Integrating bacterial molecular genetics with chemical biology for renewed antibacterial drug discovery.

The application of dyes to understanding the aetiology of infection inspired antimicrobial chemotherapy and the first wave of antibacterial drugs. The second wave of antibacterial drug discovery was driven by rapid discovery of natural products, now making up 69% of current antibacterial drugs. But now with the most prevalent natural products already discovered, ∼107 new soil-dwelling bacterial species must be screened to discover one new class of natural product. Therefore, instead of a third wave of antibacterial drug discovery, there is now a discovery bottleneck. Unlike natural products which are curated by billions of years of microbial antagonism, the vast synthetic chemical space still requires artificial curation through the therapeutics science of antibacterial drugs - a systematic understanding of how small molecules interact with bacterial physiology, effect desired phenotypes, and benefit the host. Bacterial molecular genetics can elucidate pathogen biology relevant to therapeutics development, but it can also be applied directly to understanding mechanisms and liabilities of new chemical agents with new mechanisms of action. Therefore, the next phase of antibacterial drug discovery could be enabled by integrating chemical expertise with systematic dissection of bacterial infection biology. Facing the ambitious endeavour to find new molecules from nature or new-to-nature which cure bacterial infections, the capabilities furnished by modern chemical biology and molecular genetics can be applied to prospecting for chemical modulators of new targets which circumvent prevalent resistance mechanisms.

Natural Bioactive Compounds from Macroalgae and Microalgae for the Treatment of Alzheimer's Disease: A Review.

Neuroinflammation, toxic protein aggregation, oxidative stress, and mitochondrial dysfunction are key pathways in neurodegenerative diseases like Alzheimer's disease (AD). Targeting these mechanisms with antioxidants, anti-inflammatory compounds, and inhibitors of Aß formation and aggregation is crucial for treatment. Marine algae are rich sources of bioactive compounds, including carbohydrates, phenolics, fatty acids, phycobiliproteins, carotenoids, fatty acids, and vitamins. In recent years, they have attracted interest from the pharmaceutical and nutraceutical industries due to their exceptional biological activities, which include anti-inflammation, antioxidant, anticancer, and anti-apoptosis properties. Multiple lines of evidence have unveiled the potential neuroprotective effects of these multifunctional algal compounds for application in treating and managing AD. This article will provide insight into the molecular mechanisms underlying the neuroprotective effects of bioactive compounds derived from algae based on in vitro and in vivo models of neuroinflammation and AD. We will also discuss their potential as disease-modifying and symptomatic treatment strategies for AD.

Comparing 2-day vs 3-day flu-CY lymphodepleting regimens for CD19 CAR T-cell therapy in patients with non-hodgkin's lymphoma.

Introduction: Lymphodepleting chemotherapy (LDC) is critical to CAR T-cell expansion and efficacy. Despite this, there is not a consensus in the literature regarding the optimal LDC regimen, including dose and frequency. Methods: We retrospectively reviewed consecutive patients at a single institution that received LDC prior to treatment with the CD19 directed CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel. Patients treated at our center received fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 for 3 consecutive days prior to May 2019. After this timepoint patients routinely received fludarabine 40 mg/m2 and cyclophosphamide 500 mg/m2 for 2 consecutive days. Clinical data from each cohort were obtained from the electronic medical record and compared for differences in CAR T-cell efficacy and toxicity. Results: From June 2018 to August 2023, LDC was given to 92 patients prior to CD19 directed CAR T-cell therapy for relapsed non-Hodgkin's lymphoma. Twenty-eight patients received a 3-day regimen, and 64 patients received a 2-day regimen. In the total cohort, 75% of patients received axicabtagene ciloleucel and 25% received tisagenlecleucel. The overall response rates in both the 2-day regimen group and the 3-day regimen group were similar (69% vs 75%, p= 0.21) as were the complete response rates (50% vs 54%, p=0.82). There were no significant differences between the 2-day and 3-day regimens for grade 2-4 cytokine release syndrome (55% vs 50%, p=0.82), grade 2-4 immune effector cell associated-neurotoxicity syndrome (42% vs 29%, p=0.25), or time to resolution of neutropenia or thrombocytopenia. The rate of prolonged platelet recovery lasting greater than 60 days was higher with the 3-day regimen (9% vs 27%, p=0.026). Discussion: As the number of patients eligible for CAR T-cell therapy continues to increase, optimizing each component of therapy is necessary. We show that a 2-day regimen of LDC with fludarabine and cyclophosphamide is feasible without significant impact on CAR T-cell efficacy or toxicity. Prospective studies are necessary to further determine the most effective LDC regimen.

Microbial allies: exploring fungal endophytes for biosynthesis of terpenoid indole alkaloids.

Terpenoid indole alkaloids (TIAs) are natural compounds found in medicinal plants that exhibit various therapeutic activities, such as antimicrobial, anti-inflammatory, antioxidant, anti-diabetic, anti-helminthic, and anti-tumor properties. However, the production of these alkaloids in plants is limited, and there is a high demand for them due to the increasing incidence of cancer cases. To address this research gap, researchers have focused on optimizing culture media, eliciting metabolic pathways, overexpressing genes, and searching for potential sources of TIAs in organisms other than plants. The insufficient number of essential genes and enzymes in the biosynthesis pathway is the reason behind the limited production of TIAs. As the field of natural product discovery from biological species continues to grow, endophytes are being investigated more and more as potential sources of bioactive metabolites with a variety of chemical structures. Endophytes are microorganisms (fungi, bacteria, archaea, and actinomycetes), that exert a significant influence on the metabolic pathways of both the host plants and the endophytic cells. Bio-prospection of fungal endophytes has shown the discovery of novel, high-value bioactive compounds of commercial significance. The discovery of therapeutically significant secondary metabolites has been made easier by endophytic entities' abundant but understudied diversity. It has been observed that fungal endophytes have better intermediate processing ability due to cellular compartmentation. This paper focuses on fungal endophytes and their metabolic ability to produce complex TIAs, recent advancements in this area, and addressing the limitations and future perspectives related to TIA production.

Curosurf surfactant application on preterm babies with respiratory complications-health-economic benefits.

Background: The implementation of surfactant for respiratory syndrome approbates the therapy as a revolutionary method in intensive neonatal therapy and respiratory resuscitation. It is important to investigate the costs of this treatment. Objective: The aim of the study is to analyze the data by the application of the surfactant Curosurf to preterm babies with respiratory complications and describe the treatment costs, healthcare resource utilization and evaluate economic benefits of surfactant use in the treatment of neonates with respiratory distress syndrome (RDS) and hyaline-membrane disease (HDM). Methods: A retrospective survey was performed covering 167 babies based on respiratory complications due to preterm birth and the necessity to apply a surfactant therapy. A documentary method was implemented and for each patient, an individual research protocol was filled out - a questionnaire created specifically for the purposes of the study. Results and discussion: An analysis of the data from the application of CUROSURF was made and the obtained therapeutic results were compared to expenditures for the therapy, short-term therapeutic effect, benefits and consequences of the therapy of preterm newborns with respiratory complications. The application of CUROSURF to babies with RDS resulted in the realization of net savings due to the elimination of the necessity of conducting several diagnostic and therapeutic procedures as well as their duration reduction of hospital stay, thus defining its health-economic benefits. Conclusions: The models of evaluation of cost effectiveness reveal that the medicinal product is expensive but effective from the aspect of short-term therapeutic results.

Modern paradigms in biologic sequencing of inflammatory bowel disease in Aotearoa New Zealand.

The modern treatment of inflammatory bowel disease (IBD) has evolved significantly in recent years. This includes development of new pharmacologic therapies and their implementation in clinical practice. Moderate-to-severe IBD represents a group of patients at risk of poorer outcomes, and mounting evidence suggests biologic and small molecule medications, collectively termed advanced therapies, are the most effective tools clinicians possess. Even with biologic treatment, many patients do not respond or lose response over time. Until recently, most randomised trials demonstrating efficacy and safety of biologics have been placebo-controlled with a lack of head-to-head studies. Therefore, selecting the right medication for the appropriate clinical scenario can be difficult. In addition, there is evidence of differing clinical success when positioning biologic treatments in different sequences. This is important, as one-third of patients treated with biologics will require a switch to a second agent by 12 months, and a further 20% will require a third agent. Over the years, there have been widespread calls in Aotearoa New Zealand for increasing biologic treatment options. Ustekinumab and vedolizumab received public funding for the treatment of moderate-to-severe IBD in 2023, and this has presented long-awaited opportunities for patients, but also new challenges for clinicians in regard to treatment selection. The purpose of this document is to provide guidance to clinicians on biologic selection, sequencing and optimisation for IBD. These recommendations are specific to the domestic prescribing climate, supported by the best available evidence and endorsed by the New Zealand Society of Gastroenterology IBD Working Group.

Plant Tissue Culture and Metabolite Profiling for High-Value Natural Product Synthesis.

The engineering of plant cell cultures to produce high-value natural products is suggested to be a safe, low-cost, and environmentally friendly route to produce a wide range of chemicals. Given that the expression of heterologous biosynthetic pathways in plant tissue culture is limited by a lack of detailed protocols, the biosynthesis of high-value metabolites in plant cell culture is constrained compared with that in microbes. However, both Arabidopsis thaliana and Nicotiana benthamiana can be efficiently transformed with multigene constructs to produce high-value natural products in stable plant cell cultures. This chapter provides a detailed protocol as to how to engineer the plant cell culture as bio-factories for metabolite biosynthesis.

Characterization of psoriasis patients in special body areas: real-world evidence from the Chinese Psoriasis Standardized Diagnosis and Treatment Center.

BACKGROUND: While extensive research has provided a wealth of information on psoriasis in general, there remains a critical gap in understanding the unique characteristics of psoriasis in special body areas, such as the scalp, nails, palms, and genitals. OBJECTIVE: To investigate the characterization and treatment of psoriasis patients in special body areas. METHODS: The study was a retrospective analysis of patients with psoriasis enrolled in the Psoriasis Standardized Diagnosis and Treatment Center Project between January 2020 and September 2021. RESULTS: The study encompassed 346 patients, 81% of them had psoriasis in at least two special body areas, with the nails as the most common area. Patients with genital psoriasis reported higher Dermatology Life Quality Index (DLQI) scores. A higher propensity for scalp and palmoplantar psoriasis was noted in patients with genital psoriasis. The proportion of patients treated with biologics rose, as the number of specific areas involved increased. CONCLUSIONS: Patients with genital psoriasis are more likely to have scalp and palmoplantar psoriasis. This study highlights the significant escalation in the proportion of biologics when the involvement of special body areas was ≥2.

Schisandra chinensis Bee Pollen Extract Inhibits Proliferation and Migration of Hepatocellular Carcinoma HepG2 Cells via Ferroptosis-, Wnt-, and Focal Adhesion-Signaling Pathways.

Purpose: Bee pollen possesses favorable anticancer activities. As a medicinal plant source, Schisandra chinensis bee pollen (SCBP) possesses potential pharmacological properties, such as reducing cisplatin-induced liver injury, but its anti-liver cancer effect is still rarely reported. This paper aims to investigate the effect and mechanism of SCBP extract (SCBPE) on hepatocellular carcinoma HepG2 cells. Methods: The effect of SCBPE on cell proliferation and migration of HepG2 cells was evaluated based on MTT assay, morphology observation, or scratching assay. Furthermore, tandem mass tag-based quantitative proteomics was used to study the effect mechanisms. The mRNA expression levels of identified proteins were verified by RT-qPCR. Results: Tandem mass tag-based quantitative proteomics showed that 61 differentially expressed proteins were obtained in the SCBPE group compared with the negative-control group: 18 significantly downregulated and 43 significantly upregulated proteins. Bioinformatic analysis showed the significantly enriched KEGG pathways were predominantly ferroptosis-, Wnt-, and hepatocellular carcinoma-signaling ones. Protein-protein interaction network analysis and RT-qPCR validation revealed SCBPE also downregulated the focal adhesion-signaling pathway, which is abrogated by PF-562271, a well-known inhibitor of FAK. Conclusion: This study confirmed SCBPE suppressed the cell proliferation and migration of hepatocellular carcinoma HepG2 cells, mainly through modulation of ferroptosis-, Wnt-, hepatocellular carcinoma-, and focal adhesion-signaling pathways, providing scientific data supporting adjuvant treatment of hepatocellular carcinoma using SCBP.

Boosting the Anti-Helicobacter Efficacy of Azithromycin through Natural Compounds: Insights From In Vitro, In Vivo, Histopathological, and Molecular Docking Investigations.

BACKGROUND: Antimicrobial-resistant Helicobacter pylori (H. pylori) poses a significant public health concern, especially given the limited therapeutic options for azithromycin-resistant strains. Hence, there is a necessity for new studies to reconsider the use of azithromycin, which has diminished in effectiveness against numerous strains. Thus, we aimed to augment azithromycin's anti-Helicobacter properties by combining it with curcumin in different formulations, including curcumin in clove oil, curcumin nano-gold emulsion, and curcumin nanoemulsion. METHODS: The antimicrobial activities of the investigated compounds, both individually and in combination with other anti-Helicobacter drugs, were evaluated. Their antibiofilm and anti-virulence properties were assessed using both phenotypic and genotypic methods, alongside molecular docking studies. Our findings were further validated through mouse protection assays and histopathological analysis. RESULTS: We observed high anti-Helicobacter activities of curcumin, especially curcumin nanoemulsion. A synergistic effect was detected between curcumin nanoemulsion and azithromycin with fraction inhibitory concentration index (FICI) values <0.5. The curcumin nanoemulsion was the most active anti-biofilm and anti-virulence compound among the examined substances. The biofilm-correlated virulence genes (babA and hopQ) and ureA genes were downregulated (fold change <1) post-treatment with curcumin nanoemulsion. On the protein level, the anti-virulence activities of curcumin nanoemulsion were documented based on molecular docking studies. These findings aligned with histopathological scoring of challenge mice, affirming the superior efficacy of curcumin nanoemulsion/azithromycin combination. CONCLUSION: The anti-Helicobacter activities of all curcumin physical forms pose significant challenges due to their higher  minimum inhibitory concentration (MIC) values exceeding the maximum permissible level. However, using curcumin nanoemulsion at sub-MIC levels could enhance the anti-Helicobacter activity of azithromycin and exhibit anti-virulence properties, thereby improving patient outcomes and addressing resistant pathogens. Therefore, more extensive studies are necessary to assess the safety of incorporating curcumin nanoemulsion into H. pylori treatment.

Biological Activity of Natural and Synthetic Peptides as Anticancer Agents.

Cancer is one of the leading causes of morbidity and death worldwide, making it a serious global health concern. Chemotherapy, radiotherapy, and surgical treatment are the most used conventional therapeutic approaches, although they show several side effects that limit their effectiveness. For these reasons, the discovery of new effective alternative therapies still represents an enormous challenge for the treatment of tumour diseases. Recently, anticancer peptides (ACPs) have gained attention for cancer diagnosis and treatment. ACPs are small bioactive molecules which selectively induce cancer cell death through a variety of mechanisms such as apoptosis, membrane disruption, DNA damage, immunomodulation, as well as inhibition of angiogenesis, cell survival, and proliferation pathways. ACPs can also be employed for the targeted delivery of drugs into cancer cells. With over 1000 clinical trials using ACPs, their potential for application in cancer therapy seems promising. Peptides can also be utilized in conjunction with imaging agents and molecular imaging methods, such as MRI, PET, CT, and NIR, improving the detection and the classification of cancer, and monitoring the treatment response. In this review we will provide an overview of the biological activity of some natural and synthetic peptides for the treatment of the most common and malignant tumours affecting people around the world.

ARE WE READY FOR MULTIPLE SWITCHES BETWEEN REFERENCE PRODUCTS AND BIOSIMILARS?

Inflammatory bowel diseases (IBD) currently impose an immense social and economic burden on society in terms of both direct and indirect healthcare costs. Their incurable and progressive nature results in an unavoidable lifetime expense. The introduction of infliximab more than two decades ago had revolutionized IBD treatment. Nowadays, while biologic drugs comprise various vital therapeutic options for patients, they can be associated to significant costs to healthcare systems. The most crucial benefit of biosimilars is that they bring more significant cost reduction and increase access to advanced therapies. They also allow the treatment of newly diagnosed patients and dose optimization for those who need it. There is an inverse relationship between price and demand for treatment with biologics. For a more significant reduction in cost to be possible, greater use of biosimilars is necessary. For this to occur, it is imperative not only to use biosimilars in naïve patients but also to switch to biosimilars in those patients who have started therapy with reference biologics. At present, randomized and observational studies have demonstrated effectiveness and safety results in recommending a single switch between a reference product and a biosimilar, and vice versa. The purpose of this manuscript is to review the literature and discuss whether scientific evidence is enough to support multiple switches of biologics and biosimilars in IBD patients.

Chemical language modeling with structured state space sequence models.

Generative deep learning is reshaping drug design. Chemical language models (CLMs) - which generate molecules in the form of molecular strings - bear particular promise for this endeavor. Here, we introduce a recent deep learning architecture, termed Structured State Space Sequence (S4) model, into de novo drug design. In addition to its unprecedented performance in various fields, S4 has shown remarkable capabilities to learn the global properties of sequences. This aspect is intriguing in chemical language modeling, where complex molecular properties like bioactivity can 'emerge' from separated portions in the molecular string. This observation gives rise to the following question: Can S4 advance chemical language modeling for de novo design? To provide an answer, we systematically benchmark S4 with state-of-the-art CLMs on an array of drug discovery tasks, such as the identification of bioactive compounds, and the design of drug-like molecules and natural products. S4 shows a superior capacity to learn complex molecular properties, while at the same time exploring diverse scaffolds. Finally, when applied prospectively to kinase inhibition, S4 designs eight of out ten molecules that are predicted as highly active by molecular dynamics simulations. Taken together, these findings advocate for the introduction of S4 into chemical language modeling - uncovering its untapped potential in the molecular sciences.

No difference in clinical parameters and drug retention in PsA patients receiving b/tsDMARD monotherapy versus combination with methotrexate: data from the RABBIT-SpA registry.

BACKGROUND: The potential benefit of methotrexate (MTX) in combination with biologic (b) and targeted synthetic (ts) disease modifying anti-rheumatic drugs (DMARDs) in psoriatic arthritis (PsA) is still a matter of debate. OBJECTIVES: To compare clinical and patient reported characteristics as well as drug retention rates in PsA patients receiving b/tsDMARD monotherapy or in combination with MTX. METHODS: RABBIT-SpA is a prospective longitudinal cohort study including axSpA and PsA patients. In this analysis, PsA patients were stratified into two groups: starting b/tsDMARD as monotherapy or in combination with MTX. Treatment retention was compared by drug survival analysis. RESULTS: 69% of the patients (n=900) started b/tsDMARD as monotherapy while 31% were treated in combination with MTX (n=405). At baseline, clinical domains like skin, nail and joint affection, dactylitis, enthesitis and axial involvement were similar between the groups. Only the patients' satisfaction concerning tolerability of the previous treatment was significantly better in the combination group at treatment start. Drug retention rates did not differ between the groups (p=0.4). At 6/12 months, 66%/48% of patients in monotherapy and 67%/48% in the combination group were still on their original treatment. CONCLUSIONS: We did not identify any clinical parameters with notable influence on the choice of b/tsDMARD mono or MTX-combination therapy in PsA. Drug retention rates are similar between mono and combination therapy. It seems that the decision to continue MTX at initiation of b/tsDMARDs is mostly based on the subjective tolerability of MTX treatment.

Microbiota, natural products, and human health: exploring interactions for therapeutic insights.

The symbiotic relationship between the human digestive system and its intricate microbiota is a captivating field of study that continues to unfold. Comprising predominantly anaerobic bacteria, this complex microbial ecosystem, teeming with trillions of organisms, plays a crucial role in various physiological processes. Beyond its primary function in breaking down indigestible dietary components, this microbial community significantly influences immune system modulation, central nervous system function, and disease prevention. Despite the strides made in microbiome research, the precise mechanisms underlying how bacterial effector functions impact mammalian and microbiome physiology remain elusive. Unlike the traditional DNA-RNA-protein paradigm, bacteria often communicate through small molecules, underscoring the imperative to identify compounds produced by human-associated bacteria. The gut microbiome emerges as a linchpin in the transformation of natural products, generating metabolites with distinct physiological functions. Unraveling these microbial transformations holds the key to understanding the pharmacological activities and metabolic mechanisms of natural products. Notably, the potential to leverage gut microorganisms for large-scale synthesis of bioactive compounds remains an underexplored frontier with promising implications. This review serves as a synthesis of current knowledge, shedding light on the dynamic interplay between natural products, bacteria, and human health. In doing so, it contributes to our evolving comprehension of microbiome dynamics, opening avenues for innovative applications in medicine and therapeutics. As we delve deeper into this intricate web of interactions, the prospect of harnessing the power of the gut microbiome for transformative medical interventions becomes increasingly tantalizing.

[Research progress in targeting DNA G-quadruplexes using natural products].

DNA G-quadruplex(G4) is a guanine-rich single-stranded DNA sequence that spontaneously folds into a spherical four-stranded DNA secondary structure in oncogene promoter sequences and telomeres. G4s are highly associated with the occurrence and development of cancer and have emerged as promising anticancer targets. Natural products have long been important sources of anticancer drug development. In recent years, significant progress has been made in the discovery of natural drugs targeting DNA G4s, with many DNA G4s have been confirmed as promising targets of natural products, including MYC-G4, KRAS-G4, PDGFR-ß-G4, BCL-2-G4, VEGF-G4, and telomeric G4. This review summarizes the research progress in discovering natural small molecules that target DNA G4s and their binding mechanisms. It also discusses the opportunities of and challenges in developing drugs targeting DNA G4s. This review will serve as a valuable reference for the research on natural products, particularly in the development of novel antitumor medications.

Recalcitrant Folliculitis Decalvans Treatment Outcomes With Biologics and Small Molecule Inhibitors.

Folliculitis decalvans (FD) is a rare primary neutrophilic cicatricial alopecia that commonly displays resistance to traditional therapies and remains challenging to treat. Currently, data are lacking with recommendations for therapy-recalcitrant FD. A systematic review was conducted to analyze biologics, small molecule inhibitors, tumor necrosis factor (TNF) inhibitors, Janus kinase (JAK) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and monoclonal antibodies utilized in the treatment of recalcitrant FD.

Natural Bioactive Compounds in the Management of Periodontal Diseases: A Comprehensive Review.

Periodontal diseases, chronic inflammatory conditions affecting oral health, are primarily driven by microbial plaque biofilm and the body's inflammatory response, leading to tissue damage and potential tooth loss. These diseases have significant physical, psychological, social, and economic impacts, necessitating effective management strategies that include early diagnosis, comprehensive treatment, and innovative therapeutic approaches. Recent advancements in biomanufacturing have facilitated the development of natural bioactive compounds, such as polyphenols, terpenoids, alkaloids, saponins, and peptides, which exhibit antimicrobial, anti-inflammatory, and tissue regenerative properties. This review explores the biomanufacturing processes-microbial fermentation, plant cell cultures, and enzymatic synthesis-and their roles in producing these bioactive compounds for managing periodontal diseases. The integration of these natural compounds into periodontal therapy offers promising alternatives to traditional treatments, potentially overcoming issues like antibiotic resistance and the disruption of the natural microbiota, thereby improving patient outcomes.