Systemic Toxic Effects Research Articles

A 10-year Scientometric Analysis of the Characteristics of the Worldwide Publication on the Toxic Effects of Fluoride

To perform a 10-year scientometric analysis of the characteristics of the worldwide publication on the toxic effects of fluoride. A bibliometric study of the worldwide scientific production on the toxic effects of fluoride during the years 2011-2020 was performed. All metadata from the Scopus database were evaluated. These were then exported to SciVal (Elsevier) for analysis of quantity, collaboration, and impact indicators. We found that the "Biological Trace Element Research" was the most productive journal with 22 published manuscripts and that the most productive universities on the systemic toxic effects of fluoride on the body were Shanxi Agricultural University, Guizhou Medical University, and Huazhong University of Science and Technology with 31, 11, and 10 manuscripts, respectively. In addition, it was found that most of the world scientific production on the toxic effects of fluoride was published in Q1 level journals (top 25%). Finally, it was concluded that most of the total production on this topic was published in high-impact Q1 journals, with China being the leading country in terms of number and impact of publications. Finally, there was evidence of collaboration between the United States, China, and India, being the countries that led in co-authorship by country. This research is of clinical importance as it allows the identification of the most productive institutions, authors, and countries in this field. In this way, strategic alliances can be established to enhance the development of research.

Multi-drug loaded microneedles for emergency treatment of snakebite envenomation

Snakebite envenomation is a WHO classified priority neglected disease, which manifests multiple local and systemic toxic effects. Intravenous antivenom therapy is the treatment of choice in clinical settings but it cannot be employed for pre-hospital management of envenomation cases due to certain limitations. On-field first-aid measures presently include use of pressure bandage immobilization (PBI), which has sub-optimal efficacy in managing snakebite casualties. There is therefore an urgent need for developing non-immunological, therapeutic interventions that could be self-administered immediately after snakebite, alone or in tandem with PBI, to reduce the morbidity and mortality. Venom toxins enter into the bloodstream via lymphatic pathway [e.g., high molecular weight (HMw) toxins] or directly ingress into the vasculature due to cytotoxic endothelium disruption [e.g., low molecular weight (LMw) toxins]. Recent literature has identified some pharmacological targets, which when applied topically impede the systemic absorption of HMw venom toxins by modulating lymphatic transit time, whereas a few others act as direct inhibitors of LMw toxins, when injected parentally. Based on available evidences our hypothesis shall lead to deliver formulation containing combination of drugs applied topically through convenient, self-administrated microneedles, either to delay absorption and lymphatic transit of HMw venom toxins into the bloodstream or to inhibit the mechanistic pathway of LMw toxins, and could therefore be more useful for pre-hospital management following snakebite as compared to PBI alone.

Study on the toxic-mechanism of triclosan chronic exposure to zebrafish (Danio rerio) based on gut-brain axis

Triclosan (TCS), as a broad-spectrum bactericide, is extensively used in the fine chemical and textile industries. It is recognized as a new type of environmental endocrine disruptor with frequent detection and environmental pollution. However, the toxicity mechanism regarding neurodevelopment and neurobehavior remains unclear. This study is intended to explore the underlying toxic mechanism of TCS based on gut-brain axis. TCS-chronic exposure affected the development of zebrafish, induced feminization, obesity physical signs and abnormal organ index and caused neurobehavioral abnormalities by inhibiting both neurotransmitter acetylcholinesterase and dopamine activity, promoting brain neuron apoptosis and accelerating diencephalic lesions. Meanwhile, TCS-chronic exposure led to gut microbiota dysbiosis and decreased diversity, such as increased pathogenic bacteria and decreased probiotics in adult zebrafish gut, which caused many pathological damages, including partial shedding and ablation of intestinal villi, inflammatory infiltration, thinning of intestinal wall, and increased goblet cell in villus. Based on the communication between intestinal peripheral nerves and CNS, the above histopathological injuries and disorders were well underpinned and illustrated by the changes of biomarkers and the expression of related marker genes in the gut-brain axis. Additionally, short-chain fatty acids (SCFA), as the regulators of intestinal sympathetic nerve activation, are also secreting products of intestinal microflora and play a crucial role in regulating the balance of intestinal flora and protecting intestinal homeostasis. SCFA in low doses can effectively alleviate and rescue the toxic effects under TCS exposure, which evidenced that TCS exerted systemic toxic effects on the gut-brain axis by influencing the composition and diversity of gut flora in zebrafish, and fully demonstrated the interaction effect between intestine and brain. Hence, these findings contribute to the understanding, prevention, and diagnosis of endocrine disrupting diseases caused by environmental pollutants from the perspective of the gut-brain axis, and strengthening the early warning, management and control of TCS pollution.

Impacts of exposure to topical calcineurin inhibitors on metabolism in vitiligo infants.

Tacrolimus ointment is a recently developed topical immunomodulator that has been approved for use in patients with vitiligo older than 2 years. Concern regarding potential systemic toxic effects has limited treatment options for children younger than 2 years. We wanted to determine whether topical tacrolimus therapy is safe and effective in patients with vitiligo younger than 2 years. The present 6-month clinical trial was conducted to evaluate the efficacy and safety of 0.03% tacrolimus in the treatment of vitiligo in children under 2 years of age. Meanwhile, serum and urine samples were collected, and liquid chromatography-mass spectrometry was performed to generate the serum and urine metabolic profile data of patients and healthy controls. The overall response rate at the sixth month, which was defined by the degree of re-pigmentation, was 100%. As revealed by blood monitoring and metabolite detection 6 months later, there was no difference between the treatment group and the control group. There is no evidence that long-term topical application of 0.03% tacrolimus ointment will cause metabolite or other physical changes in the body. Tacrolimus ointment appears to be effective and safe in the treatment of vitiligo in children younger than 2 year. http://www.chictr.org.cn identifier: ChiCTR 2100045920. We first reported the efficacy and safety of topical application of 0.03% tacrolimus ointment in infants with vitiligo characterized by the metabolites. There is no evidence that long-term topical application of 0.03% tacrolimus ointment will cause metabolite or other physical changes in the body. This study provide evidence for the TCI treatment of infants with vitiligo.

Metal Complexes in Target-Specific Anticancer Therapy: Recent Trends and Challenges

Cancer is characterized by abnormal cell differentiation in or on the part of the body. The most commonly used chemotherapeutic drugs are developed to target rapidly dividing cells, such as cancer cells, but they also damage healthy epithelial cells. This has serious consequences for normal cells and become responsible for the development of various disorders. Several strategies for delivering the cytotoxic drugs to cancerous sites that limit systemic toxicity and other adverse effects have recently been evolved. Among them, biomolecule-conjugated metal complexes-based cancer targeting strategies have shown tremendous advantages in cancer therapy. This review focuses on several chemoselective biomolecules-bound metal complexes as prospective cancer therapy-targeted agents. In this review, we presented the details of the various extra- and intracellular targeting mechanisms in cancer therapy. We also addressed the current clinical issues and recent therapeutic strategies in targeted cancer therapy that may pave a way for the future direction of metal complexes-based targeted cancer therapy.

Eugenol derivatives with 1,2,3-triazole moieties: Oral treatment of cutaneous leishmaniasis and a quantitative structure-activity relationship model for their leishmanicidal activity

Leishmaniasis is a group of neglected vector-borne tropical diseases caused by protozoan parasites of the genus Leishmania that multiply within phagocytic cells and have a wide range of clinical manifestations. Cutaneous leishmaniasis (CL) is a serious public health that affects more than 98 countries, putting 350 million people at risk. There are no vaccines that have been proven to prevent CL, and the treatment relies on drugs that often have severe side effects, justifying the search for new antileishmanial treatments. In the present investigation, it is demonstrated that 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(4-methylbenzyl)-1H-1,2,3-triazole (7k) presents significant antileishmanial activity (IC50 of 7.4 μmol L−1 and 1.6 μmol L−1 for promastigote and amastigote forms, respectively), low cytotoxicity against macrophage cells (IC50 of 211.9 μmol L−1), and a selective index of 132.5. Under similar conditions, compound 7k outperformed glucantime and pentamidine, two commonly used drugs in clinics. In vivo assays on CL-infected female BALB/c mice demonstrated that compound 7k had activity similar to intralesional glucantime when administered orally, with decreased lesion and parasitic load, and a low systemic toxic effect. Given the importance of understanding the relationship between compound structure and biological activity in the research and development of new drugs, the development of a quantitative structure-activity relationship (QSAR) model for the leishmanicidal activity presented by the eugenol derivatives with 1,2,3-triazole functionalities is also described herein. This study demonstrates the therapeutic potential of orally active eugenol derivatives against CL and provides useful insights into the relationship between the chemical structures of triazolic eugenol derivatives and their biological profile.

Smart dual responsive nanocarriers with reactive oxygen species amplification assisted synergistic chemotherapy against prostate cancer

Conventional chemotherapy efficacy is impeded by poor water solubility, inferior tissue targeting, and severe systemic toxic effect. Synergistic chemotherapy has become prominent with the stimulus–response drug delivery system (DDS) to treat solid malignancies. The most popularly employed responsive stimulus is reactive oxygen species (ROS), which is proven to primarily sensitize chemotherapy and enhance antitumor impact. In this study, we have successfully developed smart dual responsive nanocarriers with ROS self-amplification, particularly responding to disassemble under the high levels of ROS and esterase in the tumor microenvironment (TME) and to release docetaxel (DTX) efficiently. Additionally, we utilized palmitoyl ascorbate (PA) as a stabilizer by taking advantage of its amphiphilic structure. PA is also an excellent ROS generator that produces a large amount of hydrogen peroxide (H2O2) in TME to achieve ROS self-amplification. Also, elevated levels of ROS could continue to activate ROS-sensitive thioketal and make the remaining nanocarriers disassemble for sustaining the release of chemotherapeutics, realizing a positive feedback loop for ROS generation and ROS amplification, as well as sensitizing chemotherapy efficacy. The smart dual responsive nanocarriers may serve as a promising and prospective strategy for treating prostate cancer and promoting synergistic cancer therapy.

Inflammatory cytokines analysis in C57BL/6 mouse skin after dermal exposure with chemical threat agent phosgene oxime

Phosgene Oxime (dichloroform oxime; CX), an urticant categorized as a vesicating agent, is a potential chemical threat agent. Its exposure causes rapid and painful dermal injury and systemic toxic effects. CX exposure can result in enzyme inactivation, corrosive injury, and cell death with rapid tissue destruction, and induce the recruitment of immune cells. However, the mechanism of CX‐induced skin toxicity and inflammation is not known. Studies in our lab have shown that CX exposure causes mast cell degranulation and release of inflammatory mediators like COX‐2, MMP‐9, myeloperoxidase, and an inflammatory response in the skin. In the present study, we analyzed the inflammatory cytokine profile in male and female C57BL/6 mouse skin following dermal CX exposure (neat CX for either 0.5 or 1.0 min using two 12 mm vapor caps on the dorsal skin at MRIGlobal). Cytokine array analyses showed an increase in the pro‐inflammatory cytokines IL‐6 (Interleukin 6) and TNF‐α (Tumor Necrosis Factor Alpha) in both male and female mice at 24h post CX‐exposure. KC (neutrophil chemoattractant), MCP‐1 (Monocyte chemoattractant), MCSF (Macrophage colony‐stimulating factor) and RANTES (T cell, monocyte attractant) increased in both sexes at day 3 post CX‐exposure, showing involvement of immune cells in the CX‐induced injury. IL‐13, an allergic inflammation and several diseases’ mediator was found to be increased at later time point in female mice and at 2 hours after 1.0 min CX exposure in male mice. IL‐4 and IL‐5 levels decreased at 24 h but were increased at day 3 post 0.5 min CX exposure. Altogether, our results show immune cell infiltration with changes in inflammatory cytokines. Similar Inflammatory cytokine changes from CX exposure were observed in male and female mice; however, slightly different patterns were evident in some cytokines in female mice that related to the observed difference in the inflammatory response and somewhat faster dermal wound healing. Further molecular analysis is underway to determine the signaling pathways involved in CX‐induced dermal inflammation and toxicity for identifying the therapeutic targets.

Mechanism of Phosgene Oxime Induced Skin Toxicity in C57BL/6 Mouse Model

Phosgene Oxime (CX) is a potent chemical warfare agent. It is grouped with vesicants; however, its effect resembles of an urticant or nettle agent. CX has faster penetration compared to other vesicating chemical warfare agents and causes erythema, urticaria, blanching, itching hives, necrosis, and systemic toxic effects upon exposure. The mechanism of CX induced toxicity is not known and there are no approved therapies. We have shown that dermal CX exposure in SKH‐1 hairless mice causes clinical lesions, epidermal cell death, mast cell degranulation, infiltration of immune cells, and increase in the level of DNA damage and inflammatory markers. In this study we examined the mechanism of CX‐induced inflammatory response in C57BL/6 mice. Dorsal skin of mice was exposed to neat CX for 0.5 or 1.0 min using two 12 mm vapor caps at MRI Global. CX exposure caused decrease in heart rate and breath rate with significant mortality (50%) after 1.0 min CX exposure. CX exposure caused erythema, and edema at the exposure site and led to increase in epidermal thickness. Significant mast cell degranulation was observed within 2h of CX exposure in male and female mice at both the exposure durations. The increase in mast cell degranulation was associated with increased tryptase and chymase levels in the mouse skin. CX exposure also led to increased expression of inflammatory mediators, cyclooxygenase‐2 (COX‐2), matrix metallopeptidase‐9 (MMP‐9), myeloperoxidase (MPO), and MAP kinases JNK. Inflammatory cytokines and chemokines were analyzed in the skin tissue lysates using cytokine array. CX exposure caused increases in several pro‐inflammatory cytokines and chemokines including IL‐6 and TNF‐α, and a decrease in anti‐inflammatory cytokines IL‐4 and IL‐10. Together, these results suggest mast cells as important contributors of CX induced dermal inflammation and toxicity. Further studies are being carried out using WT (C57BL/6) and mast cell deficient mice to evaluate the role of mast cells in CX‐induced toxicity.

Multifunctional Nanoparticles Co-Loaded with Perfluoropropane, Indocyanine Green, and Methotrexate for Enhanced Multimodal Imaging of Collagen-Induced Arthritis.

Rheumatoid arthritis (RA), a common chronic inflammatory joint disease with features of synovitis and pannus formation, may lead to irreparable joint damage and disability. Methotrexate (MTX) is known as the cornerstone of therapy for RA. However, the therapeutic effects of MTX are unsatisfactory due to its low retention in the inflammatory joints as well as systemic toxic effects. Fortunately, the use of multifunctional nanoparticles for diagnostics and in treatment shows potential for application as a strategy for traceable and targeted RA therapy. This research aims to develop novel nanoparticles that carry with perfluoropropane (PFP), indocyanine green (ICG), and MTX and investigate the corresponding enhancement in multimodal imaging both in vitro and in vivo. A modified double emulsion method was applied for the construction of encapsulated PFP-O2, ICG, and MTX (OIM@NPs), and the essential properties of the developed NPs were determined. The fluorescence and ultrasonic and photoacoustic imaging characteristics were experimentally evaluated both in in vitro and in vivo models. The OIM@NPs are stable and efficient nanoagents. They enable more targeted distribution in the inflammatory joints in RA rats. Moreover, the NPs play an important role as contrast agents for prominent ultrasound and photoacoustic imaging after laser and low-intensity focused ultrasound excitation, providing precision guidance and monitoring for subsequent treatment. This research may provide a novel and efficient strategy to better enable monitoring in inflammatory joints of RA patients and the developed NPs may be a promising nanoplatform for integrating multimodal image monitoring.

Evaluation and Assessment of the Acute Toxic Potential of <i>Sansevieria cylindrica</i> and </i>Plumeria obtusa</i> Plant Extracts in Wistar Albino Rats

<em>Sansevieria cylindrica</em> (SC) Bojer ex Hook. (Asparagaceae) and <em>Plumeria obtusa</em> (PO) L. (Apocynaceae) are indoor and outdoor ornamental plants respectively. These plants are traditionally used by the local healers during accidental injuries. However, their toxicological properties are very poorly explored over folkloric usage. Therefore, the present study evaluated the toxic potencies of SC leaves and PO seed Hydro-Alcoholic Extract (SCPOHAE) through acute oral dose (14-days) administration in female Wistar rats. Safety of the SCPOHAE was evaluated as per Organization for Economic Co-operation and Development (OECD) Acute Oral Toxicity study guidelines 423. The female Wistar rats were divided into three groups (n=3). A single oral dose of 2000 mg/kg of body weight of individual extract and 1:1 blend was administered to each animal. The animals were closely observed for clinical signs, neurobehavioral changes, morbidity, and mortality if any for the first half an hour and then every hour for the first four hours followed by observation every 24–hours for 14 days. Changes in food and water consumption, body weight were monitored daily during the study. On day 1 and day 15 blood samples were collected to evaluate changes in the hematology and biochemistry parameters. The urine samples were also collected for urine analysis parameters. Animals were sacrificed on day 15 and organ samples of liver and kidney were collected for histopathological findings. The SCPOHAE individually and also as 1:1 blend at the limit dose (2000 mg/kg, body weight) did not cause death and did not induce any remarkable and abnormal clinical signs, indicative of systemic toxicity, in rats during the treatment period of 14–days. The statistically non-significant small differences in the body weight were observed. <strong>Conclusion:</strong> The oral administration of SCPOHAE did not cause any systemic toxic effects. In conclusion, the No-observed-Adverse-Effect Level (NOAEL) of these extracts in rats was found to be greater than 2000 mg/kg.

In situ Co-Delivery of Doxorubicin and Cisplatin by Injectable Thermosensitive Hydrogels for Enhanced Osteosarcoma Treatment.

PurposeOsteosarcoma is considered as the most common primary malignant bone tumor in children and adolescents, and the treatments including chemotherapy and surgery were far from satisfactory. Localized tumor treatments by hydrogels incorporating combined chemotherapeutic drugs have recently emerged as superior approaches for enhanced anti-tumor effects and reduced systemic toxicity.MethodsA novel injectable thermosensitive poly (lactide-co- glycolide)-poly (ethylene glycol)-poly(lactide-co-glycolide) triblock copolymer hydrogel containing doxorubicin and cisplatin for the localized chemotherapy of osteosarcoma were synthesized and characterized. The in vitro drug release properties of the drugs-loaded hydrogels were investigated. To study the anti-tumor efficacy of hydrogels depots in vitro, the cytotoxicity and apoptosis rate against Saos-2 and MG-63 cells were evaluated by MTT, Annexin V and PCR methods. The in vivo synergistic anti-tumor efficacy of the multi-drugs co-loaded hydrogels was investigated by human osteosarcoma xenografts. Additionally, the systemic toxic side effects were evaluated by ex vivo histological analysis of the major organs of the mice.ResultsThe PLGA-PEG-PLGA copolymer solution underwent a sol-gel transition at appropriate temperature and degraded in the PBS, presenting a friendly biocompatibility in vitro. The in vitro cell viability tests demonstrated that DOX and CDDP co-loaded hydrogels exhibited synergistic anti-proliferation effect, due to the sustained release of drugs from the drugs-loaded hydrogel. The treatment with DOX and CDDP co-loaded hydrogel led to the highest efficiency in inhibiting the tumor growth, enhanced tumor necrosis rate and increased regulation of the apoptosis-related gene expressions, indicating a synergistic anti-tumor efficacy in vivo. Additionally, ex vivo histological analysis of the nude mice exhibited low systemic toxicity.ConclusionThe combination treatment of osteosarcoma by localized, sustained co-delivery of DOX and CDDP by PLGA-PEG-PLGA hydrogel may serve as a promising strategy for efficient clinical treatment of osteosarcoma.

In Situ Nanoparticle Self-Assembly for Combination Delivery of Therapeutics to Non-Small Cell Lung Cancer.

Chemotherapy often experiences several challenges including severe systemic toxicity and adverse effects. The combination chemotherapy arose as an effective clinical practice aimed at reducing doses of drugs to achieve synergistic actions with low toxicity. Our recent efforts demonstrated a synergistic therapeutic benefit of gambogic acid (GA) and gemcitabine (Gem) against lung cancer. However, simultaneous delivery of these two drugs at the tumor site is highly challenging. Therefore, the development of an injectable formulation that can effectively deliver both hydrophobic (GA) and hydrophilic (Gem) drugs in one formulation is a clinically unmet need. Herein, this study reports an in situ human serum albumin (HSA)- and tannic acid (TA)-mediated complexed GA and Gem nanoparticles (G-G@HTA NPs). G-G@HTA NP formation was confirmed by the particle size, Fourier transform infrared spectroscopy, and 1H NMR spectroscopy. The superior therapeutic activity of G-G@HTA NPs was demonstrated by multiple in vitro functional assays. Additionally, G-G@HTA NPs revealed an obvious and precise targeting of tumors in vivo. The promoted and more synergistic anti-tumor efficacy of G-G@HTA NPs was attained than that of combined treatments and single drug treatments. These events have resulted in no apparent systemic and organ toxicities. Together, this study suggests that in situ HSA-TA-based combinatorial treatment strategy is a suitable approach for application in lung cancer treatment.

Part I: Insect stings and bites—Beyond the realm of bee and wasp allergies

Summary Background Insects are a very diverse group of animals and valuable members of any ecosystem. Allergies to bees and wasps (order: Hymenoptera) are well known in Europe. Allergies, toxicities, and the spread of diseases by other insects are also possible but quite frequently are not diagnosed. Sources A MEDLINE search on allergy caused by stinging and biting insects apart from bees and wasps was conducted. All relevant articles were evaluated, and a selection of relevant publications and cases from our outpatient units are used to illustrate our arguments. Content and implications Allergies to insects following bites and stings are common. Ant stings, mainly from imported fire ants, frequently lead to severe anaphylaxis, and their venom can elicit systemic toxic effects. Stings and bites of various other ant species can also lead to severe allergic reactions. Mosquito stings and horsefly or other Diptera stings may elicit severe local and IgE-mediated systemic reactions. True bugs (Hemiptera) are hematophagous insects and can also cause severe allergic reactions, in addition to being feared for transmitting diseases.

Radiotherapy-induced enrichment of EGF-modified doxorubicin nanoparticles enhances the therapeutic outcome of lung cancer

Chemotherapy is the primary treatment for advanced non-small-cell lung cancer (NSCLC). However, related dose-dependent toxicity limits its clinical use. Therefore, it is necessary to explore new strategies for improving the clinical outcomes while reducing the side effects of chemotherapy in the treatment of NSCLC. In this study, we designed and synthesized epidermal growth factor (EGF)-modified doxorubicin nanoparticles (EGF@DOX-NPs) that selectively targets the epidermal growth factor receptor (EGFR) overexpressed in lung tumor cells. When administered in combination with low-dose X-ray radiotherapy (RT), the NPs preferentially accumulated at the tumor site due to radiation-induced outburst of the local intra-tumoral blood vessels. Compared with DOX alone, EGF@DOX-NPs significantly decreased the viability and migration and enhanced the apoptosis rates of tumor cells in vitro. Also, the EGF@DOX-NPs significantly inhibited tumor growth in vivo, increasing the survival of the tumor-bearing mice without apparent systemic toxic effects through RT-induced aggregation. The tumor cell proliferation was greatly inhibited in the RT + EGF@DOX-NPs group. Contrarily, the apoptosis of tumor cells was significantly higher in this group. These results confirm the promising clinical application of radiotherapy in combination with EGF@DOX-NPs for lung cancer treatment.

Dual-responsive nanodroplets combined with ultrasound-targeted microbubble destruction suppress tumor growth and metastasis via autophagy blockade

The inhibition of autophagy is a feasible clinical strategy in tumor therapy. Traditional autophagy inhibitors are limited in clinical tumor therapy due to nonspecific biodistribution, systemic toxicity and limited antitumor effect. Herein, the autophagy inhibitor hydroxychloroquine (HCQ)-loaded nanodroplets (NDs) are synthesized to overcome these drawbacks. HCQ-NDs are endowed with endogenous pH- and exogenous ultrasound-responsive drug release and contrast enhanced ultrasound imaging performance. The combined application of ultrasound-targeted microbubble destruction (UTMD) and HCQ-NDs can severely break the homeostasis of tumor cells, simultaneously releasing HCQ rapidly to block autophagic flux and thus abolish the cytoprotective function. This strategy presents strong synergistic antitumor efficacy with the tumor growth inhibition value of 80.02% and synchronously inhibits tumor lung metastasis by inhibition of MMP2 and MMP9 production, eventually leading to tumor suppression. In addition, HCQ-NDs show excellent tumor-targeting, biocompatibility, biosafety and contrast-enhanced ultrasound imaging properties. Based on the above findings, this combined strategy rationally regulates the autophagic process of tumor cells and could be instructive for the design of clinical treatment modalities.

Application and prospect of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal metastasis from colorectal cancer

Colorectal cancer is one of the common malignant tumors in China, and its incidence is increasing with years. As the second most common metastatic site of colorectal cancer, peritoneum is difficult to diagnose early and with a poor prognosis. Systemic intravenous chemotherapy was used as the main treatment strategy for peritoneal metastasis in the past, but its systemic toxic and side effects were obvious, and it could not effectively control tumor progression. In recent years, the continuous development of surgical techniques, concepts, and equipment, as well as the introduction of new chemotherapy drugs and targeted drugs have significantly improved the quality of life and prognosis of patients with peritoneal metastasis of colorectal cancer. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) can effectively eradicated the intraperitoneal free cancer cells and subclinical lesions, while reducing systemic side effects of chemotherapy drugs, and achieve the radical cure of the tumor at the macro and micro levels to the greatest extent. It has been used as the first-line treatment program for peritoneal metastasis of colorectal cancer at home and abroad. This article focuses on the analysis and summary of the survival efficacy, prognostic factor analysis, and chemotherapy safety of CRS+ HIPEC in the treatment of colorectal cancer peritoneal metastasis. The existing problems and controversies of HIPEC therapy are discussed simultaneously.

Sclerotherapy of Symptomatic Nonparasitic Splenic Cysts: Excellent Long-Term Treatment Response'

Abstract Background Splenic cysts are rare and occur in 0.5 to 2% of the population. They are usually asymptomatic and do not require therapy. In case of symptomatic nonparasitic splenic cysts, potential therapy includes partial splenectomy or laparoscopic cyst de-roofing as well as ultrasound-guided sclerotherapy with 1% polidocanol or 10% sodium chloride (NaCl) as an interventional alternative. So far, single-session sclerotherapy of symptomatic nonparasitic cysts is recommended only if clear-transparent cyst fluid is aspirated. Materials and Methods We report a case series of 17 patients with symptomatic macroscopically turbid nonparasitic splenic cyst fluid who underwent ultrasound-guided fine needle sclerotherapy with either polidocanol ± 10% NaCl (n = 12) or 10% NaCl alone (n = 5) and a follow-up of a maximum of 12 years after first intervention. Clinical, sonographic, and laboratory chemistry data were recorded at baseline and during the follow-up. Results The mean follow-up time was 43.65 ± 40.18 months. At the end of the follow-up, a 79% reduction of cyst size was achieved. The maximum size reduction in the polidocanol group was 76 ± 18% and 84 ± 21% in the sodium chloride group (p >0.05). At the end of follow-up, 15 out of the 17 patients did not have any further symptoms. Despite the cystic fluid being turbid, it was hardly possible to detect a microbiological superinfection. Conclusion Sclerotherapy of splenic cysts leads to a significant size regression in all patients, independent of the sclerotherapy agent used with fewer systemic toxic side effects of polidocanol treatment. It was shown that in a tertiary care center with significant experience, sclerotherapy of splenic cysts is also safe and successful and can lead to a drastic regression of cyst size and symptoms. This shows that interventional therapy is a good alternative to surgical procedures.

Bioengineered Zinc Oxide Nanoparticle-Loaded Hydrogel for Combinative Treatment of Spinal Cord Transection.

Spinal cord injury (SCI) is one of the most destructive diseases. The neuroinflammation microenvironment needs comprehensive mitigation of damages. Thus, regulation of local, microenvironment drugs could be a potential effective treatment. However, clinical studies on SCI with common treatment have reported it to cause systemic toxicity and side effects. Zinc oxide nanoparticles (ZnONPs) have been widely reported to have satisfying anti-inflammation function. Furthermore, green synthesis procedures can improve the capability and possible utilization of ZnONPs. However, the efficient administration and underlying mechanism of ZnONPs in SCI treatment remain unclear. Herein, an innovative approach was built by utilizing ZnONPs loaded in a skeletal muscle-derived adhesive hydrogel (ZnONPs-Gel). Different from the systemic application of ZnONPs, the local administration of ZnONPs-Gel offered the ZnONPs-loaded extracellular matrix with beneficial biocompatibility to the injured spinal cord, thereby promoting effective function recovery. Mechanistically, the ZnONPs-Gel treatment not only markedly reduced ROS production but also decreased apoptosis in the injured spinal cord. Therefore, the strategy based on local administration of the ZnONPs-Gel in the early stage of SCI may be an effective therapeutic treatment.

PLGA/PEG Nanoparticles Loaded with Cyclodextrin-Peganum harmala Alkaloid Complex and Ascorbic Acid with Promising Antimicrobial Activities.

Antimicrobial drugs face numerous challenges, including drug resistance, systemic toxic effects, and poor bioavailability. To date, treatment choices are limited, which warrants the search for novel potent antivirals, including those extracted from natural products. The seeds of Peganum harmala L. (Zygophyllaceae family) have been reported to have antimicrobial, antifungal, and anticancer activities. In the present study, a 2-hydroxy propyl-β-cyclodextrin (HPβCD)/harmala alkaloid-rich fraction (HARF) host–guest complex was prepared using a thin-film hydration method to improve the water solubility and bioavailability of HARF. The designed complex was then co-encapsulated with ascorbic acid into PLGA nanoparticles coated with polyethylene glycol (HARF–HPßCD/AA@PLGA-PEG NPs) using the W/O/W multiple emulsion-solvent evaporation method. The average particle size, PDI, and zeta potential were 207.90 ± 2.60 nm, 0.17 ± 0.01, and 31.6 ± 0.20 mV, respectively. The entrapment efficiency for HARF was 81.60 ± 1.20% and for ascorbic acid was 88 ± 2.20%. HARF–HPßCD/AA@PLGA-PEG NPs had the highest antibacterial activity against Staphylococcus aureus and Escherichia coli (MIC of 0.025 mg/mL). They also exhibited high selective antiviral activity against the H1N1 influenza virus (IC50 2.7 μg/mL) without affecting the host (MDCK cells). In conclusion, the co-encapsulation of HPCD–HARF complex and ascorbic acid into PLGA-PEG nanoparticles significantly increased the selective H1N1 killing activity with minimum host toxic effects.