Pharmaceuticals

Zhao, Yinghui;Roy, Souvick;Wang, Chuanxin;Goel, Ajay

doi: 10.3390/ph15030262pmid: 35337060

The high morbidity and mortality associated with colorectal cancer (CRC) are largely due to the invariable development of chemoresistance to classic chemotherapies, as well as intolerance to their significant toxicity. Many pharmaceutical formulations screened from natural plant extracts offer safe, inexpensive, and multi-target therapeutic options. In this study, we demonstrated that Berberis vulgaris L. (Berberine) and Andrographis paniculata (Burm. f.) Nees (Andrographis) extracts exerted their synergistic amplified anti-cancer effects by jointly inhibiting cell viability, suppressing colony formation, and inducing cell cycle arrest. Consistent with our in-vitro findings, the amplified synergistic anti-cancer effects were also observed in subcutaneous xenograft preclinical animal models, as well as patient-derived primary tumor organoids. To explore the molecular mechanisms underlying the amplified synergistic anti-cancer effects, RNA sequencing was performed to identify candidate pathways and genes. A transcriptome analysis revealed that DNA-replication-related genes, including FEN1, MCM7, PRIM1, MCM5, POLA1, MCM4, and PCNA, may be responsible for the enhanced anticancer effects of these two natural extracts. Taken together, our data revealed the powerful enhanced synergistic anti-CRC effects of berberine and Andrographis and provide evidence for the combinational targeting of DNA-replication-related genes as a promising new strategy for the therapeutic option in the management of CRC patients.

Jesus, Ana;Sousa, Emília;Cruz, Maria T.;Cidade, Honorina;Lobo, José M. Sousa;Almeida, Isabel F.

doi: 10.3390/ph15030263pmid: 35337062

The use of sunscreens is an established and recommended practice to protect skin from solar-induced damage. Around 30 UV filters can be used in sunscreen products in the European Union, which ought to follow the requirements of the regulation 1223/2009 to ensure their efficacy and safety for humans. Nevertheless, low photostability and putative toxicity for humans and environment have been reported for some UV filters. Particularly, the negative impact in marine organisms has recently raised concern on the scientific community. Therefore, it is important to develop new UV filters with improved safety profile and photostability. Over the last two decades, nearly 200 new compounds have revealed promising photoprotection properties. The explored compounds were obtained through different approaches, including exploration of natural sources, synthetic pathways, and nanotechnology. Almost 50 natural products and around 140 synthetic derivatives, such as benzimidazoles, benzotriazoles, hydroxycinnamic acids, xanthones, triazines, among others, have been studied aiming the discovery of novel, effective, and safer future photoprotective agents. Herein, we provide the reader with an overview about UV filters’ challenges and prospects, offering a forward-looking to the next-generation of UV filters.

Messner, Katia;Vuong, Billy;Tranmer, Geoffrey K.

doi: 10.3390/ph15030264pmid: 35337063

In this review, the history of boron’s early use in drugs, and the history of the use of boron functional groups in medicinal chemistry applications are discussed. This includes diazaborines, boronic acids, benzoxaboroles, boron clusters, and carboranes. Furthermore, critical developments from these functional groups are highlighted along with recent developments, which exemplify potential prospects. Lastly, the application of boron in the form of a prodrug, softdrug, and as a nanocarrier are discussed to showcase boron’s emergence into new and exciting fields. Overall, we emphasize the evolution of organoboron therapeutic agents as privileged structures in medicinal chemistry and outline the impact that boron has had on drug discovery and development.

Mendes, Adélia;Azevedo-Silva, João;Fernandes, João C.

doi: 10.3390/ph15030265pmid: 35337064

Squalene is a natural linear triterpene that can be found in high amounts in certain fish liver oils, especially from deep-sea sharks, and to a lesser extent in a wide variety of vegeTable oils. It is currently used for numerous vaccine and drug delivery emulsions due to its stability-enhancing properties and biocompatibility. Squalene-based vaccine adjuvants, such as MF59 (Novartis), AS03 (GlaxoSmithKline Biologicals), or AF03 (Sanofi) are included in seasonal vaccines against influenza viruses and are presently being considered for inclusion in several vaccines against SARS-CoV-2 and future pandemic threats. However, harvesting sharks for this purpose raises serious ecological concerns that the exceptional demand of the pandemic has exacerbated. In this line, the use of plants to obtain phytosqualene has been seen as a more sustainable alternative, yet the lower yields and the need for huge investments in infrastructures and equipment makes this solution economically ineffective. More recently, the enormous advances in the field of synthetic biology provided innovative approaches to make squalene production more sustainable, flexible, and cheaper by using genetically modified microbes to produce pharmaceutical-grade squalene. Here, we review the biological mechanisms by which squalene-based vaccine adjuvants boost the immune response, and further compare the existing sources of squalene and their environmental impact. We propose that genetically engineered microbes are a sustainable alternative to produce squalene at industrial scale, which are likely to become the sole source of pharmaceutical-grade squalene in the foreseeable future.

Sovrlić, Miroslav;Mrkalić, Emina;Jelić, Ratomir;Ćendić Serafinović, Marina;Stojanović, Stefan;Prodanović, Nevena;Tomović, Jovica

doi: 10.3390/ph15030266pmid: 35337065

Human serum albumin (HSA) has a very significant role in the transport of drugs, in their pharmacokinetic and pharmacodynamic properties, as well as the unbound concentration of drugs in circulating plasma. The aim of this study was to look into the competition between tigecycline (TGC) and alkaloid (ALK) (caffeine (CAF)), and flavonoids (FLAVs) (catechin (CAT), quercetin (QUE), and diosmin (DIO)) in binding to HSA in simulated physiological conditions using multiple spectroscopic measurements and docking simulations. Fluorescence analysis was used to find the binding and quenching properties of double HSA-TGC and triple HSA-TGC-CAF/FLAV systems. The conformational change of the HSA was analyzed using synchronous fluorescence spectroscopy, Fourier transform infrared spectroscopy, and circular dichroism. Obtained results of spectroscopic analyses indicate that triple complexes of HSA-TGC-CAF/FLAVs are formed without problems and have higher binding affinities than double HSA-TGC. In addition, TGC does not change the microenvironments around the tryptophan (Trp) and tyrosine (Tyr) residues in the presence of ALK and FLAVs. Ultimately, the binding affinity, competition, and interaction nature were explored by docking modeling. Computational outcomes are in good accordance with experimentally obtained results. Accordingly, concluding remarks may be very useful for potential interactions between common food components and drugs.

Eder, Ann-Christin;Matthias, Jessica;Schäfer, Martin;Schmidt, Jana;Steinacker, Nils;Bauder-Wüst, Ulrike;Domogalla, Lisa-Charlotte;Roscher, Mareike;Haberkorn, Uwe;Eder, Matthias;Kopka, Klaus

doi: 10.3390/ph15030267pmid: 35337061

The development of PSMA-targeting low-molecular-weight hybrid molecules aims at advancing preoperative imaging and accurate intraoperative fluorescence guidance for improved diagnosis and therapy of prostate cancer. In hybrid probe design, the major challenge is the introduction of a bulky dye to peptidomimetic core structures without affecting tumor-targeting properties and pharmacokinetic profiles. This study developed a novel class of PSMA-targeting hybrid molecules based on the clinically established theranostic agent PSMA-617. The fluorescent dye-bearing candidates of the strategically designed molecule library were evaluated in in vitro assays based on their PSMA-binding affinity and internalization properties to identify the most favorable hybrid molecule composition for the installation of a bulky dye. The library’s best candidate was realized with IRDye800CW providing the lead compound. Glu-urea-Lys-2-Nal-Chx-Lys(IRDye800CW)-DOTA (PSMA-927) was investigated in an in vivo proof-of-concept study, with compelling performance in organ distribution studies, PET/MRI and optical imaging, and with a strong PSMA-specific tumor uptake comparable to that of PSMA-617. This study provides valuable insights about the design of PSMA-targeting low-molecular-weight hybrid molecules, which enable further advances in the field of peptidomimetic hybrid molecule development.

Koonjan, Shazeeda;Cardoso Palacios, Carlos;Nilsson, Anders S.

doi: 10.3390/ph15030268pmid: 35337066

In this study, we looked at the population dynamics of a two phages-one host system using phages vB_EcoP_SU10 (SU10) and vB_EcoD_SU57 (SU57) and the bacteria Escherichia coli, strain ECOR57. Phage-specific growth curves were observed where infections by SU10 resulted in a moderate production of phages and infections by SU57 resulted in a fast and extensive production of phage progeny. Sequentially adding SU10 followed by SU57 did not produce a significant change in growth rates, whereas adding SU57 followed by SU10 resulted in a decrease in SU10 titer The efficiency of the plating assays showed that ECOR57 exhibited a resistance spectrum after infection by both the single and combined phages. Phage-resistant bacteria exhibited four different morphotypes (i.e., normal, slimy, edgy, and pointy). The normal and edgy morphotypes had a high frequency of developing resistance. Bacterial growth and biofilm assays indicated that the edgy and pointy morphotypes reached a stationary phase faster and produced more biofilm compared to the wild type. These findings suggest that the dynamic structure of phage–bacteria communities dictate resistance evolution and development. Understanding when and how resistances arise and phage(s)–hosts interactions could aid in the design of phage therapy treatments.

Kamaruddin, Nurjannatul Naim;Mohd Din, Lukman Hakim;Jack, Allicia;Abdul Manan, Aina Farahiyah;Mohamad, Habsah;Tengku Muhammad, Tengku Sifzizul

doi: 10.3390/ph15030269pmid: 35337067

A constantly elevated level of low-density lipoprotein cholesterol (LDL-C) is mainly associated with the development of atherosclerosis. The use of statins as a treatment for reducing plasma LDL-C levels has led, in some cases, to adverse side effects, including a decrease in hepatic LDL receptor (LDLR), the receptor responsible for the uptake of circulating LDL-C. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme responsible for directing the LDLR–LDL-C complex to lysosomal degradation upon transport into cells, preventing the recycling of LDLR to the cell surface. Therefore, PCSK9 may offer a new target for reducing the levels of plasma LDL-C. In this study, we investigated the mechanisms of action of a selected fraction of A. planci on PCSK9 gene expression, as well as the effect of the fraction on the level of LDLR protein and the uptake of LDL-C. Using real-time PCR, it was shown that the selected A. planci fraction reduced the gene expression of PCSK9 in human liver HepG2 cells. Immunocytochemistry analysis demonstrated that the selected A. planci fraction increased the LDLR protein level and LDL-C uptake in HepG2 cells. Promoter mutational and gene expression analyses revealed that PPRE, a binding site for peroxisome proliferator–activated receptor (PPAR), was responsible for mediating the inhibitory effect of the selected fraction on PCSK9 mRNA. In addition, MAP kinase and PKC components of the signal transduction pathway were activated, inducing the action of the selected A. planci fraction in decreasing PCSK9 gene expression. These findings suggest that the selected fraction shows good potential for reducing circulating LDL-C and, thus, may be a good therapeutic intervention to prevent the progression of atherosclerosis.

Toussirot, Eric

doi: 10.3390/ph15030270pmid: 35337068

Current pharmacological treatments of axial spondyloarthritis (axSpA) are limited to non-steroidal anti-inflammatory drugs (NSAIDs) and biological agents, including TNFα inhibitors and IL-17 inhibitors. Despite the availability of these agents, many patients either fail to respond adequately, lose their initial therapeutic response over time, or develop undesirable side effects, thus highlighting the need for new treatment options. Janus kinase (JAK) and signal transducers and activators of transcription (STAT) are a group of intracellular kinases that play a role in the signaling pathway induced by cytokines and certain growth factors associated with the inflammatory process of axSpA. There are several lines of evidence implicating the JAK–STAT pathway in the pathophysiological process of axSpA, including genetic data, the use of certain JAK in the intracellular signal of specific cytokines involved in axSpA (IL-23, IL-22, and IL-6), and data from experimental models of SpA. This provides a rationale for the assessment of JAK inhibitors (JAKi) in clinical trials with patients with axSpA. In this review, we examine the role of JAK–STAT signaling in the pathogenesis of axSpA and summarize the results from recent clinical trials of JAKi (tofacitinib, upadacitinib, and filgotinib) in patients with axSpA.

Qvit, Nir;Lin, Amanda J.;Elezaby, Aly;Ostberg, Nicolai P.;Campos, Juliane C.;Ferreira, Julio C. B.;Mochly-Rosen, Daria

doi: 10.3390/ph15030271pmid: 35337069

Myocardial infarction is the leading cause of cardiovascular mortality, with myocardial injury occurring during ischemia and subsequent reperfusion (IR). We previously showed that the inhibition of protein kinase C delta (δPKC) with a pan-inhibitor (δV1-1) mitigates myocardial injury and improves mitochondrial function in animal models of IR, and in humans with acute myocardial infarction, when treated at the time of opening of the occluded blood vessel, at reperfusion. Cardiac troponin I (cTnI), a key sarcomeric protein in cardiomyocyte contraction, is phosphorylated by δPKC during reperfusion. Here, we describe a rationally-designed, selective, high-affinity, eight amino acid peptide that inhibits cTnI’s interaction with, and phosphorylation by, δPKC (ψTnI), and prevents tissue injury in a Langendorff model of myocardial infarction, ex vivo. Unexpectedly, we also found that this treatment attenuates IR-induced mitochondrial dysfunction. These data suggest that δPKC phosphorylation of cTnI is critical in IR injury, and that a cTnI/δPKC interaction inhibitor should be considered as a therapeutic target to reduce cardiac injury after myocardial infarction.