Novel cancer treatments are in high demand, and a wider range of low-cost and easily accessible inorganic compounds along the lines of cisplatin is required. This work proposes polyoxotungstates (POT) and POT-carboxymethyl chitosan (CMC) formulations as anticancer drug candidates and addresses the widely unknown influence of POT nuclearity on anticancer activity. Treating cells with WO 4 2- as a reference achieved statistically similar results to the Keggin-type [PW 12 O 40 ] 3− and lacunary [PW 9 O 34 ] 9− , in regard to their tungsten-normalized IC 50 values. The IC 50 values for each are estimated with a global fit to be 5,470 ± 580 μM tungsten were calculated for cancerous PC-3 cells and 6,040 ± 480 μM tungsten for reference MRC-5 cells. The Preyssler-type POT, [NaP 5 W 30 O 110 ] 14− {NaP 5 W 30 } afforded lower IC 50 values, requiring just. 1.2 mM tungsten (40 μM {NaP 5 W 30 }) for PC-3 cells and 210 μM tungsten (8 μM {NaP 5 W 30 }) for MRC-5 cells. The uptake of tungsten by PC-3 cells, as determined by ICP-MS analysis, is ca. 21 times higher for cells treated with {NaP 5 W 30 } than for Na 2 WO 4 . {NaP 5 W 30 } is also combined with CMC as a drug carrier to enhance the activity, selectivity, and stability of the POT. Nanoparticles could be prepared directly in cell culture media with only slight swelling, affording sizes between 90 and 240 nm, according to DLS. The respective nanoparticles (IC 50 value of 16 μM {NaP 5 W 30 }), as well as a mechanical mixture of {NaP 5 W 30 } with CMC (ca. 2 μM {NaP 5 W 30 }), significantly improved the cytotoxicity towards PC-3 cells compared to pristine {NaP 5 W 30 }. On the other hand, the nanoparticles only slightly increased the toxicity towards the non-cancerous MRC-5 cells (IC 50 of 9 μM {NaP 5 W 30 }) and favorably reduced the toxicity with the mixture (18 μM {NaP 5 W 30 }). This renders the easily accessible mechanical mixture of CMC with {NaP 5 W 30 } or other optional POTs, as opposed to the nanoparticles themselves, a promising starting platform for tests on other cancer cell lines and optimization into effective anticancer agents.

Abstract Introduction Therapeutic ultrasound has been extensively studied in ablative and sonodynamic contexts, leaving the intrinsic bioactivity of continuous non-thermal low-intensity ultrasound (LIU) largely uncharacterized. Objectives To characterize the tumor biological and immunomodulatory effects of non-thermal continuous LIU in complementary in vitro and in vivo breast cancer models, underpinned by a standardized exposure platform characterized through finite element simulations and experimental validation. Methods Acoustic and thermal fields were characterized and optimized using in silico simulations and validated against hydrophone and temperature measurements to ensure homogeneous, non-thermal exposure (1MHz, 1W/cm 2 , 100% duty cycle). 4T07 murine mammary carcinoma spheroids received 20min LIU treatment, and metabolic activity, apoptosis, and intracellular stress-associated markers were assessed. In a syngeneic orthotopic 4T07 mammary carcinoma model in BALB/c mice, up to six LIU treatment cycles were administered; tumor growth, survival, histopathology, immunohistochemistry, bulk tumor RNA sequencing, spleen volume and plasma cytokine profiles were assessed. Results In vitro and intratumoral temperatures remained within the physiological range (≤39°C) throughout exposure. In spheroids, LIU reduced ATP content by more than 40% and significantly increased apoptotic, Hsp70⁺ and Hsp90⁺ cell fractions. In vivo , cyclic LIU slowed tumor growth, increased intratumoral necrosis, and significantly prolonged time to humane endpoint compared to untreated controls. LIU promoted early intratumoral myeloid cell infiltration and shifted the tumor transcriptome (2,573 differentially expressed genes), with enrichment in gene sets associated with immunogenic cell death, pattern-recognition, inflammatory, and innate and adaptive immune programs and downregulation of pro-tumorigenic pathways. LIU enriched the transcriptional signatures of M1 macrophage polarization and, notably, B-cell compartment engagement, which has not previously been reported for standalone continuous mechanical ultrasound. LIU significantly attenuated tumor-associated splenomegaly and elevated plasma IL-1α, TNF-α, and IL-10. Conclusion These results establish a reproducible preclinical platform and provide a hypothesis-generating mechanistic basis for evaluating LIU as an adjunct to immune checkpoint blockade. Abstract Figure

IntroductionChronic and infected wounds represent a persistent global health burden. Medicinal plants offer a promising source of wound-healing agents due to their multitarget activities, long history of traditional use, and accessibility. Adiantum capillus-veneris L. (ACV), traditionally used to treat a range of ailments, such as respiratory, urinary, and skin disorders, was investigated for its in vitro wound-healing potential following methanol extraction.MethodsWe evaluated the effects of methanol extracts of ACV (ACVM) on cell proliferation, migration and antioxidative capacity in human keratinocytes (HaCaT), and anti-inflammatory activity in RAW 264.7 cells. We also explored its combination with visible light phototherapy.ResultsChemical profiling via HPTLC analysis, UV/Vis spectrophotometry and HPLC analysis, together confirmed that ACVM contained more metabolites than other extracts, yielding five visible-light absorption peaks and identifying rutin and chlorogenic acid as major metabolites. At ≤100 μg/mL, ACVM was non-toxic to HaCaT cells in the absence of visible light. However, phototoxicity was evident at 200 μg/mL. ACVM (50 μg/mL) significantly promoted HaCaT migration, with a further enhancement upon exposure to light. ACVM also suppressed H2O2-induced ROS generation in a dose-dependent manner (≤50 μg/mL), while light exerted a bidirectional modulatory effect. Additionally, ACVM markedly inhibited LPS-induced secretion of CXCL2, CCL2, CXCL10, TNF-α, and IL-6 in RAW 264.7 macrophages, with effects evident at concentrations as low as 0.1 μg/mL.DiscussionThese findings suggest that ACVM, particularly in combination with light-assisted therapy, shows promise for accelerating wound healing.

Nanoparticles composed of selected polyoxometalates (POMs) and carboxymethyl chitosan (CMC) were prepared, characterized, and tested for anticancer activity to establish structure-activity relationships. Cell viability was investigated immediately after treatment and after 24 h to assess both cell recovery and delayed cytotoxicity. The study focused on three questions: (a) trends in cytotoxicity based on POM nuclearity and heteroatoms, (b) effects of CMC encapsulation strategies on cytotoxicity, and (c) cell viability after a recovery period. Among polyoxotungstates, [NaP5W30O110]14-, with a high tungsten content, showed the greatest cytotoxicity towards PC-3 cells at low concentrations. [Co4(H2O)2(PW9O34)2]10- demonstrated moderate cytotoxicity with an IC50 of 437 ± 23 µM for MRC-5 cells, compared to 11 ± 0.3 µM for [NaP5W30O110]14-. Both POMs were encapsulated in a CMC matrix, forming nanoparticles of 100-250 nm, and analyzed by FT-IR and Raman spectroscopy, DLS, and cryo-TEM, and tested against MRC-5, PC-3, and HeLa cells. It was found that forming nanoparticles increased the magnitude of the cytotoxicity compared to the free POM, especially for the lower end of concentrations tested. Furthermore, we newly monitored the cell viability after a 24 h rest period without treatment, allowing for observations of delayed negative or positive effects on the cells. This thorough approach revealed that the preparative strategy applied for encapsulation of [Co4(H2O)2(PW9O34)2]10- in CMC selectively influences the toxicity against HeLa and PC-3 cells compared to the normal MRC-5 cell line.

Phototherapeutic methods like photodynamic therapy (PDT), photothermal therapy (PTT) and photodecaging have emerged as promising modalities for cancer treatment. Phototherapeutics are activated by light and thereby generate reactive oxygen species (ROS), heat, or release a caged, toxic carry-on. Their distinct advantages of spatial and temporal control preserve healthy tissue while promising a minimal invasive alternative to traditional therapeutic approaches. When combined with each other or with other treatment modalities like chemotherapy, immunotherapy, etc., they can exert a synergistic effect that enhances their overall efficacy by improving targeting and destroying cancer cells. Given the rapid expansion of combination therapies that incorporate phototherapeutic elements, it is crucial to gain an understanding of the most important phototherapeutic methods and their synergistic effects when used in combination. This review provides a comprehensive overview of these combinations, focusing on the benefits such as overcoming drug resistance, improving targeting, and minimizing side effects, while also addressing the current challenges that must be overcome. The clinical translation of these combination therapies is also explored, with particular attention to the regulatory hurdles and advancements required to bring these promising treatment modalities into clinical practice.

Peru is among Latin American countries with the largest Indigenous population, yet ethnical health disparities persist, particularly in the Amazon region which comprises 60% of the national territory. Healthcare models that include Indigenous medicine and traditional healers present an important avenue for addressing such inequalities, as they increase cultural adequacy of services, healthcare access, and acknowledge Indigenous Rights for their perspectives to be represented in public healthcare. Understanding the underlying epistemologies of Indigenous medicine is a prerequisite for this purpose. Thus, in order to support Indigenous Organizations and governmental initiatives to develop more inclusive healthcare approaches, the current study investigated key epistemic concepts in Indigenous-Amazonian medicine from the perspective of traditional healers. We conducted systematic in-depth interviews (semi-structured) with a sample of 13 healers of three Peruvian-Amazonian regions (Loreto, Ucayali, San Martín). Data was analysed using manifest qualitative content analysis. Our findings point to an intricate medical system based on a sophisticated understanding of health, illness, and treatment. Indigenous healers described multifactorial aetiology concepts, complex interactions between material and spirit-related aspects of body and nature, diagnosis, and treatment. These often involved carefully designed applications of ‘teacher plants’, a concept at the heart of this medical system. Furthermore, while the healers considered traditional and biomedicine as complementary systems, they identified the lack of recognition of traditional healers as a primary barrier for collaboration. Indeed, preconceptions and stigma on Indigenous medicine along with a paucity of research, still represent an impediment to countries’ ability to respond to Indigenous peoples’ health-related expectations and needs, thus maintaining existing inequalities. This work offers a significant contribution to the understanding of Indigenous-Amazonian medicine and perspectives of traditional healers, relevant for Peru and adjacent countries sharing Amazonian territory and cultures. Our findings also highlight Amazonian healers’ unique expertise around the therapeutic applications of psychoactives, from which the current revival of clinical scientific interest in psychedelic-assisted therapies may have a great deal to learn.

Iron oxide nanoparticles have been proposed for magnetic hyperthermia treatment of tumors. However, efficacy depends on the injection of large amounts of such nanoparticles and the equipment is costly. Here, a new thermal cancer treatment is described, in which a tumor containing a low concentration of nonpyrogenic pure iron oxide nanominerals coated with carboxy-methyl-dextran (M-CMD), corresponding to modified magnetosomes, are exposed to ultrasound. Heating PC3 prostate carcinoma cells between 43 and 46 degrees C using ultrasound in the presence of M-CMD resulted in significant necrotic cell death. Furthermore, deposition of M-CMD containing 3 mu g of iron per mm3 of tumor in subcutaneous xenografts of PC3-Luc tumors of 150 mm3 followed by 6 to 10 sessions of ultrasound application (1 W cm-2, 1 MHz) of 10 min each led to a tumor temperature of 43-46 degrees C per session and to total tumor disappearance without regrowth over 6 months following treatment start. Sequential histological analyses of the tumor tissues revealed partial tumor occupation by M-CMD and an increase in cell death over time. Neither lesions, nor magnetosome accumulation were found in microscopic sections of various internal organs collected from treated mice euthanized 6 months after the beginning of the treatment, indicating that M-CMD may not lead to long-term side effects.

Although the tobacco plant has been employed as a medicinal and sacred herb by Indigenous cultures across the Americas, its usage drastically changed after the 15th-century colonial arrival; its large-scale commodification and global marketing once brought to Europe lead to hedonic and addictive uses harmful to health. As a consequence, tobacco smoking is now one of the largest public health problems worldwide. However, in the Peruvian Amazon, a region of origin of tobacco species, Indigenous healers still know how to use the plant for therapeutic purposes. Due to a general disregard of Indigenous knowledge and stigma, these uses have however not so far been clinically investigated. We hence conducted for the first time a clinical field study assessing a sample of patients treated by a traditional healer specialized in tobacco in the Peruvian Amazon (observational design, pilot study, N = 27). The study was conducted within a transdisciplinary and multi-epistemic medical frame, in close partnership with an Amazonian healer. We used validated self-report scales to quantitatively assess mental health variables before and after the weeklong treatment, and mixed-methods to report experienced effects. Paired-samples t-tests comparing pre- and post-treatment scores revealed significant reductions in anxiety, depression, perceived stress, and general symptom indicators. Experienced effects included initial physical discomfort, followed by psychologically or existentially/spiritually significant insights. Our findings point to a sophisticated therapeutic approach based on Indigenous knowledge of tobacco applications, which should be further investigated. The study also contributes to the burgeoning scientific field on therapeutic uses of contentious psychoactive plants.

A partir de entrevistas y conversaciones a profundidad con cinco enfermeros técnicos de los pueblos Yine y Shipibo-Konibo que laboran en establecimientos de salud en la Amazonía de Ucayali en Perú, este estudio muestra que las prácticas desplegadas para atender a los enfermos con síntomas de Covid-19 hicieron uso de terapias y nociones biomédicas e indígenas. Dichas prácticas reflejaron su formación en salud intercultural y su capacidad para adecuar las normas establecidas por el Ministerio de Salud. En función de los síntomas observados en los pacientes, los enfermeros indígenas usaron una variedad de prácticas: vaporaciones, masajes, baños, infusiones y remedios. Las nociones de salud y enfermedad que los enfermeros técnicos indígenas comparten con sus pacientes fueron la base para interpretar el Covid-19 y estuvieron presentes en las atenciones brindadas. Esto se nutrió de la existencia de un sistema de cuidado familiar bastante articulado que fue tejiéndose y siendo negociado en función de los síntomas y las terapias aplicadas. Sus prácticas demuestran la creatividad en los pueblos indígenas. En ese sentido, el sector salud necesita repensar su mirada sobre la medicina indígena, a la que denomina "tradicional" y nos muestra la necesidad de repensar las ideas sobre adecuación de los servicios para la población indígena para colocar en el centro del debate el significado de interculturalidad en salud desde la perspectiva indígena.

Building on the successful synergy between biology and systems & network theories, Systems Biology and Systems Medicine have been instrumental to address complexity in the study of life sciences. Along this line, Systems Pharmacology is the obvious next step. In this review we focus on physical stimuli, whose analysis in pharmacology is generally neglected, despite their ability, once transduced, to show medicinal properties. To cope with this missed opportunity, our ambition is threefold: (i) highlight how different (mechanic, optic, magnetic, electric) physical stimuli impinge on inflammation; (ii) disseminate knowledge on cutting-edge network approaches as effective tools to exploit the intricacy and develop the potential of anti-inflammatory physical therapies within the systems pharmacology framework, to ultimately (iii) adding physical stimuli to the routine mindset of pharmacologists. We expect this review to raise more questions than it gives answers, thus igniting research in an area whose application gap urgently needs fulfillment.

Here, we report six novel, easily accessible BODIPY-based agents for cancer treatment. In contrast to established photodynamic therapy (PDT) agents, these BODIPY-based compounds show additional photothermal activity and their cytotoxicity is not dependent on the generation of reactive oxygen species (ROS). The agents show high photocytotoxicity upon irradiation with light and low dark toxicity in different cancer cell lines in 2D culture as well as in 3D multicellular tumor spheroids (MCTSs). The ratio of dark to light toxicity (phototoxic index, PI) of these agents reaches striking values exceeding 830,000 after irradiation with energetically low doses of light at 630 nm. The oxygen-dependent mechanism of action (MOA) of established photosensitizers (PSs) hampers effective clinical deployment of these agents. Under hypoxic conditions (0.2% O2), which are known to limit the efficiency of conventional PSs in solid tumors, photocytotoxicity was induced at the same concentration levels, indicating an oxygen-independent photothermal MOA. With a PI exceeding 360,000 under hypoxic conditions, both PI values are the highest reported to date. We anticipate that small molecule agents with a photothermal MOA, such as the BODIPY-based compounds reported in this work, may overcome this barrier and provide a new avenue to cancer therapy.

Supplementary Data from Transcriptome Profile of Human Colorectal Adenomas

IntroductionIndigenous peoples of the Amazon basin, in Peru and elsewhere, suffered disproportionately from the impacts of the COVID-19 pandemic. In part, this was due to an initial lack of support by the Ministry of Health, who did not prioritize their care despite their vulnerable situation. Consequently, during the first wave of the pandemic, health professionals in public health facilities in Amazonian Indigenous communities had to handle the disease with limited information and resources. This article analyzes the actions carried out by Indigenous nurse technicians during the first wave of the pandemic. MethodsRecurrent semi-structured interviews with six Indigenous nurse technicians focusing on their measures toward disease prevention and caring during the first wave of the COVID-19 pandemic in the Atalaya province, Ucayali region, in the Peruvian Amazon.ResultsNurse technicians worked closely with local authorities and volunteer health promotors. The limited resources they had at the health facilities, coupled with no training about how to treat COVID-19 symptoms led them to resort to their knowledge of traditional Indigenous medicine in combination with biomedical approaches, and support from Indigenous healers. Our analyses shows that this approach proved essential to alleviate symptoms and prevent complications and new infections.ConclusionsThe actions implemented by the Indigenous nurse technicians strongly contributed to the management of COVID-19 in their Indigenous communities, being both effective and culturally appropriate. Our data is in support of a health provision concept that bridges medical knowledge systems in contexts of diversity, avoiding a view on Indigenous health practices as antagonistic or in competition with biomedical practices provided by public health services.

Harmful usage of tobacco is a global public health problem associated with adverse health effects and addiction. Yet, in the Peruvian Amazon, the native region of Nicotiana rustica L., this plant is used in remarkably different manners: it is considered a potent medicinal plant, applied in liquid form for oral ingestion to treat mental health problems, a common and ancient healing practice in this region. Using a transdisciplinary field research approach with mixed ethnopsychological methods, this work aimed to report for the first time a case study in this context. The intervention took place in the Peruvian Amazon (Loreto) and involved ritual tobacco ingestion in a weeklong retreat-like frame, administered by a specialized traditional Amazonian healer. The patient was a 37-year-old woman with diagnosed mood, anxiety, and attention deficit disorders, as well as a chronic somatic condition. We applied qualitative experience-sampling during and quantitative symptom assessments pre- and post-treatment. Our findings offer a detailed description of the experiential therapeutic process during the treatment week and suggest clinically relevant improvements in patient well-being. This work is significant in view of the globally prevalent harmful uses of tobacco and the current scientific trend of revisiting herbal psychoactives (e.g., cannabis, psilocybin) for their therapeutic potentials.

Infected chronic wounds are difficult to treat, and often lead to heavy economic burden on health care systems. Bacterial resistance due to misuse/overuse of antibiotics is a challenge for infection treatment.

In this paper, we describe the development and evaluation of a novel tissue-holding device (THD) for use during robotic-assisted laparoscopic partial nephrectomy. The THD is a vacuum-based apparatus made of either 3D-printed polyethylene or stainless steel. The proximal end connects to suction tubing routed outside the body, while the distal end is conically shaped and designed to firmly interface with the tumor. Device feasibility studies were performed on six porcine kidneys, two porcine livers, and two embalmed human cadavers. A Likert-scale rating was used to assess device setup, suction, and tissue handling. Additional tests were performed using the daVinci Xi® robotic system. Finally, the holding force of the THD was assessed using different standard vacuum systems and pressure settings. In porcine tissue, the device setup, tissue suction, and handling were rated as “good”. THD insertion and removal was uncomplicated. In a simulated transabdominal approach on fixed human cadavers, the device setup, suction, and tissue handling were also rated as “good”. No macroscopic tissue compromise or device deterioration was noted. The handling and holding abilities using the daVinci Xi® robotic system were also rated “good”. The device was able to successfully hold over 300 g of tissue at a suction pressure of −600 mmHg. The preliminary evaluation of the THD demonstrated satisfactory results.

Ethnopharmacological relevance: Indigenous groups of the Amazon have developed intricate methods for the application of psychoactives, among which particularly the dieta or diet method of Peruvian-Amazonian traditional medicine stands out. It is a retreat-like intervention involving lengthy periods of social, behavioural, and alimentary restrictions, while ingesting specially prepared plant substances. The interplay of the dietary conditions and plants ingested sensitizes the dieter to receive healing, strength, guidance, and knowledge. From a clinical scientific point of view, the method has remained largely underexplored, but seems more pertinent than ever given the increasing interest in Amazonian psychoactive preparations including ayahuasca (Banisteriopsis caapi) and the burgeoning field of psychedelic-assisted therapies in general. Aim of the study: This study offers a descriptive account and emit interpretation of the Peruvian-Amazonian dieta. More specifically we document in detail the procedure, its context and purpose of application, effects, modes of action, adverse effects, and risks, from the perspectives of a sample of Peruvian traditional healers. The Peruvian Amazonian dieta is a multi-purpose method for making use of medicinal plants, many of which (but not all), are psychoactive; the current work especially focuses on its therapeutic applications in conjunction with psychoactives. Methods: We interviewed 16 healers working in the Ucayali, San Martin, and Loreto provinces of Peru using a semi-structured interview approach. Interviews were audio-recorded and transcribed verbatim. The extensive data derived from these interviews were analysed by means of computer-assisted manifest qualitative content analysis using a theory-advancing approach. Over 500 coded text segments were categorized, resulting in 7 main theme clusters and corresponding sub-themes. Results: The interviewed healers described a complex intervention with multifaceted applications (treatment, prevention, training) and effects in various domains (body, mind, spirit, energy). The process was portrayed as transformative, with benefits attributed to the effects of the so-called teacher plants in conjunction with the diet's conditions, along with the skill of the healer guiding the intervention. Further, a detailed risk assessment revealed sophisticated safety measures and tools designed to address adverse responses. The importance of adequate training of the healer that administers the diet was particularly highlighted in this context. Conclusions: The dieta is a central therapeutic concept and tool in Peruvian-Amazonian traditional medicine and a unique method for using psychoactive plants. Multidisciplinary health research that includes traditional treatment methods from Indigenous cultures, Amazonian and other, should not be neglected in the current global interest in psychedelic therapies; such research may in the long-term contribute to a more inclusive psychedelic research paradigm as well as healthcare practice in countries where rich traditional healing systems exist, and perhaps beyond. It may also contribute to the recognition of the Indigenous healers as not only historical forerunners, but also current leading experts in psychedelic medicine.