3,5,7-Trihydroxy-2-phenylchromen-4-one (THF) possesses a diverse range of pharmacological activities. Evidence suggests that THF exerts anticancer activity by distinct mechanisms of action. This study explores the anticancer potential of THF in human lung (A549) and skin (A431) cancer cells by employing different antiproliferative assays. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, neutral red uptake, sulphorhodamine B, and cell motility assays were used to confirm the anticancer potential of THF. Cell target-based and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays were used to explore the effect of THF on the initiation, promotion and progression phase biomarkers of carcinogenesis. THF suppresses the activity of lipoxygenase-5 up to ~40% in both A549 and A431 cells and up to ~50% hyaluronidase activity in A549 cells. qRT-PCR assay reveals that THF inhibits the activity of phosphatidyl inositol-3 kinase/protein kinase B/mammalian target of rapamycin in both cell lines, which is responsible for the initiation of cancer. It also arrests the G2/M phase of the cell cycle in A431 cells and increases the sub-diploid population in both A549 and A431 cell lines which leads to cell death. Annexin V-FITC assay confirmed that THF induces apoptosis and necrosis in A431 and A549 cell lines. Further investigation revealed that THF not only enhances reactive oxygen species production but also modulates mitochondrial membrane potential in both cell lines. It significantly inhibits S-180 tumour formation at 5 and 10 mg/kg bw, i.p. dose. An acute skin toxicity study on mice showed that erythema and edema scores are within the acceptable range, besides acceptable drug-likeness properties and non-toxic effects on human erythrocytes. Conclusively, THF showed potent anticancer activity on skin and lung carcinoma cell lines, suppressed the level of the biomarkers and inhibited tumour growth in mice.

BACKGROUND: Hyaluronidase remains the mainstay treatment for skin necrosis due to vascular occlusion after hyaluronic acid (HA) dermal fillers. There is wide variability in protocols for the administration of hyaluronidase. Most protocols, however, lack strong evidence regarding hyaluronidase dosages.
METHODS: We conducted a systematic review and pilot meta-analysis, searching four international databases from inception until December 2023 for clinical studies reporting on two or more patients receiving hyaluronidase for skin necrosis after hyaluronic acid fillers. Random-effects (DerSimonian and Laird) meta-analyses were conducted. The primary outcome was the pooled proportion of complete scar resolution. We rated intra-study risk of bias using the Joanna Briggs Institute checklists and assessed the certainty of evidence using the GRADE approach.
RESULTS: We included 15 studies totaling 223 patients. The pooled proportion of complete scar resolution after hyaluronidase administration was 77.8% (95%-CI: 65.5% to 86.6%, pegger = 0.093, low certainty). Patients treated with high doses of hyaluronidase (>500 international units [IUs]) had lower rates of resolution of 69.6% (95%-CI: 41.2% to 88.3%) compared to those treated with low doses (500IU or less) that had 88.1% rate of resolution (95%-CI: 86.0% to 96.2%), though not statistically significant (p= 0.18). The use of adjunct therapies did not have a statistically significant effect on outcomes.
CONCLUSIONS: A higher proportion of patients receiving low doses (500IU or less) (88.1%) had complete scar resolution compared to patients receiving high doses (69.7%), though not statistically significant (p=0.18). Future studies should provide more granular details on their protocols to benefit the formulation of evidence-based guidelines in future.
METHODS: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
BACKGROUND: CRD42024538661.

The tamarillo, or Solanum betaceum, recognized for its comprehensive nutritional profile, has long been valued for its diverse ethnobotanical uses. This study delves into the potential therapeutic applications of S. betaceum by analyzing its polyphenolic content (TPC), total flavonoid content (TFC), anti-skin aging activities against key enzymes like elastase, tyrosinase, and hyaluronidase, and its cytotoxic effects on oral carcinoma cells. Extracts from the seeds, pulp, and peel of red and yellow fruits were prepared using methanol, ethanol, and acetone. The highest TPC was found in the methanol extract from red fruit seeds (9.89 mg GAE/g), and the highest TFC was found in the methanol extract of yellow fruit peel (3.02 mg QUE/g). Some of these extracts significantly inhibited skin aging-associated enzymes with the red fruit seed extract (100 μg/mL) showing up to 50.4% inhibition of tyrosinase. Additionally, the red fruit seed extract obtained using methanol demonstrated potential anticancer effects against Ca9-22 oral carcinoma cells by inhibiting cell survival, migration, and proliferation as well as inducing apoptosis. These results underscore the potential of S. betaceum fruit extracts, especially from red fruit seeds, as promising agents for anti-skin aging and anticancer applications, meriting further exploration for therapeutic uses.

The stratum corneum of the skin presents the initial barrier to transdermal penetration. The dense structure of the extracellular matrix (ECM) further impedes local drug dispersion. Hyaluronidase (HAase) is a key component for the degradation of glycosidic bonding sites in hyaluronic acid (HA) within the ECM to overcome this barrier and enhance drug dispersion. HAase activity is optimal at 37-45 °C and in the pH range 4.5-5.5. Numerous FDA-approved formulations are available for the clinical treatment of extravasation and other diseases. HAase combined with various new nanoformulations can markedly improve intradermal dispersion. By degrading HA to create tiny channels that reduce the ECM density, these small nanoformulations then use these channels to deliver drugs to deeper layers of the skin. This deep penetration may increase local drug concentration or facilitate penetration into the blood or lymphatic circulation. Based on the generalization of 115 studies from 2010 to 2024, this article summarizes the most recent strategies to overcome the HAase-based ECM barrier for local drug delivery, discusses opportunities and challenges in clinical applications, and provides references for the future development of HAase. In the future, HAase-assisted topical administration is necessary to achieve systemic effects and to standardize HAase application protocols.

BACKGROUND: Hyaluronic acid (HA) injection in the auricular base is one of the most popular and non-surgical cosmetic procedures for correcting lying ears and optimizing the facial profile because of its minimal invasiveness, immediate effect and safety (Li et al. in Aesthet Surg J 44: 746-75, 2024). But we have recently discovered that this treatment may lead to a new and rare complication called peripheral facial paralysis that has never been reported before. Until now, the etiology, clinical traits, treatment strategies, outcomes and possible reversibility have not been characterized.
METHODS: In the present study, we enrolled 4 patients with peripheral facial paralysis after subcutaneous postauricular HA filler injection. Preoperative digital subtraction angiography revealed a vascular embolism. Then, the patients underwent super-selective facial arterial thrombolytic therapy via hyaluronidase and papaverine injections. Simultaneously, general symptomatic treatment and nutritional therapy were performed.
RESULTS: The patients were relieved of their clinical symptoms and the significant improvement was observed in terms of motor function in her left facial areas after treatment. The auricular skin necrosis of all patients was restored to near normal appearance.
CONCLUSIONS: Our results indicate that super-selective facial arterial thrombolytic therapy is feasible for patients with peripheral facial paralysis induced by HA embolism. It was also beneficial in the recovery from skin necrosis. The therapy was shown to be worthy of clinical application.
METHODS: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

UNASSIGNED: Epidermoid cysts (E.C.s), also known as sebaceous cysts, are benign asymptomatic subepidermal nodules filled with keratin material. These cysts originate from the follicular infundibulum, which when obstructed by keratin, results in cyst formation. Conventionally, E.C.s have been managed surgically with a high success rate and minimal complications. In this report, we present the successful resolution of an E.C. using a minimally invasive technique involving the intralesional injection of recombinant hydrolytic enzymes like hyaluronidase, collagenase, and lipase.
UNASSIGNED: A 44-year-old woman with no significant medical history presented to the clinic with a mass on her right cheek that had been evolving for over 10 years. Skin and soft tissue ultrasound confirmed the presence of an E.C. of 9.3×6.6 × 9.3 mm. Owing to the size and location of the cyst, a decision was made to infiltrate the lesion with recombinant enzymes. Remarkably, significant clinical improvement was observed on Day 21, and complete dissolution of the E.C. occurred 40 days after the initial intervention. Importantly, no recurrences were observed during the 4-year follow-up period.
UNASSIGNED: Intralesional administration of hydrolytic enzymes represents an innovative technique in the management of E.C.s. However, further controlled studies are required to determine the efficacy and safety of this procedure.

BACKGROUND: Long-term anti-angiogenesis leads to pruned vasculature, densely deposited extracellular matrix (ECM), and consequently reduced chemotherapy delivery in esophagogastric cancer (EGC). To address this issue, we evaluated the efficacy of adding a hyaluronidase or a NO-donor to the regimen of chemotherapy and anti-angiogenic drugs.
METHODS: A patient-derived EGC xenograft model was developed. Grafted mice were randomly assigned to four experimental groups and one control group. The experimental groups received DC101, a murine angiogenesis inhibitor, and nab-paclitaxel (NPTX), with the addition of hyaluronidase (PEGPH20), or NO-donor (nitroglycerine, NTG), or their combination, respectively. We compared tumor growth during 17 days of treatment. We performed immunohistochemistry for ECM components hyaluronan (HA) and collagen, CD31 for endothelial cells, and γH2AX for DNA damage. The positively stained areas were quantified, and vessel diameters were measured using QuPath software.
RESULTS: Prolonged DC101 treatment induced deposition of HA (p<0.01) and collagen (p<0.01). HA was effectively degraded by PEGPH20 (p<0.001), but not by NTG as expected. Both PEGPH20 (p<0.05) and NTG (p<0.01) dilated vessels collapsed in response to long-term DC101 treatment. However, only PEGPH20 (rather than NTG) was found to significantly inhibit tumor growth (p<0.05) in combination with NPTX and DC101.
CONCLUSIONS: These findings suggest that the mechanical barrier of HA is the major reason responsible for the resistance developed during prolonged anti-angiogenesis in EGC. Incorporating PEGPH20 into the existing treatment regimen is promising to improve outcomes for patients with EGC.

The two cases discussed in this report investigate the efficacy and safety of a novel injectable therapy for treating neck wrinkles and skin laxity, utilizing a combination of hyperdiluted calcium hydroxylapatite (CaHA), platelet-rich plasma (PRP), and hyaluronidase. Two patients presenting with moderate neck wrinkles and laxity underwent treatment and were evaluated several months later. The combined therapy demonstrated improvements in skin texture and laxity following a single treatment. The rationale behind incorporating PRP and hyaluronidase was their potential to amplify the regenerative effects of CaHA. PRP contains growth factors that stimulate collagen production and tissue regeneration while hyaluronidase facilitates the breakdown of hyaluronic acid, promoting better diffusion and more even product dispersion. The findings from these cases provide emerging preliminary evidence supporting the safety and efficacy of this innovative combination therapy for addressing neck wrinkles and laxity. This is the first documented instance of skin priming CaHA with hyaluronidase and PRP. Future investigations are warranted to explore the application of this treatment for other anatomical regions and to delineate the role of each injected component.

Opuntia plants are abundant but still underexplored edible resources of the Algerian region. This work chemically characterizes extracts of different parts of the fruit of the commercial Opuntia ficus-indica (L.) Mill. and the wild Opuntia stricta (Haw.) Haw. growing in Bejaia, and evaluates their anti-inflammatory potential through different cell and cell-free bioassays. The LC-ESI-UHR-QqTOF-MS/MS analysis enabled the identification of 18 compounds, with azelaic acid and 1-O-vanilloyl-β-d-glucose reported here for the first time. Aqueous extracts of seeds were the most effective in scavenging superoxide anion radical (IC50 = 111.08 μg/mL) and presented the best anti-inflammatory potential in LPS-stimulated macrophages (IC50 = 206.30 μg/mL). The pulp of O. stricta suggested potential for addressing post-inflammatory hyperpigmentation, with piscidic and eucomic acids predicted with the strongest binding affinity towards tyrosinase, exhibiting higher scoring values than the reference inhibitor kojic acid. This pioneer study brings valuable perspectives for the pharmacological, nutritional and economic valorization of the wild O. stricta for functional foods.

Hyaluronan (HA) is a large polysaccharide that is broadly distributed and highly abundant in the soft connective tissues and embryos of vertebrates. The constitutive turnover of HA is very high, estimated at 5 g per day in an average (70 kg) adult human, but HA turnover must also be tightly regulated in some processes. Six genes encoding homologues to bee venom hyaluronidase (HYAL1, HYAL2, HYAL3, HYAL4, HYAL6P/HYALP1, SPAM1/PH20), as well as genes encoding two unrelated G8-domain-containing proteins demonstrated to be involved in HA degradation (CEMIP/KIAA1199, CEMIP2/TMEM2), have been identified in humans. Of these, only deficiencies in HYAL1, HYAL2, HYAL3 and CEMIP have been identified as the cause or putative cause of human genetic disorders. The phenotypes of these disorders have been vital in determining the biological roles of these enzymes but there is much that is still not understood. Deficiencies in these HA-degrading proteins have been created in mice and/or other model organisms where phenotypes could be analyzed and probed to expand our understanding of HA degradation and function. This review will describe what has been found in human and animal models of hyaluronidase deficiency and discuss how this has advanced our understanding of HA\'s role in health and disease.