal pathway

The terminal differentiation of B cells into plasma cells is central to the generation of protective, long-lived humoral immune responses. In mammals, interleukin-2 (IL-2) has been shown to play a role in B cell proliferation and differentiation. However, it remains unclear whether fish IL-2 is involved in B cell proliferation and differentiation. To this end, we investigated the regulatory role of IL-2 in B cell proliferation and differentiation in large yellow croaker (Larimichthys crocea). We found that L. crocea IL-2 (LcIL-2) significantly increased IgM+ B cells proliferation both in vivo and in vitro and facilitated IgM+ B cells differentiation into plasma cells. Furthermore, LcIL-2 increased the production of specific antibodies after immunization with the Vibrio alginolyticus subunit vaccine, recombinant dihydrolipoamide dehydrogenase (rDLD); simultaneous administration of LcIL-2 and rDLD prior to challenge with Vibrio parahaemolyticus or V. alginolyticus significantly increased relative percent survival. Mechanistically, LcIL-2 promoted B cell proliferation and regulated B cell differentiation by triggering the JAK-STAT5 signaling pathway. Collectively, our results demonstrated that LcIL-2 improved B cell proliferation and specific antibody production via the conserved JAK-STAT5 signaling pathway in large yellow croaker, providing valuable insights into the mechanisms underlying the IL-2-mediated regulation of the humoral immune response in fish.

Innovative challenge for the inhibition of hepatocellular carcinoma progression by combined targeting of HSP90 and STAT3/HIF-1α signaling

Hepatocellular carcinoma (HCC) is the third foremost cause of cancer-related deaths. HCC has a very bad prognosis because it is asymptomatic in the early stages, resulting in a late diagnosis, and it is highly resistant to conventional chemotherapy. Such chemotherapies have been proven disappointing because they provide extremely low survival benefits. This study discloses that the STAT3/HIF-1α is an auspicious therapeutic attack site for conceivable repression of HCC development. A site that can be targeted by simultaneous administration of a STAT3 inhibitor in the context of HSP90 inhibition. 17-DMAG binds to HSP90 and constrains its function, resulting in the degradation of HSP90 client proteins HIF-1α and STAT3. Hypoxia recruits STAT3/HIF-1α complex within the VEGF promoter. Additionally, it was acknowledged that STAT3 is an essential mediator of VEGF transcription by direct binding to its promoter. Furthermore, it induces HIF-1α stability and enhances its transcriptional activity. Herein, we revealed that the combination therapy using 17-DMAG and nifuroxazide, a STAT3 inhibitor, repressed the diethylnitrosamine-induced alterations in the structure of the liver. This effect was mediated via decreasing the levels of the HSP90 client proteins HIF-1α and pSTAT3 resulting in the suppression of the STAT3/HIF-1α complex transcriptional activity. To conclude, 17-DMAG/NFXZD combination therapy-induced disruption in the STAT3/HIF-1α loop led to a potential antiangiogenic activity and showed apoptotic potential by inhibiting autophagy and inducing ROS/apoptosis signaling. Additionally, this combination therapy exhibited promising survival prolongation in mice with HCC. Consequently, the use of 17-DMAG/NFXZD renders an inspirational perspective in managing HCC. However, further investigations are compulsory.

Парацентез передней камеры глаза при глаукоме как метод экстренного снижения внутриглазного давления у собак и кошек

The article presents the technique of paracentesis of the anterior chamber of the eye with simultaneous intra-chamber administration of 0,5% pilocarpine solution, to identify the dynamics of intraocular pressure reduction, as well as to determine the effectiveness of this procedure both immediately after its execution and in the long term; based on the analysis of the data obtained, to determine complications. The study included 37 animals (39 eyes): 24 dogs and 13 cats with glaucoma, which, according to the anamnesis, developed no more than 10 days. without any prior hypotensive treatment. All animals underwent paracentesis without the use of general anesthesia or sedation. The procedure was performed under 6x magnification using frontal illumination, with a 27G needle for 9 hours for the right eye and for 3 hours for the left eye. The puncture was carried out on the periphery of the cornea at a distance of 1 mm from the limb. The volume of aspirated intraocular fluid was no more than 2 drops. Then a 0,5 % solution of pilocarpine was injected into the anterior chamber through the opening of the paracentesis. The volume of the injected solution did not exceed 0,3 ml. After paracentesis and pilocarpine administration, dexamethasone solution was subconjunctively instilled in combination with gentamicin and novocaine. Then hypotensive therapy was prescribed from a combination of eye drops. The study shows that the method with simultaneous intra-chamber injection of 0,5 % pilocarpine solution is effective in dogs and cats without any pronounced side effects. These results allow us to suggest anterior chamber paracentesis as a procedure for emergency reduction of intraocular pressure, especially in acute attacks of glaucoma in dogs and cats.

Dietary effects of procyanidin and Bio-Aqua® on hematological and immune indices of rainbow trout (Oncorhynchus mykiss).

The role of immunostimulants in reducing diseases and enhancing fish performance has been proven in various studies. In this study, the effects of antioxidant procyanidin and commercial probiotic Bio-Aqua® on some hematological and immune indices of rainbow trout (Oncorhynchus mykiss) were investigated. A total number of 525 fingerlings in seven treatments (each treatment in triplicates) with experimental diets, including (1) commercial food without supplements (CTL), (2) 400 mg procyanidin kg-1 feed (PC400) , (3) 800 mg procyanidin kg-1 feed (PC800), (4) 0.50% probiotic diet (PB0.5), (5) 1.00% probiotic diet (PB1), (6) probiotic and procianidin 0.50% and 800 mg kg-1 feed, respectively (PB0.5 + PC800) and (7) probiotic and procianidin 1.00% and 400 mg kg-1 feed, respectively, (PB1 + PC400) were fed for eight weeks. The results showed that the use of procyanidin alone did not have any significant effect on blood biochemistry and immune indices. However, the individual use of Bio-Aqua® probiotic could affect the hematological and immune indices of fish, except for monocyte, compared to the control and procyanidin treatments. However, the combined use of the supplements improved the hematological and immune indices of fish. It was concluded that the simultaneous dietary administration of procyanidin and probiotic Bio-Aqua® could improve the general health of rainbow trout.

Methylthioacetic acid, a derivative of aroma compounds from Cucumis melo var. conomon dose-dependently triggers differentiation and apoptosis of RCM-1 human colorectal cancer cells.

Methylthioacetic acid (MTA) is an acid-hydrolyzed derivative of a natural aroma compound, methylthioacetic acid ethyl ester isolated from Cucumis melo var. conomon (Katsura-uri, Japanese Picking Melon), and induces a villiform-like structure dome in RCM-1 human colorectal cancer cell culture. Thus far, the physiological and molecular properties of MTA-mediated dome formation remain unknown. Herein, MTA (not more than 2 mM) was demonstrated to differentiate the unorganized cell mass into the dome in RCM-1 cell culture by disclosing the correlation between dome formation and several intestinal differentiation markers such as alkaline phosphatase activity and the protein levels of dipeptidyl peptidase 4, villin, and Krüppel-like factor 4. Dome formation in RCM-1 cell culture was additively enhanced by the simultaneous administration of MTA and butyric acid (BA), suggesting that MTA directs the differentiation of RCM-1 cells, potentially through the same or similar pathway(s) shared with BA. Notably, a high dose of MTA (2 mM or more) elevated several apoptosis markers, such as DNA fragmentation, caspase-3/7 activity, and cleavage of poly(ADP-ribose) polymerase. Altogether, in addition to RCM-1 cell differentiation, MTA triggers apoptosis. These results indicate that MTA is a potential anticarcinogenic agent applicable in differentiation therapy and traditional chemotherapy against colorectal cancers.

Interaction of Phenytoin with Enteral Formulas, Proteins, and Dietary Fiber in Vitro and in Vivo

Simultaneous administration of enteral formula and phenytoin in the clinical setting is known to reduce the plasma concentration of phenytoin. In this study, we examined the binding of phenytoin with enteral formulas and its components by quantifying the free phenytoin concentration. Furthermore, we investigated the effect of enteral formulas on gastrointestinal absorption of phenytoin in rats. The free phenytoin rate was reduced in vitro when phenytoin and enteral formula or pectin, a dietary fiber in enteral formulas, were co-administered. In vivo, when phenytoin and the enteral formula Mei Balance R® were co-administered, the time to maximum plasma concentration (Tmax) after oral administration was significantly increased. Moreover, the area under the phenytoin concentration-time curve from time zero to 6 h (AUC0-6 h) was significantly increased by co-administration of phenytoin with the enteral formula PG Soft EJ®. These results showed the gastrointestinal absorption of phenytoin differs according to the type of enteral formula. In addition, we found the first time that plasma phenytoin levels increase when combined with enteral formula. Among the components of enteral formulas, in particular, milk protein delayed the absorption of phenytoin. Moreover, milk protein, casein and carrageenan tended to increase AUC0-6 h. These results suggest the change in phenytoin concentration is due not only to the binding of enteral formula but also to the disintegration of components such as protein. Therefore, when co-administrated of phenytoin and enteral formula, phenytoin must be monitored frequently according to the enteral formula interaction.

Ultrasound monitoring of the regenerative treatment of Biceps Tendonitis and Tenosynovitis in dogs by stem cells injections

Foot-and-mouth disease (FMD) and bluetongue disease (BT) are two of the most devastating viral diseases affecting domestic and wild ruminants. They cause significant economic losses, and vaccination is the most important method for combating both FMD and BT. Simultaneous vaccinations are crucial for animal welfare as well as labor and cost savings. No reports were found on the simultaneous administration of FMD and BT vaccines to sheep. This study evaluated the effect of the simultaneous administration of an inactivated FMD vaccine and an attenuated BT vaccine on the humoral immune response to both diseases. A total of 75 sixmonth- old Akkaraman-Kıvırcık crossbred sheep that did not have any vaccination history were used as research material. Before the experiment, the animals were tested for the absence of FMD and BT antibodies. The sheep were divided into three experimental groups and vaccinated with an FMD vaccine alone, a BT vaccine alone, and both. Blood samples were taken on days 30 and 60 post-vaccination. The blood samples were evaluated using liquid-phase blocking ELISA (LPBE) and virus neutralization test (VNT) for FMD antibodies, as well as competitive ELISA (c-ELISA) and VNT for BT antibodies. The study revealed that differences between the FMD and BT antibody titers of the group vaccinated simultaneously and the FMD and BT antibody titers obtained from the groups vaccinated separately were not statistically significant (p > 0.05). It was concluded that the antibody response these diseases was not altered when the FMD and BT vaccines were administered together.

Cinnamon and ginger extracts attenuate diabetes-induced inflammatory testicular injury in rats and modulating SIRT1 expression

The current study aimed to evaluate the efficacy of simultaneous administration of Zingiber officinale (ginger) and Cinnamomum cassia (cinnamon) extracts in mitigating testicular changes associated with diabetes mellitus in rats and to investigate its molecular mode of action. After induction of diabetes using streptozotocin, 36 male rats were divided to six groups namely control, diabetic, metformin-treated, cinnamon-treated, ginger-treated and combined, each group having 6 rats. Fasting blood glucose, serum insulin, testosterone was measured. Expression of inflammatory mediators; tumor necrosis factor-alpha (TNF-α), Nuclear factor kappa B (NF-κB) and Sirtuin 1 (SIRT1) was assessed in the testicular tissue. Histopathological changes in the testis were observed and spermatogenesis and apoptosis were assessed immunohistochemically. The histological and biochemical studies of the untreated group confirmed structural changes in testes induced by diabetes. Oral administration of ginger and cinnamon increased insulin level significantly increased while the blood glucose level significantly decreased in diabetic rats, improving structural testicular changes considerably. Joint intake of ginger and cinnamon increased antihyperglycemic, antioxidant and anti-inflammatory effects markedly improving the testicular injury compared to the administration of either of them. SIRT1 expression in the testis significantly increased in ginger plus cinnamon-treated rats. These results indicate that when administrated together, ginger and cinnamon synergistically enhanced antioxidant, antiapoptotic and anti-inflammatory effects and induced antihyperglycemic effect comparable to metformin. The combination of ginger and cinnamon also upregulated SIRT1 in the testis.

Presynchronization with simultaneous administration of GnRH and prostaglandin F2α (PGF2α) 7 days prior to Ovsynch improves reproductive profile in Hariana zebu cow

This study is aimed at assessing the impact of simultaneous administration of GnRH and prostaglandin F2α (PGF2α) 7days prior to Ovsynch in Hariana cow. Two hundred cyclic cows (> 4months postpartum) were assigned to control (n = 54) and pre-OV (n = 146). As per Ovsynch protocol, buserelin acetate (10μg), cloprostenol (500μg), and buserelin acetate (10μg) were injected i.m. on days 0, 7, and 9, respectively, in cows irrespective of treatment. But in pre-OV cows, buserelin acetate (10μg) and cloprostenol (500μg) were also injected i.m. simultaneously 7days prior to initiate the Ovsynch protocol. Artificial insemination was performed between 18 and 24h after the 2nd GnRH of Ovsynch in both treatments. Ultrasonography and blood sampling for hormonal analysis were done on each day of treatment, on day of AI, and 12days post-AI. Pre-OV treatment resulted to increased (45.20% vs 29.62%; P < 0.05) pregnancy outcomes and higher (P < 0.01) ovulation rate to first GnRH of Ovsynch than control. Cows showing complete luteolysis in response to PGF2α of Ovsynch were also higher (P < 0.05) in pre-OV than control. Greater (P < 0.05) synchronization rate was recorded in pre-OV than control (86.76% and 68.75%). The circulating concentrations of estradiol on day of AI and progesterone on day 12 post-AI were higher (P < 0.01) in cows diagnosed pregnant than non-pregnant in both control and pre-OV treatment. In conclusion, simultaneous administration of GnRH and PGF2α 7days before Ovsynch improved the synchronization rate and luteal profile in terms of CL area and hence resulted in higher conception rate in Hariana zebu cow.

Safety of prescribed herbal medicines for hepatic and renal function of polypharmacy patients with stroke: A single-center retrospective study

In Korea, herbal medicines (HMs) are primarily used to treat diseases. Patients with stroke are generally older and take several conventional medicines (CMs) to address other underlying diseases, which is known as polypharmacy. Therefore, there is a growing concern about hepatotoxicity and nephrotoxicity due to drug interactions between HMs and CMs. Therefore, this study retrospectively investigated liver and renal tests in patients with stroke treated with polypharmacy to clarify the safety of simultaneous HM and CM administration. The medical records of 111 patients with stroke treated at a single center and who met the inclusion criteria between March 1, 2017, and March 1, 2022, were reviewed. The HMs and HM prescription frequency, CMs, and liver and kidney test results were recorded. Additionally, the Roussel Uclaf Causality Assessment Method and Kidney Disease Improving Global Outcome scores were documented, which are standard criteria for assessing liver and kidney injury, respectively. The study included 53 men and 58 women (average age: 67.8 years). On average, the patients took 6 types of CMs. No patient showed liver injury during the co-administration of CMs and HMs. Only 1 patient had initial hepatic damage but recovered after taking HMs. Furthermore, 2 patients had liver test abnormalities 2 times the upper limit of normal, possibly from Seogyeong-tang and atorvastatin, with Roussel Uclaf Causality Assessment Method scale scores of 3 and 5, respectively. No patient had a renal injury. HM is safe for patients with stroke taking multiple CMs. However, consulting an HM expert is essential to avoid hepatotoxicity, nephrotoxicity, and other adverse effects. These results highlight the benefits of Korea's dual medical system.

New insight into GARP striking role in cancer progression: application for cancer therapy.

T regulatory cells play a crucial role in antitumor immunity suppression. Glycoprotein-A repetitions predominant (GARP), transmembrane cell surface marker, is mostly expressed on Tregs and mediates intracellular organization of transforming growth factor-beta (TGF-β). The physiological role of GARP is immune system homeostasis, while it may cause tumor development by upregulating TGF-β secretion. Despite the vast application of anti- programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte Antigen-4 (CTLA-4) antibodies in immunotherapy, anti-GARP antibodies have the advantage of better response in patients who has resistance to anti-PD-1/PD-L1. Furthermore, simultaneous administration of anti-GARP antibody and anti-PD-1/PD-L1 antibody is much more effective than anti-PD-1/PD-L1 alone. It is worth mentioning that the GARP-mTGF-β complex is more potent than secretory TGF-β to induce T helper 17 cells differentiation in HIV + patients. On the other hand, TGF-β is an effective cytokine in cancer development, and some microRNAs could control its secretion by regulating GARP. In the present review, some information is provided about the undeniable role of GARP in cancer progression and its probable importance as a novel prognostic biomarker. Anti-GARP antibodies are also suggested for cancer immunotherapy.

Precise delivery of doxorubicin and imiquimod through pH-responsive tumor microenvironment-active targeting micelles for chemo- and immunotherapy.

Recently, combining immunotherapy and chemotherapy has become a promising strategy to treat cancer. However, this therapeutic strategy still has its limitations because of the adverse effects caused by the simultaneous administration of multiple therapeutic agents. Using nanoparticles is an effective approach to successfully combine these therapies because they can reduce side effects, increase circulation time, and ensure the delivery of cytotoxic agents to tumor tissues. In this study, dual pH-sensitive and tumor microenvironment (TME)-active targeting micelles comprising poly(propyl methacrylate-co-glucosamine/histidine/doxorubicin) (P(PAA-co-GLU/HIS/DOX) and methoxy-poly(ethylene glycol)-block-poly(l-lysine) were prepared to encapsulate an immunomodulator, imiquimod (IMQ). Because these micelles can expose glucose targeting ligands at the TME and pH-dependently release IMQ and DOX, micelles effectively inhibit the growth of 4T1 cells selectively and highly accumulate in 4T1 cells as the pH decreased to 6.5. Moreover, in RAW 264.7​cells, these micelles prevent cell death and induce M1 macrophage polarization. In 4T1 orthotopic tumor-bearing mice, micelles not only exhibited high tumor accumulation, effective tumor inhibition, and fewer adverse effects, but also dramatically increased the number of mature dendritic cells, activate cytotoxic T cells, and polarize M1-like macrophages in tumor tissues. Overall, these micelles exhibit precise pH responsiveness and ideal drug delivery capabilities for combined chemo- and immunotherapy; these results significantly contribute to the future development of nanomedicines in cancer therapy.

Synergistic effect of metformin and doxorubicin on the metastatic potential of T24 cells

BackgroundThe motor ability of cancer cells to cross the basement membrane contributes to their implantation in a new location. Metastasis is a significant factor that worsens the prognosis of cancer patients. Thus, reducing cell invasiveness is an important aspect of anticancer therapy, also in bladder cancer treatment. MaterialThe study material was the T24 cell line of human urinary bladder cancer. The migratory potential of the cells and the effect of the treatment with individually doses and synergistic combination of doxorubicin and metformin in the 500:1 ratio for 24 h were analyzed. ResultsThe results obtained show a compound-initiated decrease in the motor abilities of bladder cancer cells compared to controls. A decrease in the rate of colony formation was observed, as well as inhibition of migration through inserts. The visualized reorganization of the vimentin and actin networks confirms the drug-initiated limitation of the metastatic potential of T24 cells. ConclusionAccording to our knowledge, we are the first to show, that combination of doxorubicin and metformin also worth considering in the treatment of bladder cancer. We showed that simultaneous administration of these cytostatic enhances the antiproliferative effect of drugs, but also limits cells' migratory potential.