Natural-product-based, carrier-free, noncovalent nanoparticles for tumor chemo-photodynamic combination therapy.

Cancer, with its diversity, heterogeneity, and complexity, is a significant contributor to global morbidity, disability, and mortality, highlighting the necessity for transformative treatment approaches. Photodynamic therapy (PDT) has aroused continuous interest as a viable alternative to conventional cancer treatments that encounter drug resistance. Nanotechnology has brought new advances in medicine and has shown great potential in drug delivery and cancer treatment. For precise and efficient therapeutic utilization of such a tumor therapeutic approach with high spatiotemporal selectivity and minimal invasiveness, the carrier-free noncovalent nanoparticles (NPs) based on chemo-photodynamic combination therapy is essential. Utilizing natural products as the foundation for nanodrug development offers unparalleled advantages, including exceptional pharmacological activity, easy functionalization/modification, and well biocompatibility. The natural-product-based, carrier-free, noncovalent NPs revealed excellent synergistic anticancer activity in comparison with free photosensitizers and free bioactive natural products, representing an alternative and favorable combination therapeutic avenue to improve therapeutic efficacy. Herein, a comprehensive summary of current strategies and representative application examples of carrier-free noncovalent NPs in the past decade based on natural products (such as paclitaxel, 10-hydroxycamptothecin, doxorubicin, etoposide, combretastatin A4, epigallocatechin gallate, and curcumin) for tumor chemo-photodynamic combination therapy. We highlight the insightful design and synthesis of the smart carrier-free NPs that aim to enhance PDT efficacy. Meanwhile, we discuss the future challenges and potential opportunities associated with these NPs to provide new enlightenment, spur innovative ideas, and facilitate PDT-mediated clinical transformation.

Black Truffle Extract Exerts Antidiabetic Effects through Inhibition of Inflammation and Lipid Metabolism Regulation.

Black truffle, a culinary and medical fungus, is highly valued worldwide for its nutritional and therapeutic importance. To enhance the existing knowledge about the beneficial properties, this study investigates the antioxidant, antihyperlipidemic, and anti-inflammatory effects of black truffle extract in in vitro biochemical assays and animal study. Briefly, black truffle extract was administered orally to treat streptozotocin- (STZ-) induced diabetic Wistar rats for 45 days. At the end of the experimental duration, rats were sacrificed to perform biochemical and gene expression analyses related to lipid regulatory and inflammatory pathways. Our results indicated that total cholesterol, triglycerides, free fatty acids, phospholipids, and low-density lipoprotein in different tissues and circulation were significantly increased in diabetic rats. Furthermore, the ß-hydroxy ß-methylglutaryl-CoA enzyme was also significantly increased; lipoprotein lipase and lecithin-cholesterol acyltransferase enzymes were significantly decreased in diabetic rats. However, the above conditions were reversed upon black truffle extract feeding. Furthermore, black truffle extract was also found to downregulate the expression of proinflammatory cytokines (tumor necrosis factor-α and interleukin-6) and lipid regulatory genes (serum regulatory element-binding protein-1 and fatty acid synthase). The truffle extract-treated effects were comparable to glibenclamide and medication commonly used to treat diabetes mellitus. Overall, our results suggested that black truffle possesses strong antihyperlipidemic and anti-inflammatory effects on diabetic rats. These findings will enhance the current knowledge about the therapeutic importance of black truffles. They might be exploited as a possible food supplement or even as a natural source of pharmaceutical agents for diabetes prevention and treatment.

Clinical translation of advanced colonic drug delivery technologies.

Targeted drug delivery to the colon offers a myriad of benefits, including treatment of local diseases, direct access to unique therapeutic targets and the potential for increasing systemic drug bioavailability and efficacy. Although a range of traditional colonic delivery technologies are available, these systems exhibit inconsistent drug release due to physiological variability between and within individuals, which may be further exacerbated by underlying disease states. In recent years, significant translational and commercial advances have been made with the introduction of new technologies that incorporate independent multi-stimuli release mechanisms (pH and/or microbiota-dependent release). Harnessing these advanced technologies offers new possibilities for drug delivery via the colon, including the delivery of biopharmaceuticals, vaccines, nutrients, and microbiome therapeutics for the treatment of both local and systemic diseases. This review details the latest advances in colonic drug delivery, with an emphasis on emerging therapeutic opportunities and clinical technology translation.

The natural product berberine synergizes with osimertinib preferentially against MET-amplified osimertinib-resistant lung cancer via direct MET inhibition.

Berberine is a natural product that has long been used in traditional Chinese medicine due to its antimicrobial, anti-inflammatory and metabolism-regulatory properties. Osimertinib is the first third-generation EGFR-tyrosine kinase inhibitor (TKI) approved for the treatment of non-small cell lung cancer (NSCLC) with activating EGFR mutations and those resistant to earlier generation EGFR-TKIs due to a T790M mutation. However, emergence of acquired resistance to osimertinib limits its long-term efficacy in the clinic. One known mechanism of acquired resistance to osimertinib and other EGFR-TKIs is MET (c-MET) gene amplification. Here, we report that berberine, when combined with osimertinib, synergistically and selectively decreased the survival of several MET-amplified osimertinib-resistant EGFR mutant NSCLC cell lines with enhanced induction of apoptosis likely through Bim elevation and Mcl-1 reduction. Importantly, this combination effectively enhanced suppressive effect on the growth of MET-amplified osimertinib-resistant xenografts in nude mice and was well tolerated. Molecular modeling showed that berberine was able to bind to the kinase domain of non-phosphorylated MET, occupy the front of the binding pocket, and interact with the activation loop, in a similar way as other known MET inhibitors do. MET kinase assay showed clear concentration-dependent inhibitory effects of berberine against MET activity, confirming its kinase inhibitory activity. These findings collectively suggest that berberine can act as a naturally-existing MET inhibitor to synergize with osimertinib in overcoming osimertinib acquired resistance caused by MET amplification.

Pharmacological Approaches to Attenuate Inflammation and Obesity with Natural Products Formulations by Regulating the Associated Promoting Molecular Signaling Pathways.

Obesity is a public health problem characterized by increased body weight due to abnormal adipose tissue expansion. Bioactive compound consumption from the diet or intake of dietary supplements is one of the possible ways to control obesity. Natural products with adipogenesis-regulating potential act as obesity treatments. We evaluated the synergistic antiangiogenesis, antiadipogenic and antilipogenic efficacy of standardized rebaudioside A, sativoside, and theasaponin E1 formulations (RASE1) in vitro in human umbilical vein endothelial cells (HUVECs), 3T3-L1 preadipocytes respectively, and in vivo using a high-fat and carbohydrate diet-induced obesity mouse model. Orlistat was used as a positive control, while untreated cells and animals were normal controls (NCs). Adipose tissue, liver, and blood were analyzed after dissection. Extracted stevia compounds and green tea seed saponin E1 exhibited pronounced antiobesity effects when combined. RASE1 inhibited HUVEC proliferation and tube formation by suppressing VEGFR2, NF-κB, PIK3, and-catenin beta-1 expression levels. RASE1 inhibited 3T3-L1 adipocyte differentiation and lipid accumulation by downregulating adipogenesis- and lipogenesis-promoting genes. RASE1 oral administration reduced mouse body and body fat pad weight and blood cholesterol, TG, ALT, AST, glucose, insulin, and adipokine levels. RASE1 suppressed adipogenic and lipid metabolism gene expression in mouse adipose and liver tissues and enhanced AMP-activated protein kinase levels in liver and adipose tissues and in serum adiponectin. RASE1 suppressed the NF-κB pathway and proinflammatory cytokines IL-10, IL-6, and TNF-α levels in mice which involve inflammation and progression of obesity. The overall results indicate RASE1 is a potential therapeutic formulation and functional food for treating or preventing obesity and inflammation.

Design of Biopharmaceutical Formulations Accelerated by Machine Learning.

In addition to activity, successful biological drugs must exhibit a series of suitable developability properties, which depend on both protein sequence and buffer composition. In the context of this high-dimensional optimization problem, advanced algorithms from the domain of machine learning are highly beneficial in complementing analytical screening and rational design. Here, we propose a Bayesian optimization algorithm to accelerate the design of biopharmaceutical formulations. We demonstrate the power of this approach by identifying the formulation that optimizes the thermal stability of three tandem single-chain Fv variants within 25 experiments, a number which is less than one-third of the experiments that would be required by a classical DoE method and several orders of magnitude smaller compared to detailed experimental analysis of full combinatorial space. We further show the advantage of this method over conventional approaches to efficiently transfer historical information as prior knowledge for the development of new biologics or when new buffer agents are available. Moreover, we highlight the benefit of our technique in engineering multiple biophysical properties by simultaneously optimizing both thermal and interface stabilities. This optimization minimizes the amount of surfactant in the formulation, which is important to decrease the risks associated with corresponding degradation processes. Overall, this method can provide high speed of converging to optimal conditions, the ability to transfer prior knowledge, and the identification of new nonlinear combinations of excipients. We envision that these features can lead to a considerable acceleration in formulation design and to parallelization of operations during drug development.

Neuro-nutraceuticals: Natural products nourish the brain but be aware of contrary effects.

In this Special Issue on "Nutraceuticals: Molecular and Functional Insights into how Natural Products Nourish the Brain", the editors bring together contributions from experts in nutraceutical research to provide a contemporary overview of how select chemically identified molecules from natural products can beneficially affect brain function at the molecular level. Other contributions address the holistic benefit of herbal medicines and their multi-targeted actions, which improve brain function in diverse cellular and animal models of brain injury. Not only are new targets for nutraceuticals reported, but their benefits on neurobehavioural problems are elucidated in conditions as diverse as obesity and menopause. Inflammation in neuropathologies, including Alzheimer's disease (AD), remains a huge focus and diverse nutraceuticals demonstrate therapeutic applicability via glial-mediated actions. While contrary actions should be borne in mind in the search for novel neurotherapeutics, the great promise offered by herbal medicines and their newly identified active principles offers unique options for the management of diverse neurological and psychiatric conditions.

Rationalization of Mushroom-Based Preventive and Therapeutic Approaches to COVID-19: Review.

Since December 2019, a de novo pattern of pneumonia, later named coronavirus disease 2019 (COVID-19), has caused grave upset throughout the global population. COVID-19 is associated with several comorbidities; thus, preventive and therapeutic strategies targeting those comorbidities along with the causative agent, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), seem imperative. In this state-of-the-art review, edible and medicinal mushrooms are featured in the treatment of SARS-CoV-2, COVID-19 pathomanifestations, and comorbid issues. Because this is not an original research article, we admit our shortcomings in inferences. Yet we are hopeful that mushroom-based therapeutic approaches can be used to achieve a COVID-free world. Among various mushroom species, reishi or lingzhi (Ganoderma lucidum) seem most suitable as anti-COVID agents for the global population.

Biologic therapy for amyloid A amyloidosis secondary to rheumatoid arthritis treated with interleukin 6 therapy: Case report and review of literature.

INTRODUCTION: Secondary amyloidosis is a rare complication of rheumatoid arthritis (RA) that is histologically characterized by the deposition of amyloid fibrils in target organs, such as the kidneys and gastrointestinal tract. Controlling the inflammatory response is essential to prevent organ dysfunction in amyloid A (AA) amyloidosis secondary to RA, and no clear treatment strategy exists. PATIENT CONCERNS AND DIAGNOSIS: A 66-year-old woman with RA, who had been treated with disease-modifying anti-rheumatic drugs for 1 year, presented with recurrent abdominal pain and prolonged diarrhea. Endoscopy showed chronic inflammation, and colon tissue histology confirmed AA amyloidosis. INTERVENTIONS AND OUTCOMES: After tocilizumab therapy was begun, her diarrhea and abdominal pain subsided, and articular symptoms improved. Biologic drugs for RA have been used in patients with secondary AA amyloidosis, including tumor necrosis factor and Janus kinase inhibitors, interleukin 6 blockers, and a T cell modulator. Here, we systematically review existing case reports and compare the outcomes of RA-related AA amyloidosis after treatment with various drugs. CONCLUSION: The data indicate that biologic drugs like tocilizumab might be treatments of choice for AA amyloidosis secondary to RA.

Saffron Pre-Treatment Promotes Reduction in Tissue Inflammatory Profiles and Alters Microbiome Composition in Experimental Colitis Mice.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with an incompletely understood pathogenesis. Long-standing colitis is associated with increased risk of colon cancer. Despite the availability of various anti-inflammatory and immunomodulatory drugs, many patients fail to respond to pharmacologic therapy and some experience drug-induced adverse events. Dietary supplements, particularly saffron (Crocus sativus), have recently gained an appreciable attention in alleviating some symptoms of digestive diseases. In our study, we investigated whether saffron may have a prophylactic effect in a murine colitis model. Saffron pre-treatment improved the gross and histopathological characteristics of the colonic mucosa in murine experimental colitis. Treatment with saffron showed a significant amelioration of colitis when compared to the vehicle-treated mice group. Saffron treatment significantly decreased secretion of serotonin and pro-inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6, in the colon tissues by suppressing the nuclear translocation of NF-κB. The gut microbiome analysis revealed distinct clusters in the saffron-treated and untreated mice in dextran sulfate sodium (DSS)-induced colitis by visualization of the Bray-Curtis diversity by principal coordinates analysis (PCoA). Furthermore, we observed that, at the operational taxonomic unit (OTU) level, Cyanobacteria were depleted, while short-chain fatty acids (SCFAs), such as isobutyric acid, acetic acid, and propionic acid, were increased in saffron-treated mice. Our data suggest that pre-treatment with saffron inhibits DSS-induced pro-inflammatory cytokine secretion, modulates gut microbiota composition, prevents the depletion of SCFAs, and reduces the susceptibility to colitis.

Multi-Electrode Array of Sensory Neurons as an In Vitro Platform to Identify the Nociceptive Response to Pharmaceutical Buffer Systems of Injectable Biologics.

PURPOSE: Pharmaceutical buffer systems, especially for injectable biologics such as monoclonal antibodies, are an important component of successful FDA-approved medications. Clinical studies indicate that buffer components may be contributing factors for increased injection site pain. METHODS: To determine the potential nociceptive effects of clinically relevant buffer systems, we developed an in vitro multi-electrode array (MEA) based recording system of rodent dorsal root ganglia (DRG) sensory neuron cell culture. This system monitors sensory neuron activity/firing as a surrogate of nociception when challenged with buffer components used in formulating monoclonal antibodies and other injectable biologics. RESULTS: We show that citrate salt and citrate mannitol buffer systems cause an increase in mean firing rate, burst frequency, and burst duration in DRG sensory neurons, unlike histidine or saline buffer systems at the same pH value. Lowering the concentration of citrate leads to a lower firing intensity of DRG sensory neurons. CONCLUSION: Increased activity/firing of DRG sensory neurons has been suggested as a key feature underlying nociception. Our results support the utility of an in vitro MEA assay with cultured DRG sensory neurons to probe the nociceptive potential of clinically relevant buffer components used in injectable biologics.

Computational study on novel natural inhibitors targeting BCL2.

Ideal lead compounds and candidate drugs with inhibitory effect on BCL2 were screened from ZINC database, which laid a foundation for drug development and compound improvement of drug treatment for diffuse large B-cell lymphoma (DLCBL). Identification of potential BCL2 inhibitors by computer-aided virtual screening. Libdock was applied to 17,931 compounds and the top 20 were selected for further analysis. Selected compounds were performed absorption, distribution, metabolism, and excretion (ADME) and toxicity prediction. The binding affinity between the selected ligands and BCL2 was confirmed by Molecular docking. The new natural compounds, ZINC00000255131 and ZINC00013298233, were found to bind closely with BCL2. Furthermore, they all scored lower in ames-induced mutagenicity, rodent carcinogenicity, non-developmental toxicity potential, and cytochrome P4502D6 tolerance. Molecular dynamics simulation shows that the combinations of ZINC00000255131 and ZINC00013298233 with BCL2 in the natural environment are more stable. Two new compounds, ZINC00000255131 and ZINC00013298233, were found to be potential inhibitors of BCL2. These compounds have been proved to be safe, which is of great significance for the development and improvement of DLCBL drugs.

Glutathione-Conjugated Hydrogels: Flexible Vehicles for Personalized Treatment of Bacterial Infections.

PURPOSE: Skin and soft tissue infections are increasingly prevalent and often complicated by potentially fatal therapeutic hurdles, such as poor drug perfusion and antibiotic resistance. Delivery vehicles capable of versatile loading may improve local bioavailability and minimize systemic toxicities yet such vehicles are not clinically available. Therefore, we aimed to expand upon the use of glutathione-conjugated poly(ethylene glycol) GSH-PEG hydrogels beyond protein delivery and evaluate the ability to deliver traditional therapeutic molecules. METHODS: PEG and GSH-PEG hydrogels were prepared using ultraviolet light (UV)-polymerization. Hydrogel loading and release of selected drug candidates was examined using UV-visible spectrometry. Therapeutic molecules and GST-fusion protein loading was examined using UV-visible and fluorescent spectrometry. Efficacy of released meropenem was assessed against meropenem-sensitive and -resistant P. aeruginosa in an agar diffusion bioassay. RESULTS: For all tested agents, GSH-PEG hydrogels demonstrated time-dependent loading whereas PEG hydrogels did not. GSH-PEG hydrogels released meropenem over 24 h. Co-loading of biologic and traditional therapeutics into a single vehicle was successfully demonstrated. Meropenem-loaded GSH-PEG hydrogels inhibited the growth of meropenem-sensitive and resistant P. aeruginosa isolates. CONCLUSION: GSH ligands within GSH-PEG hydrogels allow loading and effective delivery of charged therapeutic agents, in addition to biologic therapeutics.

Pharmacokinetics and tissue distribution of cantharidin after oral administration of aqueous extracts from Mylabris in rats.

A sensitive gas chromatography-mass spectroscopy method was established for the determination of cantharidin (CTD) in rat plasma and liver homogenates. During the experiment, rats were randomly divided into two groups (low, high) and were administered aqueous extract of Mylabris compound for 7 days. Then, plasma and tissue samples were taken at different time points to study the pharmacokinetics and tissue distribution of CTD in rats. The selected reaction monitoring transitions for CTD and clofibrate (internal standard) were m/z 128 → 85 and m/z 169 → 141, respectively. The calibration curve ranged from 10.26 to 3,078 ng/ml for plasma and from 10.26 to 246.24 ng/ml for liver homogenates. The lower limits of quantification were 10.26 ng/ml for both plasma and liver. The intra- and inter-day precision and accuracy were <20% for both plasma and liver homogenates. Extraction recovery ranged from 89.21 to 103.61% for CTD in rat plasma and liver and from 83.79 to 102.74% for IS in rat plasma and liver. Matrix effects ranged from 93.06 to 110.44% for CTD and from 91.65 to 110.80% for IS.

Network pharmacology-based evaluation of natural compounds with paclitaxel for the treatment of metastatic breast cancer.

Metastatic breast cancer is a prevalent life-threatening disease. Paclitaxel (PTX) is widely used in metastatic breast cancer therapy, but the side effects limit its chemotherapeutic application. Multidrug strategies have recently been used to maximize potency and decrease the toxicity of a particular drug by reducing its dosage. Therefore, we have evaluated the combined anti-cancerous effect of PTX with tested natural compounds (andrographolide (AND), silibinin (SIL), mimosine (MIM) and trans-anethole (TA)) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, trypan blue dye exclusion assay, proliferating cell nuclear antigen (PCNA) staining, network pharmacology, molecular docking, molecular dynamics (MD) and in vivo chick chorioallantoic membrane (CAM) angiogenesis assay. We observed a reduction in the IC50 value of PTX with tested natural compounds. Further, the network pharmacology-based analysis of compound-disease-target (C-D-T) network showed that PTX, AND, SIL, MIM and TA targeted 55, 61, 56, 31 and 18 proteins of metastatic breast cancer, respectively. Molecular docking results indicated that AND and SIL inhibited the C-D-T network's core target kinase insert domain receptor (KDR) protein more effectively than others. While MD showed that the binding of AND with KDR was stronger and more stable than others. In trypan blue dye exclusion assay and PCNA staining, AND and SIL along with PTX were found to be more effective than PTX alone. CAM assay results suggested that AND, SIL and TA increase the anti-angiogenic potential of PTX. Thus, natural compounds can be used to improve the anti-cancer potential of PTX.

A safety review of biologic therapies for the management of hidradenitis suppurativa and unmet needs.

INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disorder characterized by nodules, abscesses, fistulae, and significant scarring in intertriginous areas rich in apocrine glands. Immunomodulator drugs, including biologics, are a mainstay of treatment for this disease. AREAS COVERED: This review details the safety profiles of various biologic therapies currently available commercially that have been tried for HS as assessed in clinical trials and observational studies. As the only Food and Drug Administration (FDA)-approved medication for the treatment of moderate-to-severe HS, adalimumab is discussed in the most detail. Additional biologic medications, including tumor necrosis factor α (TNFα) inhibitors, interleukin 1 (IL-1) inhibitors, IL-12 and IL-23 inhibitors, IL-17 inhibitors, and IL-23 inhibitors, are discussed as well. Safety concerns in special populations, including pregnant women and children, are outlined. EXPERT OPINION: Existing data support excellent short-term and long-term safety profiles for adalimumab, although caution must be taken with use in high-risk patient populations, including those with chronic infections or increased risk of malignancy. Based on their safety data for other indications, additional biologic agents appear safe in HS as well. However, further research is needed to fully understand the safety profiles of these medications in the HS population.

Factors affecting persistence with biologic treatments in patients with rheumatoid arthritis: a systematic literature review.

Introduction: Biologic treatments are a milestone in the management of rheumatoid arthritis (RA) patients with an inadequate response to conventional synthetic treatments. With the increase in the number of biologic treatments, predictor factors of discontinuation are needed to choose the right treatment for the right patient.Areas covered: In this article, the factors affecting persistence with biologic treatments will be covered: factors associated with the demographic characteristics and comordidities of the patients, those with the characteristics of the disease, the biomarkers, and the adherence.Expert opinion: Seeking factors affecting persistence with biologic treatments is an important field of clinical research to offer the best management to the RA patients. Personalized medicine is the ultimate goal in this field to choose the biological therapy with the highest persistence for every patient. To achieve this goal, biomarkers could be a milestone.

Considering a Biologic: What's a Clinician to Do? Management of Biologics in Surgery, Vaccinations, and Cancer.

In the past two decades, biologic therapy has become ubiquitous in the treatment of psoriasis; however, important considerations should be taken with regard to biologic use in the context of surgery, vaccinations, and cancers. With conflicting evidence on the effects of perioperative biologic use, we recommend withholding tumor necrosis factor alpha (TNF-α) inhibitor therapy for one dose prior to surgical procedures.1 Although no studies have shown a direct link between live vaccines and infection in patients receiving biologics, due to the theoretical risk of live vaccines producing infection in patients with altered immune responses, we recommend withholding biologic therapy for 4 to 5 half-lives prior to the administration of live or live-attenuated vaccines.2,3 Finally, although an increased rate of cancer recurrence has not been demonstrated with biologic use, experts recommend withholding biologic therapy for 2 years after the completion of treatment for invasive cancers and 5 years after the completion of treatment for aggressive malignancies (including melanomas, breast cancers, sarcomas, urinary tract cancers, and myelomas)4; however, exceptions should be considered depending on the patient's circumstances and severity of the psoriasis. (SKINmed. 2021;19:17-0).

A postbiotic from Aspergillus oryzae attenuates the impact of heat stress in ectothermic and endothermic organisms.

Heat stress is detrimental to food-producing animals and animal productivity remains suboptimal despite the use of heat abatement strategies during summer. Global warming and the increase of frequency and intensity of heatwaves are likely to continue and, thus, exacerbate the problem of heat stress. Heat stress leads to the impairment of physiological and cellular functions of ectothermic and endothermic animals. Therefore, it is critical to conceive ways of protecting animals against the pathological effects of heat stress. In experiments with endothermic animals highly sensitive to heat (Bos taurus), we have previously reported that heat-induced systemic inflammation can be ameliorated in part by nutritional interventions. The experiments conducted in this report described molecular and physiological adaptations to heat stress using Drosophila melanogaster and dairy cow models. In this report, we expand previous work by first demonstrating that the addition of a postbiotic from Aspergillus oryzae (AO) into the culture medium of ectothermic animals (Drosophila melanogaster) improved survival to heat stress from 30 to 58%. This response was associated with downregulation of genes involved in the modulation of oxidative stress and immunity, most notably metallothionein B, C, and D. In line with these results, we subsequently showed that the supplementation with the AO postbiotic to lactating dairy cows experiencing heat stress decreased plasma concentrations of serum amyloid A and lipopolysaccharide-binding protein, and the expression of interleukin-6 in white blood cells. These alterations were paralleled by increased synthesis of energy-corrected milk and milk components, suggesting enhanced nutrient partitioning to lactogenesis and increased metabolic efficiency. In summary, this work provides evidence that a postbiotic from AO enhances thermal tolerance likely through a mechanism that entails reduced inflammation.

Atopic dermatitis: new insight into the etiology, pathogenesis, diagnosis and novel treatment strategies.

Atopic dermatitis (AD) is the long-lasting chronic inflammatory skin condition associated with cutaneous hyper-reactivity and triggered by environmental factors. The attributes of AD include dry skin, pruritus, lichenification and frequent eczematous abrasions. This has a strong heritable aspect and typically occurs with asthma and allergic rhinitis. The complex pathological mechanism behind AD etiology is epidermal barrier destruction resulting in the lack of filaggrin protein that can induce inflammation and T-cell infiltration. T-helper 2 cell-mediated pathways also bear the responsibility of damage to the epidermal barrier. Certain causative factors for AD include microbial imbalance of skin microbiota, immunoglobulin-E-induced sensitization and neuro-inflammation. Numerous beneficial topical and oral treatments have been available to patients and there are even more drugs in the pipeline for the treatment of AD. Topical moisturizers, corticosteroids, anti-inflammatory agents such as calcineurin inhibitors, phototherapy, cAMP-specific 3, 5 half-cyclic phosphodiesterase 4 inhibitors and systemic immunosuppressants are widely available for AD treatments. Different positions and pathways inside the immune system including JAK-STAT, phosphodiesterase 4, aryl hydrocarbon receptor and T-helper 2 cytokines are targeted by above-mentioned drug treatments. Instead of the severe side effects of topical steroids and oral antihistamines, herbal plants and their derived phytoconstituents are commonly used for the treatment of AD. A clear understanding of AD's cellular and molecular pathogenesis through substantial advancement in genetics, skin immunology and psychological factors resulted in advancement of AD management. Therefore, the review highlights the recent advancements in the understanding of clinical features, etiology, pathogenesis, treatment and management and non-adherence to AD treatment.