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Metabolic homeostasis requires dynamic catabolic and anabolic processes. Autophagy, an intracellular lysosomal degradative pathway, can rewire cellular metabolism linking catabolic to anabolic processes and thus sustain homeostasis. This is especially relevant in the liver, a key metabolic organ that governs body energy metabolism. Autophagy's role in hepatic energy regulation has just begun to emerge and autophagy seems to have a much broader impact than what has been appreciated in the field. Though classically known for selective or bulk degradation of cellular components or energy-dense macromolecules, emerging evidence indicates autophagy selectively regulates various signaling proteins to directly impact the expression levels of metabolic enzymes or their upstream regulators. Hence, we review three specific mechanisms by which autophagy can regulate metabolism: A) nutrient regeneration, B) quality control of organelles, and C) signaling protein regulation. The plasticity of the autophagic function is unraveling a new therapeutic approach. Thus, we will also discuss the potential translation of promising preclinical data on autophagy modulation into therapeutic strategies that can be used in the clinic to treat common metabolic disorders., Graphical abstract Three major modes of regulation of hepatic metabolism by autophagy. Autophagy can regenerate nutrients, quality control cellular organelles, and regulate levels of signaling proteins related to hepatic metabolism.Image 1

Background Myocytes exposed to stress exhibit significant swelling and reduced contractility. These consequences are ameliorated by adenosine triphosphate–sensitive potassium (KATP) channel opener diazoxide (DZX) via an unknown mechanism. KATP channel openers also provide cardioprotection in multiple animal models. Nitric oxide donors are similarly cardioprotective, and their combination with KATP activation may provide synergistic benefit. We hypothesized that mitochondria-targeted S-nitrosating agent (MitoSNO) would provide synergistic cardioprotection with DZX. Methods Myocyte volume and contractility were compared following Tyrode's physiologic solution (20 minutes) and stress (hyperkalemic cardioplegia [CPG] ± DZX; n = 5-20 each; 20 minutes) with or without MitoSNO (n = 5-11 each) at the end of stress, followed by Tyrode's solution (20 minutes). Isolated mouse hearts received CPG ± DZX (n = 8-10 each) before global ischemia (90 minutes) with or without MitoSNO (n = 8 each) at the end of ischemia, followed by reperfusion (30 minutes). Left ventricular (LV) pressures were compared using a linear mixed model to assess the impact of treatment on the outcome, adjusting for baseline and balloon volume. Results Stress (CPG) was associated with reduced myocyte contractility that was prevented by DZX and MitoSNO individually; however, their combination was associated with loss of cardioprotection. Similarly, DZX and MitoSNO improved LV function after prolonged ischemia compared with CPG alone, and cardioprotection was lost with their combination. Conclusions MitoSNO and DZX provide cardioprotection that is lost with their combination, suggesting mutually exclusive mechanisms of action. The lack of a synergistic beneficial effect informs the current knowledge of the cardioprotective mechanisms of DZX and will aid planning of future clinical trials.

Graphical abstract, Introduction Neomenthol, a cyclic monoterpenoid, is a stereoisomer of menthol present in the essential oil of Mentha spp. It is used in food as a flavoring agent, in cosmetics and medicines because of its cooling effects. However, neomenthol has not been much explored for its anticancer potential. Additionally, targeting hyaluronidase, Cathepsin-D, and ODC by phytochemicals is amongst the efficient approach for cancer prevention and/or treatment. Objectives To investigate the molecular and cell target-based antiproliferative potential of neomenthol on human cancer (A431, PC-3, K562, A549, FaDu, MDA-MB-231, COLO-205, MCF-7, and WRL-68) and normal (HEK-293) cell lines. Methods The potency of neomenthol was evaluated on human cancer and normal cell line using SRB, NRU and MTT assays. The molecular target based study of neomenthol was carried out in cell-free and cell-based test systems. Further, the potency of neomenthol was confirmed by quantitative real-time PCR analysis and molecular docking studies. The in vivo anticancer potential of neomenthol was performed on mice EAC model and the toxicity examination was accomplished through in silico, ex vivo and in vivo approaches. Results Neomenthol exhibits a promising activity (IC50 17.3 ± 6.49 μM) against human epidermoid carcinoma (A431) cells by arresting the G2/M phase and increasing the number of sub-diploid cells. It significantly inhibits hyaluronidase activity (IC50 12.81 ± 0.01 μM) and affects the tubulin polymerization. The expression analysis and molecular docking studies support the in vitro molecular and cell target based results. Neomenthol prevents EAC tumor formation by 58.84% and inhibits hyaluronidase activity up to 10% at 75 mg/kg bw, i.p. dose. The oral dose of 1000 mg/kg bw was found safe in acute oral toxicity studies. Conclusion Neomenthol delayed the growth of skin carcinoma cells by inhibiting the tubulin polymerization and hyaluronidase activity, which are responsible for tumor growth, metastasis, and angiogenesis.

Pure drug-assembled nanomedicines (PDANs) are currently under intensive investigation as promising nanoplatforms for cancer therapy. However, poor colloidal stability and less tumor-homing ability remain critical unresolved problems that impede their clinical translation. Herein, we report a core-matched nanoassembly of pyropheophorbide a (PPa) for photodynamic therapy (PDT). Pure PPa molecules are found to self-assemble into nanoparticles (NPs), and an amphiphilic PEG polymer (PPa-PEG2K) is utilized to achieve core-matched PEGylating modification via the π‒π stacking effect and hydrophobic interaction between the PPa core and the PPa-PEG2K shell. Compared to PCL-PEG2K with similar molecular weight, PPa-PEG2K significantly increases the stability, prolongs the systemic circulation and improves the tumor-homing ability and ROS generation efficiency of PPa-nanoassembly. As a result, PPa/PPa-PEG2K NPs exert potent antitumor activity in a 4T1 breast tumor-bearing BALB/c mouse xenograft model. Together, such a core-matched nanoassembly of pure photosensitizer provides a new strategy for the development of imaging-guided theragnostic nanomedicines., Graphical abstract Pyropheophorbide a (PPa)-driven nanoassembly was formed by the core-matched modification of PPa-PEG2K. Afterwards, PPa/PPa-PEG2K NPs are endocytosed by tumor cells to exert effective photodynamic under laser irradiation.Image 1

Chemotherapy-induced side effects affect the quality of life and efficacy of treatment of cancer patients. Current approaches for treating the side effects of chemotherapy are poorly effective and may cause numerous harmful side effects. Therefore, developing new and effective drugs derived from natural non-toxic compounds for the treatment of chemotherapy-induced side effects is necessary. Experiments in vivo and in vitro indicate that Panax ginseng (PG) and its ginsenosides are undoubtedly non-toxic and effective options for the treatment of chemotherapy-induced side effects, such as nephrotoxicity, hepatotoxicity, cardiotoxicity, immunotoxicity, and hematopoietic inhibition. The mechanism focus on anti-oxidation, anti-inflammation, and anti-apoptosis, as well as the modulation of signaling pathways, such as nuclear factor erythroid-2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1), P62/keap1/Nrf2, c-jun N-terminal kinase (JNK)/P53/caspase 3, mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinases (ERK), AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinase 4 (MKK4)/JNK, and phosphatidylinositol 3-kinase (PI3K)/AKT. Since a systemic review of the effect and mechanism of PG and its ginsenosides on chemotherapy-induced side effects has not yet been published, we provide a comprehensive summarization with this aim and shed light on the future research of PG., Graphical abstract Image 1

Acute respiratory distress syndrome (ARDS) is characterized by the severe inflammation and destruction of the lung air-blood barrier, leading to irreversible and substantial respiratory function damage. Patients with coronavirus disease 2019 (COVID-19) have been encountered with a high risk of ARDS, underscoring the urgency for exploiting effective therapy. However, proper medications for ARDS are still lacking due to poor pharmacokinetics, non-specific side effects, inability to surmount pulmonary barrier, and inadequate management of heterogeneity. The increased lung permeability in the pathological environment of ARDS may contribute to nanoparticle-mediated passive targeting delivery. Nanomedicine has demonstrated unique advantages in solving the dilemma of ARDS drug therapy, which can address the shortcomings and limitations of traditional anti-inflammatory or antioxidant drug treatment. Through passive, active, or physicochemical targeting, nanocarriers can interact with lung epithelium/endothelium and inflammatory cells to reverse abnormal changes and restore homeostasis of the pulmonary environment, thereby showing good therapeutic activity and reduced toxicity. This article reviews the latest applications of nanomedicine in pre-clinical ARDS therapy, highlights the strategies for targeted treatment of lung inflammation, presents the innovative drug delivery systems, and provides inspiration for strengthening the therapeutic effect of nanomedicine-based treatment., Graphical abstract Nanomedicine has demonstrated great potential in achieving specific targeting and amplifying therapeutic efficiency. This review focuses on the recent breakthroughs and targeting strategies to provide insights into nanomedicine for acute respiratory distress syndrome treatment.Image 1

Diabetic nephropathy (DN) has been recognized as a severe complication of diabetes mellitus and a dominant pathogeny of end-stage kidney disease, which causes serious health problems and great financial burden to human society worldwide. Conventional strategies, such as renin-angiotensin-aldosterone system blockade, blood glucose level control, and bodyweight reduction, may not achieve satisfactory outcomes in many clinical practices for DN management. Notably, due to the multi-target function, Chinese medicine possesses promising clinical benefits as primary or alternative therapies for DN treatment. Increasing studies have emphasized identifying bioactive compounds and molecular mechanisms of reno-protective effects of Chinese medicines. Signaling pathways involved in glucose/lipid metabolism regulation, antioxidation, anti-inflammation, anti-fibrosis, and podocyte protection have been identified as crucial mechanisms of action. Herein, we summarize the clinical efficacies of Chinese medicines and their bioactive components in treating and managing DN after reviewing the results demonstrated in clinical trials, systematic reviews, and meta-analyses, with a thorough discussion on the relative underlying mechanisms and molecular targets reported in animal and cellular experiments. We aim to provide comprehensive insights into the protective effects of Chinese medicines against DN., Graphical abstract Diabetic nephropathy is one of the most severe complications of diabetes mellitus. Chinese medicines have been intensively studied in treating diabetic nephropathy. This review comprehensively summarizes and discusses the clinical efficacies and underlying mechanisms of Chinese medicines for diabetic nephropathy, providing deep insights and profound perspectives into this field.Image 1

Background Anthracycline-induced cardiomyopathy (AIC) is a significant source of morbidity and mortality in cancer survivors. The role of mesenchymal stem cells (MSCs) in treating AIC was evaluated in the SENECA trial, a Phase 1 National Heart, Lung, and Blood Institute–sponsored study, but the mechanisms underpinning efficacy in human tissue need clarification. Objectives The purpose of this study was to perform an in vitro clinical trial evaluating the efficacy and putative mechanisms of SENECA trial–specific MSCs in treating doxorubicin (DOX) injury, using patient-specific induced pluripotent stem cell–derived cardiomyocytes (iCMs) generated from SENECA patients. Methods Patient-specific iCMs were injured with 1 μmol/L DOX for 24 hours, treated with extracellular vesicles (EVs) from MSCs by either coculture or direct incubation and then assessed for viability and markers of improved cellular physiology. MSC-derived EVs were separated into large extracellular vesicles (L-EVs) (>200 nm) and small EVs (, Central Illustration

Invasive fungal infections (IFIs) represent a growing public concern for clinicians to manage in many medical settings, with substantial associated morbidities and mortalities. Among many current therapeutic options for the treatment of IFIs, amphotericin B (AmB) is the most frequently used drug. AmB is considered as a first-line drug in the clinic that has strong antifungal activity and less resistance. In this review, we summarized the most promising research efforts on nanocarriers for AmB delivery and highlighted their efficacy and safety for treating IFIs. We have also discussed the mechanism of actions of AmB, rationale for treating IFIs, and recent advances in formulating AmB for clinical use. Finally, this review discusses some practical considerations and provides recommendations for future studies in applying AmB for combating IFIs., Graphical abstract Amphotericin B (AmB), placed in BCS class IV with low solubility and permeability, is a commonly used drug to combat Invasive fungal infections. In this review, research efforts on nanocarriers to improve AmB delivery are summarized.Image 1

The tumor development and metastasis are closely related to the structure and function of the tumor microenvironment (TME). Recently, TME modulation strategies have attracted much attention in cancer immunotherapy. Despite the preliminary success of immunotherapeutic agents, their therapeutic effects have been restricted by the limited retention time of drugs in TME. Compared with traditional delivery systems, nanoparticles with unique physical properties and elaborate design can efficiently penetrate TME and specifically deliver to the major components in TME. In this review, we briefly introduce the substitutes of TME including dendritic cells, macrophages, fibroblasts, tumor vasculature, tumor-draining lymph nodes and hypoxic state, then review various nanoparticles targeting these components and their applications in tumor therapy. In addition, nanoparticles could be combined with other therapies, including chemotherapy, radiotherapy, and photodynamic therapy, however, the nanoplatform delivery system may not be effective in all types of tumors due to the heterogeneity of different tumors and individuals. The changes of TME at various stages during tumor development are required to be further elucidated so that more individualized nanoplatforms could be designed., Graphical abstract Image 1, Highlights • In responsive to the changes in TME, nanoparticles target tumor microenvironment and enhance the therapeutic effect. • Nanoparticles modulate the activation and maturation of DC. • Nanoparticles could reprogram polarization of TAM and relieve hypoxia. • Nanoparticles could transfer the immunosuppressive TME to immunosupportive.

Here, evodiamine (EVO) and the photosensitizer indocyanine green (ICG) were integrated into a liposomal nanoplatform for noninvasive diagnostic imaging and combinatorial therapy against oral squamous cell carcinoma (OSCC). EVO, as an active component extracted from traditional Chinese medicine, not only functioned as an antitumor chemotherapeutic agent but was also capable of 68Ga-chelation, thus working as a contrast agent for positron emission tomography/computed tomography (PET/CT) imaging. Moreover, EVO could exhibit peroxidase-like catalytic activity, converting endogenous tumor H2O2 into cytotoxic reactive oxygen species (ROS), enabling Chemo catalytic therapy beyond the well-known chemotherapy effect of EVO. As proven by in vitro and in vivo experiments, guided by optical imaging and PET/CT imaging, we show that the theragnostic liposomes have a significant inhibiting effect on in situ tongue tumor through photodynamic therapy combined with chemodynamic chemotherapy., Graphical abstract Image 1, Highlights • Proposing water-soluble nanoliposomes to solve the problem of drug insoluble in water. • Evodiamine is found to have HRP mimic catalase activity. • EI@lipo displays photodynamic/chemodynamic/chemo therapy abilities. • Ei@Lipo significantly inhibits tongue tumor through in situ.

Breast cancer arises as a result of multiple interactions between environmental and genetic factors. Conventionally, breast cancer is treated based on histopathological and clinical features. DNA technologies like the human genome microarray are now partially integrated into clinical practice and are used for developing new “personalized medicines” and “pharmacogenetics” for improving the efficiency and safety of cancer medications. We investigated the effects of four established therapies—for ER+ ductal breast cancer—on the differential gene expression. The therapies included single agent tamoxifen, two-agent docetaxel and capecitabine, or combined three-agents CAF (cyclophosphamide, doxorubicin, and fluorouracil) and CMF (cyclophosphamide, methotrexate, and fluorouracil). Genevestigator 8.1.0 was used to compare five datasets from patients with infiltrating ductal carcinoma, untreated or treated with selected drugs, to those from the healthy control. We identified 74 differentially expressed genes involved in three pathways, i.e., apoptosis (extrinsic and intrinsic), oxidative signaling, and PI3K/Akt signaling. The treatments affected the expression of apoptotic genes (TNFRSF10B [TRAIL], FAS, CASP3/6/7/8, PMAIP1 [NOXA], BNIP3L, BNIP3, BCL2A1, and BCL2), the oxidative stress-related genes (NOX4, XDH, MAOA, GSR, GPX3, and SOD3), and the PI3K/Akt pathway gene (ERBB2 [HER2]). Breast cancer treatments are complex with varying drug responses and efficacy among patients. This necessitates identifying novel biomarkers for predicting the drug response, using available data and new technologies. GSR, NOX4, CASP3, and ERBB2 are potential biomarkers for predicting the treatment response in primary ER+ ductal breast carcinoma.

Recent studies have revealed that cancer stem cells (CSCs) undergo metabolic alterations that differentiate them from non-CSCs. Inhibition of specific metabolic pathways in CSCs has been conducted to eliminate the CSC population in many types of cancer. However, there is conflicting evidence about whether CSCs depend on glycolysis or mitochondrial oxidative phosphorylation (OXPHOS) to maintain their stem cell properties. This review summarizes the latest knowledge regarding CSC-specific metabolic alterations and offers recent evidence that the surrounding microenvironments may play an important role in the maintenance of CSC properties., Highlights • CSCs use conflicting metabolic alterations, glycolysis and mitochondrial OXPHOS, differently depending on the circumstances. • Metabolic interactions between CSCs and the stromal niche are important for the maintenance of CSC mitochondrial OXPHOS. • CSCs generally maintain low ROS levels and exhibit redox patterns to survive and retain their stemness.

Graphical abstract, Even given recent advances in nanomedicine development of breast cancer treatment in recent years and promising results in pre-clinical models, cancer nanomedicines often fail at the clinical trial stage. Limitations of conventional in vitro models include the lack of representation of the stromal population, the absence of a three-dimensional (3D) structure, and a poor representation of inter-tumor and intra-tumor heterogeneity. Herein, we review those cell culture strategies that aim to overcome these limitations, including cell co-cultures, advanced 3D cell cultures, patient-derived cells, bioprinting, and microfluidics systems. The in vivo evaluation of nanomedicines must consider critical parameters that include the enhanced permeability and retention effect, the host's immune status, and the site of tumor implantation. Here, we critically discuss the advantages and limitations of current in vivo models and report how the improved selection and application of breast cancer models can improve the clinical translation of nanomedicines.

Highlights • Obesity contributes to male infertility. • Can lycopene or moringa improve male infertility? • Tested in a rodent model of diet-induced obesity. • Lycopene was superior to Moringa in improving male fertility parameters., Obesity is a condition of chronic tissue inflammation and oxidative stress that poses as a risk factor for male infertility. Moringa oleifera oil extract is known to have cholesterol-lowering properties and a potential to treat obesity, while lycopene is a potent antioxidant. We hypothesize that Moringa or lycopene may improve male fertility markers in an animal model of diet-induced obesity. Male Albino rats (n = 60) were randomized to receive regular chow (RC) or high-fat diet (HFD) for 12 weeks (n = 30 each). Animals in each arm were further randomized to receive gavage treatment with corn oil (vehicle), lycopene (10 mg/kg), or Moringa (400 mg/kg) for four weeks starting on week 9 (n = 10 each). Animals were sacrificed at 12 weeks, and blood was collected to assess lipid profile, serum testosterone, and gonadotropin levels. The testes and epididymides were removed for sperm analysis, oxidative stress and inflammatory markers, and histopathological assessment. In comparison to their RC littermates, animals on HFD showed an increase in body weights, serum lipids, testosterone and gonadotrophin levels, testicular oxidative stress and inflammatory markers, as well as sperm abnormalities and disrupted testicular histology. Moringa or lycopene reduced body weight, improved oxidative stress, and male fertility markers in HFD-fed animals with lycopene exhibiting better anti-antioxidant and anti-lipidemic effects. Lycopene is superior to Moringa in improving male fertility parameters, possibly by attenuating oxidative stress.

The role of natural antioxidants in preventing of age-relating diseases is evident. The vegetable industry generates a large amount of waste, which is a good source of antioxidants. The aim of the study was the investigation of the antioxidant effect of long-term consumption of ethanolic yellow onion husk extract in ageing laboratory rodents. Twenty male Wistar albino rats were divided randomly into two groups (n = 10): a control group and an experimental group that received ethanolic yellow onion husk extract (2 mL/rat diluted with distilled water; activity of 4.44 µmol-equiv. quercetin) for 188 days. Oxygen radical absorbance capacity and ferric reducing antioxidant power assays were used to determine the total antioxidant capacity of the extract, which amounted to 941.4 ± 32.7 µmol equiv. Trolox/g raw material and 167.4 ± 16.4 µmol-equiv. quercetin/g raw material, respectively. Oral intake of the onion husk extract affected the indicators of the antioxidant system of the liver and the brain but not of the blood and plasma, mainly due to elevations in the activity of catalase and superoxide dismutase in the liver by 44.4% and 79.1%, respectively, and in the brain by three-fold and 79.1%, respectively. The availability, cheapness and high antioxidant potential of onion waste qualifies it a good source of functional ingredients and bioactive substances applicable in the food and pharmaceutical industries.

Objectives Epilepsy is a neurological disease characterized by sudden, abnormal, and hyper- discharges in the central nervous system (CNS). Valproic acid (VPA) is commonly used as a broad-spectrum antiepileptic therapeutic. However, in many cases, patients develop resistance to VPA treatment due to overwhelming oxidative stress, which in turn might be a major catalyst for disease progression. Therefore, antioxidants can potentially become therapeutic agents by counteracting reactive oxygen species (ROS)-mediated damage. The present study is aimed to evaluate the potential antiepileptic effect of astaxanthin (ASTA) in pentylenetetrazol (PTZ) induced epileptic model rats that are chronically treated with VPA for 8 weeks. Method Fifty-male Wistar rats were randomly divided into five groups: Non-PTZ group, PTZ, PTZ/VPA, PTZ/ASTA, and PTZ/VPA/ASTA treated groups. Results PTZ/VPA treated group showed a neuroprotective effect with improvement in antioxidant levels, behavioral test, and histopathological changes induced by PTZ. VPA also exhibited an anti-inflammatory effect as its treatment resulted in the reduction of tumor necrosis factor-α (TNF-α). ASTA exhibited an anticonvulsant effect and enhanced anti-inflammatory effect as compared to VPA. During the combined therapy, ASTA potentiated the antiepileptic effect of the VPA by reducing the oxidative stress and TNF-α as well as increased the glutathione (GSH) levels. Also, there were substantial improvements in the behavioral and histopathological changes in the VPA/ASTA treated group as compared to the VPA treated group. Conclusion ASTA could have an antiepileptic and anti-inflammatory effect by reducing ROS generation. Therefore, co-administration of both the therapeutics (VPA/ASTA) has a synergistic effect in treating epilepsy and could potentially minimize recurrence and/or exacerbation of seizures.

Colostrum, the sole diet for newborns, is an emerging nutraceutical. To date, the chemopreventive effect of Bovine Colostrum against liver injury induced by the potent carcinogen, 7,12-dimethyl-Benz[a]anthracene (DMBA) is unexplored. Humans are daily exposed to DMBA which is a highly lipophilic environmental organic pollutant. The study aimed to investigate the hepatoprotective role of Bovine Colostrum against DMBA-induced hepatotoxicity using a rat model. Fifty male rats were divided into five groups; GI (control), GII (olive oil, vehicle for DMBA), GIII (DMBA), GIV (DMBA + Bovine Colostrum), GV (Bovine Colostrum). After 12 weeks, body weight changes and mortality were calculated. Histological and ultrastructural examinations of liver tissue were performed. Expressions of p53, TGFβ2, TNF-α, S6K2, and c20orf20 were assessed by RT-PCR. Post-treatment with Bovine Colostrum increased both the body weight and the survival rate of rats treated with DMBA. In addition, remarkable protection against the pathological effect of DMBA was noted. Ultrastructurally, Bovine Colostrum ameliorated/prevented most of the toxic effects of DMBA on hepatocytes, including irregularities of nuclear envelope, clumping, and margination of heterochromatin aggregates, segregated nucleoli, and mitochondrial pleomorphism. Bovine Colostrum administration down-regulated p53, C20orf20, and S6K2 mRNA levels, and up-regulated TNF-α and TGFβ2. In conclusion, Bovine Colostrum have a protective effect against DMBA-induced toxicity on the liver of albino rats. Consequently, Bovine Colostrum may prevent polycyclic aromatic hydrocarbons-induced hepatotoxicity and may be useful in promoting human health if supplemented in the diet.

The DNA demethylating agent 5-aza-2′-deoxycytidine (DAC, decitabine) has anti-cancer therapeutic potential, but its clinical efficacy is hindered by DNA damage-related side effects and its use in solid tumours is debated. Here we describe how paracetamol augments the effects of DAC on cancer cell proliferation and differentiation, without enhancing DNA damage. Firstly, DAC specifically upregulates cyclooxygenase-2-prostaglandin E2 pathway, inadvertently providing cancer cells with survival potential, while the addition of paracetamol offsets this effect. Secondly, in the presence of paracetamol, DAC treatment leads to glutathione depletion and finally to accumulation of ROS and/or mitochondrial superoxide, both of which have the potential to restrict tumour growth. The benefits of combined treatment are demonstrated here in head and neck squamous cell carcinoma (HNSCC) and acute myeloid leukaemia cell lines, further corroborated in a HNSCC xenograft mouse model and through mining of publicly available DAC and paracetamol responses. The sensitizing effect of paracetamol supplementation is specific to DAC but not its analogue 5-azacitidine. In summary, the addition of paracetamol could allow for DAC dose reduction, widening its clinical usability and providing a strong rationale for consideration in cancer therapy., Highlights • Paracetamol works in synergy with DAC (decitabine) to reduce cancer cell viability. • The synergistic effect is specific for decitabine and not observed for 5-azacitidine. • Paracetamol allows for DAC dose reduction without inducing DNA damage. • Paracetamol counteracts DAC-triggered activation of COX-2-PGE2 pathway. • In the presence of paracetamol DAC induces mimicry of paracetamol overdose leading to oxidative stress.

The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon-γ (IFN-γ), macrophages, and T cell-dependent immune responses, play a vital role in tumor growth by affecting the HH signaling pathway. Moreover, inhibition of proliferating cancer-associated fibroblasts (CAFs) and inflammatory factors can normalize the TME by suppressing HH signaling. Furthermore, aberrant HH signaling activation is favorable to both the proliferation of cancer stem cells (CSCs) and the drug resistance of gastrointestinal tumors. This review discusses the current understanding of the role and mechanism of aberrant HH signaling activation in gastrointestinal carcinogenesis, the gastrointestinal TME, tumor immune tolerance and drug resistance and highlights the underlying therapeutic opportunities., Graphical abstract Hedgehog pathway (HH) is one of the most important modulators of gastrointestinal cancer. This review concludes the role of HH pathway in gastrointestinal carcinogenesis as well as the development of tumor microenvironment, which indicates the mechanisms of immune tolerance and drug resistance in gastrointestinal cancers and highlights the potential therapeutics.Image 1

Fibrosis is a pathological reparative process that can occur in most organs and is responsible for nearly half of deaths in the developed world. Despite considerable research, few therapies have proven effective and been approved clinically for treatment of fibrosis. Artemisinin compounds are best known as antimalarial therapeutics, but they also demonstrate antiparasitic, antibacterial, anticancer, and anti-fibrotic effects. Here we summarize literature describing anti-fibrotic effects of artemisinin compounds in in vivo and in vitro models of tissue fibrosis, and we describe the likely mechanisms by which artemisinin compounds appear to inhibit cellular and tissue processes that lead to fibrosis. To consider alternative routes of administration of artemisinin for treatment of internal organ fibrosis, we also discuss the potential for more direct oral delivery of Artemisia plant material to enhance bioavailability and efficacy of artemisinin compared to administration of purified artemisinin drugs at comparable doses. It is our hope that greater understanding of the broad anti-fibrotic effects of artemisinin drugs will enable and promote their use as therapeutics for treatment of fibrotic diseases., Graphical abstract Artemisinin drugs, isolated from Artemisia, effectively prevent or treat multiple types of tissue fibrosis when administered to several preclinical animal models of varied etiologies.Image 1

Cancer therapy is a strategic measure in inhibiting breast cancer stem cell (BCSC) pathways. Naringenin, a citrus flavonoid, was found to increase breast cancer cells’ sensitivity to chemotherapeutic agents. Bioinformatics study and 3D tumorsphere in vitro modeling in breast cancer (mammosphere) were used in this study, which aims to explore the potential therapeutic targets of naringenin (PTTNs) in inhibiting BCSCs. Bioinformatic analyses identified direct target proteins (DTPs), indirect target proteins (ITPs), naringenin-mediated proteins (NMPs), BCSC regulatory genes, and PTTNs. The PTTNs were further analyzed for gene ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, protein–protein interaction (PPI) networks, and hub protein selection. Mammospheres were cultured in serum-free media. The effects of naringenin were measured by MTT-based cytotoxicity, mammosphere forming potential (MFP), colony formation, scratch wound-healing assay, and flow cytometry-based cell cycle analyses and apoptosis assays. Gene expression analysis was performed using real-time quantitative polymerase chain reaction (q-RT PCR). Bioinformatics analysis revealed p53 and estrogen receptor alpha (ERα) as PTTNs, and KEGG pathway enrichment analysis revealed that TGF-ß and Wnt/ß-catenin pathways are regulated by PTTNs. Naringenin demonstrated cytotoxicity and inhibited mammosphere and colony formation, migration, and epithelial to mesenchymal transition in the mammosphere. The mRNA of tumor suppressors P53 and ERα were downregulated in the mammosphere, but were significantly upregulated upon naringenin treatment. By modulating the P53 and ERα mRNA, naringenin has the potential of inhibiting BCSCs. Further studies on the molecular mechanism and formulation of naringenin in BCSCs would be beneficial for its development as a BCSC-targeting drug.

Graphical abstract, Highlights • Al2O3-NPs induce severe toxicity and apoptosis in the hippocampal cells. • Al2O3-NPs Stimulated of oxidative stress and increase in Aβ protein levels that activating pro-apoptotic pathway via cleaved caspase-3, P53, and P450. • Al2O3-NPs increasing the levels of total peroxide and the activities of MAO-A and MAO-B as well as decreasing the expression of Sox2 and Oct4 proteins. • AD-MSCs suppress oxidative stress and stimulate immunity when rat are exposed to Al2O3-NPs. • AD-MSCs alleviate the toxicity action of Al2O3-NPs via regulation of P53, Aβ, SOX2, OCT4, and CYP2E1signaling in a hippocampal cells., Mesenchymal stem cells (MSCs) possess a preventive capacity against free radical toxicity in various tissues. The present study aimed to demonstrate the reformative and treatment roles of adipose-derived MSCs (AD-MSCs) against severe toxicity in the hippocampal cells of the brain caused by aluminum oxide nanoparticles (Al2O3-NPs). Rats were divided into five experimental groups: an untreated control group, a control group receiving NaCl, a group receiving Al2O3-NPs (6 mg/kg) for 20 days, a group that was allowed to recover (R) for 20 days following treatment with Al2O3-NPs, and a Al2O3-NPs + AD-MSCs group, where each rat was injected with 0.8 × 106 AD-MSCs via the caudal vein. Oral administration of Al2O3-NPs increased the protein levels of P53, cleaved caspase-3, CYP2E1, and beta-amyloid (Aβ); contrarily, AD-MSCs transplantation downregulated the levels of these proteins. In addition, the AD-MSCs-treated hippocampal cells were protected from Al2O3-NPs-induced toxicity, as detected by the expression levels of Sox2 and Oct4 that are essential for the maintenance of self-renewal. It was also found that AD-MSCs injection significantly altered the levels of brain total peroxide and monoamine oxidase (MAO)-A and MAO-B activities. Histologically, our results indicated that AD-MSCs alleviated the severe damage in the hippocampal cells induced by Al2O3-NPs. Moreover, the role of AD-MSCs in reducing hippocampal cell death was reinforced by the regulation of P53, cleaved caspase-3, Aβ, and CYP2E1 proteins, as well as by the regulation of SOX2 and OCT4 levels and MAO-A and MAO-B activities.

Diabetic nephropathy (DN) is considered the primary causes of end-stage renal disease (ESRD) and is related to abnormal glycolipid metabolism, hemodynamic abnormalities, oxidative stress and chronic inflammation. Antagonism of vascular endothelial growth factor B (VEGF-B) could efficiently ameliorate DN by reducing renal lipotoxicity. However, this pharmacological strategy is far from satisfactory, as it ignores numerous pathogenic factors, including anomalous reactive oxygen species (ROS) generation and inflammatory responses. We found that the upregulation of VEGF-B and downregulation of interleukin-22 (IL-22) among DN patients were significantly associated with the progression of DN. Thus, we hypothesized that a combination of a VEGF-B antibody and IL-22 could protect against DN not only by regulating glycolipid metabolism but also by reducing the accumulation of inflammation and ROS. To meet these challenges, a novel anti-VEGFB/IL22 fusion protein was developed, and its therapeutic effects on DN were further studied. We found that the anti-VEGFB/IL22 fusion protein reduced renal lipid accumulation by inhibiting the expression of fatty acid transport proteins and ameliorated inflammatory responses via the inhibition of renal oxidative stress and mitochondrial dysfunction. Moreover, the fusion protein could also improve diabetic kidney disease by increasing insulin sensitivity. Collectively, our findings indicate that the bifunctional VEGF-B antibody and IL-22 fusion protein could improve the progression of DN, which highlighted a novel therapeutic approach to DN., Graphical abstract The expression of VEGF-B was increased and that of IL-22 was decreased in diabetic nephropathy (DN) patients. Anti-VEGFB/IL22 fusion protein combining VEGF-B antibody and IL22 ameliorated DN by alleviating ectopic lipid accumulation, inflammatory responses and insulin resistance.Image 1

Background & Aims Immune checkpoint inhibitors have shed light on the importance of antitumor immunity as a therapeutic strategy for hepatocellular carcinoma (HCC). The altered glucose metabolism known as the Warburg effect recently has gained attention as a cancer immune-resistance mechanism. Considering glycolysis inhibitors as therapeutic agents, their specific delivery to cancer cells is critical not to induce adverse effects. Thus, we investigated antitumor effects of a glycolysis inhibitor, consisting of 2-deoxy-D-glucose (2DG)-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (2DG-PLGA-NPs), against hepatocellular carcinoma in mice. Methods The antitumor effects of 2DG-PLGA-NPs were examined using hepatoma cell lines, xenograft tumors, and hepatocarcinogenic and syngeneic mouse models. Results The 2DG-PLGA-NPs induced cytotoxic effects and antitumor immunity through enhanced T-cell trafficking. In addition, 2DG-PLGA-NPs induced decreased lactate production and increased interferon-γ–positive T cells in liver tumors. Human CD8+ T cells cocultured with 2DG-PLGA-NP–treated Huh7 cells showed their increased interferon-γ production and glucose uptake compared with the CD8+ T cells co-cultured with PLGA-NP–treated Huh7 cells. Chemotaxis of CD8+ T cells was suppressed by lactate and enhanced by glucose. Interferon-γ enhanced CD8+ T-cell chemotaxis in both an autocrine and paracrine manner. Notably, the 2DG-PLGA-NPs augmented chemokine (CXCL9/CXCL10) production in liver tumors via interferon-γ–Janus kinase–signal transducers and activator of transcription pathway and 5' adenosine monophosphate-activated protein kinase–mediated suppression of histone H3 lysine 27 trimethylation. These 2DG-PLGA-NPs not only amplified antitumor effects induced by sorafenib or an anti–programmed death-1 antibody, but also suppressed anti–programmed death-1–resistant tumors. Conclusions The newly developed 2DG-PLGA-NPs showed antitumor immunity and cytotoxicity in liver tumors in mice, suggesting the potential of 2DG-PLGA-NPs for future clinical applications., Graphical abstract

Background & Aims TNFSF15 genetic variants leading to increased TNF superfamily member 15 (TNFSF15) expression confer risk for inflammatory bowel disease (IBD), and TNFSF15 is being explored as a therapeutic target in IBD patients. Although the focus for TNFSF15-mediated inflammatory outcomes has been predominantly on its action on T cells, TNFSF15 also promotes inflammatory outcomes in human macrophages. Given the critical role for macrophages in bacterial clearance, we hypothesized that TNFSF15 promotes antimicrobial pathways in human macrophages and that macrophages from TNFSF15 IBD risk carriers with higher TNFSF15 expression have an advantage in these antimicrobial outcomes. Methods We analyzed protein expression, signaling, bacterial uptake, and intracellular bacterial clearance in human monocyte-derived macrophages through flow cytometry, enzyme-linked immunosorbent assay, and gentamicin protection. Results Autocrine/paracrine TNFSF15 interactions with death receptor 3 (DR3) were required for optimal levels of pattern-recognition-receptor (PRR)-induced bacterial clearance in human macrophages. TNFSF15 induced pyruvate dehydrogenase kinase 1-dependent bacterial uptake and promoted intracellular bacterial clearance through reactive oxygen species, nitric oxide synthase 2, and autophagy up-regulation. The TNFSF15-initiated TNF receptor-associated factor 2/receptor-interacting protein kinase 1/RIP3 pathway was required for mitogen-activated protein kinase and nuclear factor-κB activation, and, in turn, induction of each of the antimicrobial pathways; the TNFSF15-initiated Fas-associated protein with death domain/mucosa-associated lymphoid tissue lymphoma translocation protein 1/caspase-8 pathway played a less prominent role in antimicrobial functions, despite its key role in TNFSF15-induced cytokine secretion. Complementation of signaling pathways or antimicrobial pathways restored bacterial uptake and clearance in PRR-stimulated macrophages where TNFSF15:DR3 interactions were inhibited. Monocyte-derived macrophages from high TNFSF15-expressing rs6478108 TT IBD risk carriers in the TNFSF15 region showed increased levels of the identified antimicrobial pathways. Conclusions We identify that autocrine/paracrine TNFSF15 is required for optimal PRR-enhanced antimicrobial pathways in macrophages, define mechanisms regulating TNFSF15-dependent bacterial clearance, and determine how the TNFSF15 IBD risk genotype modulates these outcomes., Graphical abstract

Background and Aims TRIM21 is a ubiquitin E3 ligase that is implicated in numerous biological processes including immune response, cell metabolism, redox homeostasis, and cancer development. We recently reported that TRIM21 can negatively regulate the p62-Keap1-Nrf2 antioxidant pathway by ubiquitylating p62 and prevents its oligomerization and protein sequestration function. As redox homeostasis plays a pivotal role in many cancers including liver cancer, we sought to determine the role of TRIM21 in hepatocarcinogenesis. Methods We examined the correlation between TRIM21 expression and the disease using publicly available data sets and 49 cases of HCC clinical samples. We used TRIM21 genetic knockout mice to determine how TRIM21 ablation impact HCC induced by the carcinogen DEN plus phenobarbital (PB). We explored the mechanism that loss of TRIM21 protects cells from DEN-induced oxidative damage and cell death. Results There is a positive correlation between TRIM21 expression and HCC. Consistently, TRIM21-knockout mice are resistant to DEN-induced hepatocarcinogenesis. This is accompanied by decreased cell death and tissue damage upon DEN treatment, hence reduced hepatic tissue repair response and compensatory proliferation. Cells deficient in TRIM21 display enhanced p62 sequestration of Keap1 and are protected from DEN-induced ROS induction and cell death. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient mutant TRIM21 impedes the protection from DEN-induced oxidative damage and cell death in TRIM21-deficient cells. Conclusions Increased TRIM21 expression is associated with human HCC. Genetic ablation of TRIM21 leads to protection against oxidative hepatic damage and decreased hepatocarcinogenesis, suggesting TRIM21 as a preventive and therapeutic target.

Graphical abstract, Highlights • Ethanol extract of Eleutherine plicata showed low in vitro and in vivo cytotoxic potential. • The dichloromethane fraction was cytotoxic to HepG2 and caused DNA. However, no toxicity was observed in vivo. • Isoeleutherin caused DNA damage by the comet method and activated caspase-8 in the in silico study., Eleutherine plicata has been shown to be a promising medicinal plant, and its activity has been associated with naphthoquinones. The present study aimed at evaluating the cytotoxicity, genotoxicity, and oral toxicity of the ethanol extract (EEEp), dichloromethane fraction (FDMEp) of E. plicata, and isoeleutherin. For the cytotoxicity evaluation, the viability test (MTT) was used. Genotoxicity was accessed through the Comet assay (alkaline version), acute and subacute oral toxicities were also evaluated. The antioxidant capacity of the samples in the wells where the cells were treated with E. plicata was evaluated. Furthermore, the participation of caspase-8 in the possible mechanism of action of isoeleutherin, eleutherin, and eleutherol was also investigated through a docking study. FDMEp and isoeleutherin were cytotoxic, with higher rates of DNA fragmentation observed for FDMEp and isoeleutherin, and all samples displayed higher antioxidant potential than the control. In the acute oral toxicity test, EEEp, FDMEp, and isoeleutherin did not cause significant clinical changes. In the subacute toxicity assay, EEEp and FDMEp also did not cause clinical, hematological, or biochemical changes. The three compounds bound similarly to caspase-8. Despite the results of cytotoxicity, in vitro studies demonstrated that the use of EEEp appears to be safe and cell death may involve its binding to caspase-8.

COVID-19 pandemic caused by SARS-CoV-2 has already claimed millions of lives worldwide due to the absence of a suitable anti-viral therapy. The CoV envelope (E) protein, which has not received much attention so far, is a 75 amino acid long integral membrane protein involved in assembly and release of the virus inside the host. Here we have used artificial intelligence (AI) and pattern recognition techniques for initial screening of FDA approved pharmaceuticals and nutraceuticals to target this E protein. Subsequently, molecular docking simulations have been performed between the ligands and target protein to screen a set of 9 ligand molecules. Finally, we have provided detailed insight into their mechanisms of action related to the varied symptoms of infected patients., Highlights • This work focuses on integral membrane Envelope (E) Protein as the target which is the most conserved among all. • We implemented artificial intelligence (AI) and pattern recognition techniques for initial screening • Next level screening incorporates their (a) existing functions (b) FDA approval status and (c) severity of the side effects. • Blind molecular docking simulation has been done and 9 ligand molecules have been screened. • A detailed insight into the mode of action of these 9 drugs related to the varied symptoms of infected patients is provided.

Graphical abstract, This research investigated the reno-protective effect of Thunbergia laurifolia Linn. (TL) in a lead-induced toxicity test through the modulation of cell signaling pathways. The study carried out to evaluate the effect of TL leaf extracts in Swiss Albino mice exposed to lead acetate (PbAc). Prior to in vivo study, a probable kidney-protective effect of the plant leaf extract was presumed through an activity-specific (PASS) molecular docking analysis. In animal model study, albino mice were divided in seven groups and co-treated with PbAc and TL (100, 200 mg/kgBW) or vitamin E (100 mg/kgBW) for 38 days, whereas the untreated control, TL control, and vehicle control groups received sodium acetate, PbAc, sodium acetate plus mineral oil, respectively. At the end of treatment, blood and kidney tissue were collected for investigating Pb concentration, estimating biochemical profile, evaluating oxidative stress and inflammatory parameters. The histopathological change of kidney along with apoptosis was assessed from kidney sections using H & E staining and TUNEL assay. Pb-exposed mice were found to be increased concentration of Pb in the blood and kidney sample, which further led to increased MDA levels in the plasma, blood, and tissue. Followed by kidney damage, increased expression of TNF-α, iNOS, and COX-2 in kidney tissues were noticed, which were related to elevated TNF-α in the systemic circulation of Pb-treated mice. Co-treatment with TL or vitamin E significantly reduced altered structure and apoptosis of kidney tissues. Downregulation of inflammatory markers especially TNF-α, iNOS, and COX-2 with simultaneous improvement of renal function through reduced plasma BUN and creatinine levels demonstrate that TL act as a potential dietary supplement to detoxify Pb in kidney showing an antioxidant and anti-inflammatory effect.

Highlights • Definition and pathogenesis of metabolic syndrome is briefly described. • Sesquiterpene lactones isolated from medicinal plants used in traditional medicine. • In vivo and in vitro biological activities of sesquiterpene lactones are considered. • Chemical and biological properties of natural sesquiterpene lactones are documented., Metabolic syndrome comprises a cluster of metabolic disorders related to the development of cardiovascular disease and type 2 diabetes mellitus. In latter years, plant secondary metabolites have become of special interest because of their potential role in preventing and managing metabolic syndrome. Sesquiterpene lactones constitute a large and diverse group of biologically active compounds widely distributed in several medicinal plants used for the treatment of metabolic disorders. The structural diversity and the broad spectrum of biological activities of these compounds drew significant interests in the pharmacological applications. This review describes selected sesquiterpene lactones that have been experimentally validated for their biological activities related to risk factors of metabolic syndrome, together with their mechanisms of action. The potential beneficial effects of sesquiterpene lactones discussed in this review demonstrate that these substances represent remarkable compounds with a diversity of molecular structure and high biological activity, providing new insights into the possible role in metabolic syndrome management.

Since accelerated metabolism produces much higher levels of reactive oxygen species (ROS) in cancer cells compared to ROS levels found in normal cells, human MutT homolog 1 (MTH1), which sanitizes oxidized nucleotide pools, was recently demonstrated to be crucial for the survival of cancer cells, but not required for the proliferation of normal cells. Therefore, dozens of MTH1 inhibitors have been developed with the aim of suppressing cancer growth by accumulating oxidative damage in cancer cells. While several inhibitors were indeed confirmed to be effective, some inhibitors failed to kill cancer cells, complicating MTH1 as a viable target for cancer eradication. In this review, we summarize the current status of developing MTH1 inhibitors as drug candidates, classify the MTH1 inhibitors based on their structures, and offer our perspectives toward the therapeutic potential against cancer through the targeting of MTH1., Graphical abstract As an essential enzyme for the survival of cancer cells, human MutT homolog 1 (MTH1), was recently demonstrated as a promising target for cancer eradication. This review summarizes the current progress of developing MTH1 inhibitors with various structures as drug candidates and presents our perspectives toward the therapeutic potential.Image 1

Graphical abstract, Background The therapeutic utility of the effective chemotherapeutic agent cisplatin is hampered by its nephrotoxic effect. We aimed from the current study to examine the possible protective effects of amlodipine through gamma-glutamyl transpeptidase (GGT) enzyme inhibition against cisplatin nephrotoxicity. Methods Amlodipine (5 mg/kg, po) was administered to rats for 14 successive days. On the 10th day, nephrotoxicity was induced by a single dose of cisplatin (6.5 mg/kg, ip). On the last day, blood samples were collected for estimation of kidney function, while kidney samples were used for determination of GGT activity, oxidative stress, inflammatory, and apoptotic markers, along with histopathological evaluation. Results Amlodipine alleviated renal injury that was manifested by significantly diminished serum creatinine and blood urea nitrogen levels, compared to cisplatin group. Amlodipine inhibited GGT enzyme, which participates in the metabolism of extracellular glutathione (GSH) and platinum-GSH-conjugates to a reactive toxic thiol. Besides, amlodipine diminished mRNA expression of NADPH oxidase in the kidney, while enhanced the anti-oxidant defense by activating Nrf2/HO-1 signaling. Additionally, it showed marked anti-inflammatory response by reducing expressions of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB), with subsequent down-regulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1). Moreover, amlodipine reduced Bax/Bcl-2 ratio and elevated hepatocyte growth factor (HGF), thus favoring renal cell survival. Conclusions Effective GGT inhibition by amlodipine associated with enhancement of anti-oxidant defense and suppression of inflammatory signaling and apoptosis support our suggestion that amlodipine could replace toxic GGT inhibitors in protection against cisplatin nephrotoxicity.

Highlights • Purinergic signaling is involved in the pathogenesis of neuroinfectious disease. • P2 receptors have pro-inflammatory and deleterious effects in viral Neuroinfections. • ATP-P2X7 receptor signaling contributes to sepsis-associated encephalopathy. • Adenosine favors brain parasite persistence in cerebral toxoplasmosis., The incidence of infectious diseases affecting the central nervous system (CNS) has been increasing over the last several years. Among the reasons for the expansion of these diseases and the appearance of new neuropathogens are globalization, global warming, and the increased proximity between humans and wild animals due to human activities such as deforestation. Neurotropism affecting normal brain function is shared by organisms such as viruses, bacteria, fungi, and parasites. Neuroinfections caused by these agents activate immune responses, inducing neuroinflammation, excitotoxicity, and neurodegeneration. Purinergic signaling is an evolutionarily conserved signaling pathway associated with these neuropathologies. During neuroinfections, host cells release ATP as an extracellular danger signal with pro-inflammatory activities. ATP is metabolized to its derivatives by ectonucleotidases such as CD39 and CD73; ATP and its metabolites modulate neuronal and immune mechanisms through P1 and P2 purinergic receptors that are involved in pathophysiological mechanisms of neuroinfections. In this review we discuss the beneficial or deleterious effects of various components of the purinergic signaling pathway in infectious diseases that affect the CNS, including human immunodeficiency virus (HIV-1) infection, herpes simplex virus type 1 (HSV-1) infection, bacterial meningitis, sepsis, cryptococcosis, toxoplasmosis, and malaria. We also provide a description of this signaling pathway in emerging viral infections with neurological implications such as Zika and SARS-CoV-2.

Background Laparoscopic procedures under certain pressure have the potential to cause intra-abdominal adhesions. However, the pathomechanism of this disorder is unknown. Release of mast cell mediators due to mast cell degranulation is thought to be the cause. Materials and methods Thirty male Sprague-Dawley rats were grouped into five groups (n = 6 per group): one control group and four intervention groups to which 60 min insufflation was performed using carbon dioxide at 5, 8, 10 and 12 mmHg. Seven days after laparoscopy, we euthanized and evaluated the levels of histamine, tryptase, and chymase of peritoneal fluid, the thickness of ECM of peritoneal tissue, and intraabdominal adhesion scoring system. Results Histamine and tryptase levels in peritoneal fluid were significantly higher at the 10- and 12 mm Hg intervention compared to control (histamine: 0.50 ± 0.35 vs. 0.41 ± 0.41 vs. 0.04 ± 0.02 ng/mL, respectively; and tryptase: 0.69 ± 0.11 vs. 0.65 ± 0.05 vs. 0.48 ± 0.02 ng/ml respectively). The ECM was significantly thicker in the intervention groups at 10- and 12-mm Hg compared to control (71.3 [66.7–85.2] vs. 48.4 [34.5–50.3] vs. 10.25 [8.7–12.1] μm, respectively). Moreover, the intra-abdominal scoring was also significantly higher in the intervention groups at 10- and 12 mm Hg compared to control (4 [0–4] vs. 4.5 [4–5], vs. 0, respectively). Conclusions Laparoscopic procedures increase the release of mast cell mediators in peritoneal fluid, the thickness of ECM and intraabdominal adhesion scoring in rats, implying that it might increase the possibility of intrabdominal adhesion in humans., Highlights • Laparoscopic procedures at specific pressures potentially cause intra-abdominal adhesion, however, its pathomechanism is still challenging to understand. • Laparoscopic procedures increase the release of mast cell mediators in peritoneal fluid, the thickness of ECM and intraabdominal adhesion scoring in rats. • Our findings imply that laparoscopic procedures might increase the possibility of intrabdominal adhesion in humans.

Background & Aims High-dose irradiation is an essential tool to help control the growth of hepatic tumors, but it can cause radiation-induced liver disease (RILD). This life-threatening complication manifests itself months following radiation therapy and is characterized by fibrosis of the pericentral sinusoids. In this study, we aimed to establish a mouse model of RILD to investigate the underlying mechanism of radiation-induced liver fibrosis. Methods Using a small animal image-guided radiation therapy platform, an irradiation scheme delivering 50 Gy as a single dose to a focal point in mouse livers was designed. Tissues were analyzed 1 and 6 days, and 6 and 20 weeks post-irradiation. Irradiated livers were assessed by histology, immunohistochemistry, imaging mass cytometry and RNA sequencing. Mitochondrial function was assessed using high-resolution respirometry. Results At 6 and 20 weeks post-irradiation, pericentral fibrosis was visible in highly irradiated areas together with immune cell infiltration and extravasation of red blood cells. RNA sequencing analysis showed gene signatures associated with acute DNA damage, p53 activation, senescence and its associated secretory phenotype and fibrosis. Moreover, gene profiles of mitochondrial damage and an increase in mitochondrial DNA heteroplasmy were detected. Respirometry measurements of hepatocytes in vitro confirmed irradiation-induced mitochondrial dysfunction. Finally, the highly irradiated fibrotic areas showed markers of reactive oxygen species such as decreased glutathione and increased lipid peroxides and a senescence-like phenotype. Conclusions Based on our mouse model of RILD, we propose that irradiation-induced mitochondrial DNA instability contributes to the development of fibrosis via the generation of excessive reactive oxygen species, p53 pathway activation and a senescence-like phenotype. Lay summary Irradiation is an efficient cancer therapy, however, its applicability to the liver is limited by life-threatening radiation-induced hepatic fibrosis. We have developed a new mouse model of radiation-induced liver fibrosis, that recapitulates the human disease. Our model highlights the role of mitochondrial DNA instability in the development of irradiation-induced liver fibrosis. This new model and subsequent findings will help increase our understanding of the hepatic reaction to irradiation and to find strategies that protect the liver, enabling the expanded use of radiotherapy to treat hepatic tumors.

Cancer is a major public health problem worldwide, and there has been a sustained rise in its incidence in both developing and developed countries. Although there are currently numerous effective therapeutic options for cancer, they sometimes exhibit resistance and obvious side effects. Traditional Chinese medicine (TCM) currently plays a major role in cancer therapy by downregulating the growth of cancer cells through various pathways and by relieving side effects. Studies in cultured human malignant cell lines have demonstrated that Solanum nigrum can control cancer cell proliferation and cancer progression by inducing autophagic and apoptotic cell death. Case–control studies have indicated that TCM can relieve the side effects of cancer therapy. This review provides brief insights into the anticancer effects of TCM, the side effects relieved by TCM, and the role of TCM doctors in cancer treatment., Graphical abstract Image 1, Highlights • Aqueous extracts of Solanum nigrum can control cancer cell proliferation and cancer progression by inducing autophagic and apoptotic cell death. • TCM can relieve side effects such as hematotoxicity, hepatotoxicity, and paronychia caused by conventional anticancer treatments. • A TCM doctor consulting and referral system for patients with cancer should be established.

Two patients with X-linked chronic granulomatous disease without NAPDH oxidase activity and with high responses of flow-mediated vasodilation are reported. Bone marrow transplantation restored oxidative stress to the levels of those in healthy subjects and decreased flow-mediated vasodilation to the levels of those in healthy subjects in both of the patients. (Level of Difficulty: Advanced.), Graphical abstract, Two patients with X-linked chronic granulomatous disease without NAPDH oxidase activity and with high responses of flow-mediated vasodilation are reported…

In 30% of epileptic individuals, intractable epilepsy represents a problem for the management of seizures and severely affects the patient's quality of life due to pharmacoresistance with commonly used antiseizure drugs (ASDs). Surgery is not the best option for all resistant patients due to its post-surgical consequences. Therefore, several alternative or complementary therapies have scientifically proven significant therapeutic potential for the management of seizures in intractable epilepsy patients with seizure-free occurrences. Various non-pharmacological interventions include metabolic therapy, brain stimulation therapy, and complementary therapy. Metabolic therapy works out by altering the energy metabolites and include the ketogenic diets (KD) (that is restricted in carbohydrates and mimics the metabolic state of the body as produced during fasting and exerts its antiepileptic effect) and anaplerotic diet (which revives the level of TCA cycle intermediates and this is responsible for its effect). Neuromodulation therapy includes vagus nerve stimulation (VNS), responsive neurostimulation therapy (RNS) and transcranial magnetic stimulation therapy (TMS). Complementary therapies such as biofeedback and music therapy have demonstrated promising results in pharmacoresistant epilepsies. The current emphasis of the review article is to explore the different integrated mechanisms of various treatments for adequate seizure control, and their limitations, and supportive pieces of evidence that show the efficacy and tolerability of these non-pharmacological options.

Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy (PDT) suffers from the undesirable impediment of local hypoxia in tumors. Moreover, PDT could further worsen hypoxia. Therefore, developing effective strategies for manipulating hypoxia and improving the effectiveness of PDT has been a focus on antitumor treatment. In this review, the mechanism and relationship of tumor hypoxia and PDT are discussed. Moreover, we highlight recent trends in the field of nanomedicines to modulate hypoxia for enhancing PDT, such as oxygen supply systems, down-regulation of oxygen consumption and hypoxia utilization. Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of PDT., Graphical abstract Review of mechanisms and relationships of tumor hypoxia and photodynamic therapy as well as four nanomedicine delivery systems for manipulating tumor hypoxia to enhance the photodynamic therapy.Image 1

Alcoholic liver disease (ALD) is a broad-spectrum disorder, covering fatty liver, cirrhosis, alcoholic hepatitis and in extreme untreated condition hepatocellular carcinoma (HCC) may also develop. Cladonia rangiferina (CR) is a class of lichen having a broad spectrum of pharmacological activity. It is used like traditional natural sources in ancient times in India, China, Sri Lanka, etc. Folkloric record about CR has reported their use as an antimicrobial, antitumor, antioxidant, anti-inflammatory activities, etc. Hence, the present study was requested to ascertain the effect of the ethanolic extract of Cladonia rangiferina (CRE) on alcohol-induced hepatotoxicity. The animals were evaluated for the estimation of the liver in vivo biochemical antioxidant parameters. The liver tissues were further evaluated histopathologically and western blotting examination for localization of apoptotic gene expression that plays a pivotal role in hepatotoxicity. The results of this study reveal that CRE proves to be helpful in the treatment of alcohol-induced hepatotoxicity and oxidative stress. Results of different markers have shown that among all, CRE has demonstrated the best hepatoprotective activity. These observations say about the importance of the components of the extract. The ameliorative action of CRE in alcoholic liver damage may exist due to antioxidant, anti-inflammatory, and anti-apoptotic activities. Keywords: Hepatotoxicity, Cladonia rangiferina, Inflammation, Apoptosis

Highlights • Intravenous iron supplementation provides symptomatic relief in patients with heart failure and concomitant iron deficiency. • The current definition of iron deficiency based on ferritin, Summary To date, 3 clinical trials have shown symptomatic benefit from the use of intravenous (IV) iron in patients with heart failure (HF) with low serum iron. This has led to recommendations in support of the use of IV iron in this population. However, the systemic and cellular mechanisms of iron homeostasis in cardiomyocyte health and disease are distinct, complex, and poorly understood. Iron metabolism in HF appears dysregulated, but it is still unclear whether the changes are maladaptive and pathologic or compensatory and protective for the cardiomyocytes. The serum markers of iron deficiency in HF do not accurately reflect cellular and mitochondrial iron levels, and the current definition based on the ferritin and transferrin saturation values is broad and inclusive of patients who do not need IV iron. This is particularly relevant in view of the potential risks that are associated with the use of IV iron. Reliable markers of cellular iron status may differentiate subgroups of HF patients who would benefit from cellular and mitochondrial iron chelation rather than IV iron.

Herpes simplex virus type 1 (HSV-1), a neurotropic herpes virus, is able to establish a lifelong latent infection in the human host. Following primary replication in mucosal epithelial cells, the virus can enter sensory neurons innervating peripheral tissues via nerve termini. The viral genome is then transported to the nucleus where it can be maintained without producing infectious progeny, and thus latency is established in the cell. Yin–Yang balance is an essential concept in traditional Chinese medicine (TCM) theory. Yin represents stable and inhibitory factors, and Yang represents the active and aggressive factors. When the organism is exposed to stress, especially psychological stress caused by emotional stimulation, the Yin–Yang balance is disturbed and the virus can re-engage in productive replication, resulting in recurrent diseases. Therefore, a better understanding of the stress-induced susceptibility to HSV-1 primary infection and reactivation is needed and will provide helpful insights into the effective control and treatment of HSV-1. Here we reviewed the recent advances in the studies of HSV-1 susceptibility, latency and reactivation. We included mechanisms involved in primary infection and the regulation of latency and described how stress-induced changes increase the susceptibility to primary and recurrent infections., Graphical abstract Following primary infection, HSV-1 establishes latency and reactivates under stress. Stress disturbs inner immune Yin–Yang balance, increasing the susceptibility to HSV-1 infection. In latent infection, stress induces changes in hormone level, chromosomal modification and oxidation, thereby disturbing the Yin–Yang balance between HSV-1 and the host defense, leading to recurrent diseases.Image 1

Visual Abstract, Highlights • The reactive oxygen species–generating enzyme Nox2 is up-regulated in the leaflets of both rabbit and human with CAVD. • Nox2 is markedly induced in cultured porcine AVICs after osteogenic stimulation. Knockdown of endogenous Nox2 substantially suppressed AVIC calcification. • Celastrol, a natural compound capable of inhibiting Nox2 activity, significantly decreased AVIC calcification in vitro, and mitigated the severity of aortic valve fibrosis, calcification, and stenosis in a rabbit model of CAVD in vivo. • The protective effects of celastrol may, in part, involve the inhibition of Nox2-mediated glycogen synthase kinase 3 beta/β-catenin pathway., Summary This study sought to investigate whether reactive oxygen species (ROS)–generating reduced nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2) contributes to calcific aortic valve disease (CAVD) or whether celastrol, a natural Nox2 inhibitor, may provide potential therapeutic target for CAVD. CAVD is an active and cellular-driven fibrocalcific process characterized by differentiation of aortic valvular interstitial cells (AVICs) toward an osteogenic-like phenotype. ROS levels increase in calcified aortic valves, while the sources of ROS and their roles in the pathogenesis of CAVD are elusive. The roles of Nox2 and the effects of celastrol were studied using cultured porcine AVICs in vitro and a rabbit CAVD model in vivo. Nox2 proteins were significantly upregulated in human aortic valves with CAVD. In vitro, Nox2 was markedly induced upon stimulation of AVICs with osteogenic medium, along with the increases in ROS production and calcium nodule formation. Celastrol significantly decreased calcium deposition of AVICs by 35%, with a reduction of ROS generation. Knockdown of endogenous Nox2 substantially suppressed AVIC calcification by 39%, the inhibitory effect being similar to celastrol treatment. Mechanistically, either celastrol treatment or knockdown of Nox2 significantly inhibited glycogen synthase kinase 3 beta/β-catenin signaling, leading to attenuation of fibrogenic and osteogenic responses of AVICs. In a rabbit CAVD model, administration of celastrol significantly reduced aortic valve ROS production, fibrosis, calcification, and severity of aortic stenosis, with less left ventricular dilatation and better preserved contractile function. Upregulation of Nox2 is critically involved in CAVD. Celastrol is effective to alleviate CAVD, likely through the inhibition of Nox2-mediated glycogen synthase kinase 3 beta/β-catenin pathway in AVICs.

Background & Aims Interleukin (IL)23 is a major contributor to inflammatory bowel disease (IBD) pathogenesis and is being pursued as a therapeutic target, both through targeting IL23 alone or in combination with IL12. Unexpected trial outcomes highlight the importance of understanding the cell types through which IL23 regulates immune responses, and how IL23 and IL12 compare in these responses. Macrophages are key players in IBD, and IL23 recently was found to promote inflammatory outcomes in human macrophages. This raises the possibility that IL23 may be required for additional essential macrophage functions, in particular microbial clearance, such that either blocking the IL23 pathway or the IL23R–R381Q IBD-protective variant may reduce macrophage-mediated microbial clearance. Methods We analyzed protein expression, signaling, bacterial uptake, and intracellular bacterial clearance in human monocyte-derived macrophages through Western blot, flow cytometry, and gentamicin protection. Results Autocrine/paracrine IL23 was critical for optimal levels of pattern-recognition-receptor (PRR)-induced intracellular bacterial clearance in human macrophages. Mechanisms regulated by IL23 included induction of pyruvate dehydrogenase kinase 1-dependent bacterial uptake, and up-regulation of reactive oxygen species through nicotinamide adenine dinucleotide phosphate oxidase members, nitric oxide synthase 2, and autophagy through ATG5 and ATG16L1. Complementing these pathways in IL23R-deficient macrophages restored PRR-induced bacterial uptake and clearance. Janus kinase 2, TYK2, and STAT3 were required for IL23-induced mechanisms. IL23 and IL12 induced antimicrobial pathways to similar levels in human macrophages. Relative to IL23R–R381, transfected IL23R–Q381, or monocyte-derived macrophages from IL23R–Q381 carriers showed reduced bacterial uptake and clearance. Conclusions We identify that autocrine/paracrine IL23 is required for optimal PRR-enhanced macrophage bacterial uptake and intracellular bacterial clearance, define mechanisms regulating IL23R-induced bacterial clearance, and determine how the IBD-protective IL23R–R381Q variant modulates these processes., Graphical abstract

Severe inborn cardiac malformations are typically corrected in cardioplegia, with a cardio-pulmonary bypass (CPB) taking over body circulation. During the operation the arrested hearts are subjected to a global ischemia/reperfusion injury. Although the applied cardioplegic solutions have a certain protective effect, application of additional substances to reduce cardiac damage are of interest.18 domestic piglets (10–15 kg) were subjected to a 90 min CPB and a 120 min reperfusion phase without or with the application of epigallocatechin-3-gallate (10 mg/kg body weight) or minocycline (4 mg/kg body weight), with both drugs given before and after CPB. 18 additional sham-operated piglets without or with epigallocatechin-3-gallate or minocycline served as controls. In total 36 piglets were analyzed (3 CPB-groups and 3 control groups without or with epigallocatechin-3-gallate or minocycline respectively; 6 piglets per group). Hemodynamic and blood parameters and ATP-measurements were assessed. Moreover, a histological evaluation of the heart muscle was performed. Results: Piglets of the CPB-group needed more catecholamine support to achieve sufficient blood pressure. Ejection fraction and cardiac output were not different between the 6 groups. However, cardiac ATP-levels and blood lactate were significantly lower and creatine kinase was significantly higher in the three CPB-groups. Markers of apoptosis, hypoxia, nitrosative and oxidative stress were significantly elevated in hearts of the CPB-group. Nevertheless, addition of epigallocatechin-3-gallate or minocycline significantly reduced markers of myocardial damage. Noteworthy, EGCG was more effective in reducing markers of hypoxia, whereas minocycline more efficiently decreased inflammation. Conclusions: While epigallocatechin-3-gallate or minocycline did not improve cardiac hemodynamics, markers of myocardial damage were significantly lower in the CPB-groups with epigallocatechin-3-gallate or minocycline supplementation. Keywords: Cardio-pulmonary bypass, Heart, Minocycline, EGCG, ischemia/reperfusion injury

Graphical abstract, This study examined the changes in haematological and biochemical variables in response to gastric mucosa injury in male Wistar rats divided into four groups according to their ages (3, 6, 12, and 18 months). 0.2 ml of acetic acid was injected intraluminal into the stomach glandular portion of each rat for 45 seconds under anaesthesia. Collection of blood and stomach samples occurred on days 3, 7, 14 and 21 post-induction of gastric ulcer. The results obtained from this study showed 100 % area of gastric mucosa healed in 3-month old rats, 91.72 %, 68.52 % and 62.81 % area of mucosa treated in 6, 12 and 18-month old rats respectively on day 21 post-induction of gastric ulcer. Increased circulation of blood cells in younger rats occurred, neutrophil-lymphocyte ratio (NLR) was decreased in younger rats (3 and 6 months) significantly (p < 0.05) when compared to older rats (12 and 18 months). Lipid peroxidation and glutathione (GSH) levels were elevated in older rats (12 and 18 months) significantly (p < 0.05) when compared to younger rats (3 and 6 months). In comparison, superoxide dismutase (SOD) and catalase levels were decreased in older rats (12 and 18 months) significantly (p < 0.05) when compared to younger rats (3 and 6 months). Histological evaluation showed evidence of early healing with re-epithelialisation and angiogenesis in younger rats, but older rats showed delayed healing. The study showed that the slower rate of healing of gastric ulcer with advancing age in rats might be due to reducing circulating blood cells and anti-inflammatory activities during healing via a lipid peroxidation-dependent mechanism.

Highlights • Occurrence of parasites in fish could bio accumulate heavy metals by as much as 200 % more than values present in fish tissues. • Parasitic infection in fish is positively skewed towards male fish. • Parasitism in fish alters histological structures of vital fish organs. • Combined effects of parasitism and heavy metal pollution in fish elicits antioxidant response in fish., Heavy metal toxicity in aquatic life as a result of human activities poses a grave health threat to water quality, aquatic and human life. Parasites may serve as indicators of heavy metal pollution. This research investigated the health status of the fish Heterotis niloticus viz-a-viz quality of the water and sediments in Lekki lagoon, parasitic infection, presence of heavy metals and oxidative stress response in the liver and intestine of the fish. Parasites recovered were also analyzed for the extent of bioaccumulation of heavy metals. The metals in water, sediments, parasites, and fish were analyzed using Atomic Absorption Spectrometry. Heavy metal concentrations in the surface water were generally below regulatory limits of World Health Organization. Sediment had high levels of aluminium (124.78 mg/kg) and iron (327.41 mg/kg); other heavy metals were below regulatory limits. Tenuisentis niloticus, an acanthocephalan, was the only parasite recovered. Seventy (70) out of 100 fish sampled were infected with the parasite. T. niloticus bioaccumulated Cd, Ni, and Pb between 65 to 100 times more than the liver and 12 to 200 times more than the intestine. Other metals bioaccumulated from the host tissues by the parasite had the magnitude between 1 to 12 times as the liver and 1 to 30 times as the intestine. There were significant differences in the activities of antioxidant enzymes between the parasitized and non-parasitized fishes. Fish tissues also showed histological alterations, ranging from mild infiltration of inflammatory cells to moderate inflammation and haemorrhagic lesions. Human activities that introduce stressors into the lagoon should be controlled.

Parenteral nutrition-associated liver disease (PNALD) is a liver dysfunction caused by various risk factors presented in patients receiving total parenteral nutrition (TPN). Omega-6 rich Intralipid® and omega-3 rich Omegaven® are two intravenous lipid emulsions used in TPN. TPN could affect the hepatic expression of genes in anti-oxidative stress, but it's unknown whether TPN affects genes in drug metabolism. In this study, either Intralipid®- or Omegaven®-based TPN was administered to mice and the expression of a cohort of genes involved in anti-oxidative stress or drug metabolism was analyzed, glutathione (GSH) levels were measured, and protein levels for two key drug metabolism genes were determined. Overall, the expression of most genes was downregulated by Intralipid®-based TPN (Gstp1, Gstm1, 3, 6, Nqo1, Ho-1, Mt-1, Gclc, Gclm, Cyp2d9, 2f2, 2b10, and 3a11). Omegaven® showed similar results as Intralipid® except for preserving the expression of Gstm1 and Cyp3a11, and increasing Ho-1. Total GSH levels were decreased by Intralipid®, but increased by Omegaven®. CYP3A11 protein levels were increased by Omegaven®. In conclusion, TPN reduced the expression of many genes involved in anti-oxidative stress and drug metabolism in mice. However, Omegaven® preserved expression of Cyp3a11, suggesting another beneficial effect of Omegaven® in protecting liver functions., Graphical abstract Total parenteral nutrition reduces the expression of genes involved in drug metabolism in mice, including Cyp3a11, with the degree more severe by a plant lipid-based formulation than fish-oil-based formulation. Therefore, patients on total parenteral nutrition should be monitored closely for drug–drug interactions.Image 1

Graphical abstract, Highlights • Lipoteichoic acid (LTA) reduced the levels of the antioxidant enzymes in H9c2 cells. • LTA from Streptococcus sanguinis induced ROS production in H9c2 cells. • Low antioxidant enzymes levels and ROS production could be related to infective endocarditis (IE). • Antioxidants could protect against oxidative stress induced by LTA in IE., Infective endocarditis (IE) is an illness where the heart is invaded by bacteria, like Streptococcal and Staphylococcal species that contain lipoteichoic acid (LTA) related to an essential role in this disease. This study is the first in evaluating antioxidant enzyme levels in embryonic cardiomyocyte cell line (H9c2) induced by LTA from Streptococcus sanguinis. LTA increased reactive oxygen species (ROS) and reduced the levels of the antioxidant enzymes glutathione peroxidase, superoxide dismutase (SOD)-1 and catalase (CAT) but did not affect glutathione content. At the highest LTA concentration (15 μg/ml), SOD-1 and CAT levels did not change, and this effect was related to the induction of mRNA levels of Nrf2 induced by LTA. These results suggest that low antioxidant enzyme levels and ROS production could be related to IE.